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Acute lung injury (ALI) occurs in patients with severe sepsis and has a mortality rate of 40%–60%. Severe sepsis promotes the release of histones from dying cells, which can induce platelet aggregation, activate coagulation and cause endothelial cell (EC) death. We previously reported that the expression of membrane complement receptor type 1‐related gene Y (Crry)/p65, which plays a principal role in defence against abnormal activation of complement in the blood, is reduced in response to peritoneal mesothelial cell injury, and we hence hypothesized that a similar mechanism occurs in pulmonary ECs. In this study, we examined the role of Crry/p65 in histone‐mediated ALI using an experimental animal model. In ALI model mice, exposure to extracellular histones induces lung injury and results in a decrease in Crry/p65 expression. The levels of lactic acid dehydrogenase (LDH), a marker of cell damage, were significantly increased in the serum of ALI model compared with vehicle mice. The significant inverse correlation between the expression of Crry/p65 and LDH levels in plasma revealed an association between Crry/p65 expression and cell damage. The levels of complement component 3a (C3a) were also significantly increased in the serum of the ALI model compared with vehicle mice. Notably, a C3a receptor antagonist ameliorated lung injury induced by histones. We hypothesize that extracellular histones induce complement activation via down‐regulation of Crry/p65 and that C3a might serve as a therapeutic target for the treatment of ALI., Extracellular histones decrease the expression of complement receptor type 1‐related gene Y (Crry)/p65 in an experimental model of acute lung injury (ALI). Dysfunction of Crry/p65 is associated with endothelial damage and promotes C3a production resulting from complement activity. C3a is a potential therapeutic target for ALI.

The first line of treatment for pemphigus is systemic corticosteroids. When steroids alone do not result in remission, additional immunosuppressants are recommended. Twenty‐two patients with pemphigus vulugris were treated with steroids and other immunomodulators. However, they were refractory, and hence, methotrexate (MTX) was administered. The efficacy of MTX was assessed for 16 patients who were able to continue MTX therapy for 1 year. Steroid dose reduction was possible in 11 patients. One patient with severe infections had diabetes and was elderly. Our results suggested that MTX was useful as a steroid‐sparing agent in treating recalcitrant pemphigus, when an initial immunosuppressant treatment had failed. However, adverse effects should be closely monitored.

Background/Aim: Concomitant proton pump inhibitor (PPI) and immune checkpoint inhibitor (ICPI) were determined as risk factors of acute kidney injury. To identify the type of PPI associated with ICPI-induced nephritis, we used the Japanese Adverse Drug Event Report database. Patients and Methods: ICPIs (nivolumab, pembrolizumab, ipilimumab, atezolizumab, durvalumab, and avelumab) and PPIs (esomeprazole, omeprazole, vonoprazan, rabeprazole, and lansoprazole) were selected as suspected nephritis-inducing drugs. Results: The cases of concomitant use of atezolizumab and rabeprazole, ipilimumab and omeprazole, ipilimumab and lansoprazole, nivolumab and esomeprazole, nivolumab and omeprazole, nivolumab and rabeprazole, nivolumab and lansoprazole, pembrolizumab and esomeprazole, as well as pembrolizumab and lansoprazole had a significantly higher reported odds ratio than monotherapy cases. Conclusion: Male patients or patients using ICPIs and PPIs (excluded vonoprazan) concomitantly should be monitored for renal function after chemotherapy.

Background Although the 2018 revised International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification was proposed recently, until now, no reports have been made comparing the association of renal prognosis between the 2018 revised ISN/RPS classification and the 2003 ISN/RPS classification. The present study aimed to assess the usefulness, especially of activity and chronicity assessment, of the 2018 revised ISN/RPS classification for lupus nephritis (LN) in terms of renal prognosis compared to the classification in 2003. Methods We retrospectively collected medical records of 170 LN patients from the database of renal biopsy at Fujita Health University from January 2003 to April 2019. Each renal biopsy specimen was reevaluated according to both the 2003 ISN/RPS classification and the 2018 revised ISN/RPS classification. Renal endpoint was defined as a 30% decline of estimated glomerular filtration rate (eGFR). Results A total of 129 patients were class III/IV±V (class III, 44 patients; class IV, 35 patients; class III/IV+V, 50 patients). The mean age was 42 years, 88% were female, and the median observation period was 50.5 months. Renal prognosis was significantly different among the classes and significantly poor in the patients with higher modified National Institute of Health (mNIH) chronicity index (C index, ≥ 4) by a log-rank test (p = 0.05 and p = 0.02, respectively). By Cox proportional hazard models, only the C index was significantly associated with renal outcome (hazard ratio 1.32, 95% CI 1.11–1.56, p ≤ 0.01), while the classes, the 2003 activity and chronicity subdivision, and the mNIH activity index had no significant association with renal outcome. Each component of the C index was significantly associated with renal outcome in different models. Conclusion This study demonstrates that the 2018 revised ISN/RPS classification was more useful in terms of association with renal prognosis compared to the 2003 ISN/RPS classification.

Background The present study aimed to investigate associations between long-term renal function, whether IgG4-related tubulointerstitial nephritis (TIN) was diagnosed by renal biopsy at initial examination, chronic kidney disease (CKD) stage, and histological stage in patients with IgG4-related TIN. Methods This study used a retrospective cohort design including almost all patients who underwent renal biopsy at Fujita Health University Hospital and Nagoya University or its affiliated hospitals in Aichi between April 2003 and March 2015 (n = 6977 renal biopsies). The primary outcome was longitudinal changes in eGFR. Main exposures were whether IgG4-related TIN was diagnosed by renal biopsy at the initial examination, CKD stage, and its histological stage. Linear mixed models were performed to examine associations. Results Of the 6977 samples, there were 24 patients (with 201 records due to repeated measures) with IgG4-related TIN (20 men, mean age, 68.7 ± 9.7 years). They were followed up 6.6 ± 2.8 years after the renal biopsy and underwent glucocorticoid treatment. We found significant increase in eGFR from the baseline to 2 and 6 months after treatment initiation, which was maintained until 60 months. Patients initially diagnosed with IgG4-related TIN had higher eGFR from the baseline (at the start of treatment) to 60 months than those who were not. Compared with patients with CKD stage 3, patients with CKD stages 4 and 5 had lower eGFR at the baseline and other time points. Patients with histological stage B had comparatively lower eGFR at each point than stage A patients. Those mean differences of eGFR were stable from the baseline to 60 months. Conclusions After the treatment initiation, renal function rapidly improved and maintained for a long period, even with advanced CKD stage. We showed importance of early diagnosis of IgG4-related TIN in maintaining eGFR.

Renal anemia in chronic kidney disease is treated with recombinant human erythropoietin (rhEPO). However, some patients with anemia do not respond well to rhEPO, emphasizing the need for a more biocompatible EPO. Differentiation protocols for hepatic lineages have been modified to enable production from human induced pluripotent stem cell (hiPSC)‐derived EPO‐producing cells (EPO cells). However, markers for hiPSC‐EPO cells are lacking, making it difficult to purify hiPSC‐EPO cells and therefore to optimize EPO production and cell counts for transplantation. To address these issues, we investigated whether CD140b and CD73 could be used as markers for hiPSC‐EPO cells. We measured the expression of EPO, CD140b, and CD73 in hiPSC‐EPO cells and the EPO concentration in the cell supernatant by immunohistochemistry and enzyme‐linked immunosorbent assays on culture day 13, revealing that expression levels of CD140b and CD73 are correlated with the level of EPO. In addition, rates of CD140b+ CD73+ cells were observed to be correlated with the concentration of EPO. Thus, our results suggest that CD140b and CD73 may be markers for hiPSC‐EPO cells., We established differentiation protocols for human induced pluripotent stem cell (hiPSC)‐derived erythropoietin‐producing cells (EPO cells). However, markers for hiPSC‐EPO cells are lacking, making it difficult to purify hiPSC‐EPO cells and therefore to optimize EPO production and cell counts for transplantation. Here, we elucidated that CD140b and CD73 may be markers for hiPSC‐EPO cells.

Introduction There are few studies on the association between serum uric acid (UA) level and mortality in incident dialysis patients. We aimed to clarify whether the serum UA level at dialysis initiation is associated with mortality during maintenance dialysis. Methods We enrolled 1486 incident dialysis patients who participated in a previous multicenter prospective cohort study in Japan. We classified the patients into the following five groups according to their serum UA levels at dialysis initiation: G1 with a serum UA level

Cell-free and concentrated ascites reinfusion therapy (CART) by internal filtration pressure method (internal method) and external filtration pressure method (external method) using the same cancerous ascites was performed. The rate of rise in circuit pressure and recovered components were compared between the two methods. The factors related to circuit pressure rise were also researched. In both methods, circuit pressure rose in 50% of cases. The recovery rates of IgG, IgA, IgM, and haptoglobin were significantly higher for the internal method than for the external method, whereas the recovery rate of α1 -antitrypsin was significantly lower in the internal method than in the external method. The levels of IL-6, haptoglobin, α1 -antitrypsin, and fibrinogen/fibrindegradation products (FDP) in the original ascites were significantly higher in the group wherein circuit pressure rose than in that without circuit pressure rise. These proteins might be related to the rise in circuit pressure.

It has been reported that C7 and C8 nerve root impairment can cause drop finger; however, the clinical characteristics of each injured nerve root and post-operative outcomes remain unclear. This study aimed to investigate the detailed features and surgery-related prognostic factors of drop finger caused by cervical radiculopathy. We retrospectively investigated the clinical characteristics, paralysis patterns and surgery-related prognostic factors of 23 patients with drop finger caused by cervical radiculopathy who underwent posterior cervical foraminotomy. We classified paralysis into three patterns based on the fingers predominantly exhibiting extensor digitorum communis (EDC) muscle weakness: index finger side-dominant, middle and ring fingers-dominant and little finger side-dominant. The aetiologies were cervical disc hernia (CDH) in ten patients, cervical spondylotic radiculopathy (CSR) in eight and both CDH and CSR in five. The levels of the decompressed root were C7 in one patient, C8 in 11 and both C7 and C8 in 11. Scapular pain was frequently observed as the initial symptom (78%), especially in patients with only C8 nerve root disorder (91%). Drop finger recovered to a score of ≥ 3 on manual muscle testing in 17 patients; patients with the little finger side-dominant pattern tended to have poor recoveries. Patients with CDH improved significantly than those with CSR or both CDH and CSR (p

IntroductionDegenerative aortic valve stenosis (AS) is a chronic progressive disease that resembles atherosclerosis development. Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is reportedly associated with accelerated atherosclerosis. This study aimed to examine the development of AS in patients with myeloperoxidase-AAV (MPO-AAV) with renal involvement at more than 1 year after the onset of vasculitis.MethodsWe performed a retrospective review of clinical records of MPO-AAV patients with renal involvement without AS at the onset of vasculitis who were treated in three hospitals and three dialysis clinics.ResultsThe study included 97 MPO-AAV patients with renal involvement and 230 control patients with chronic kidney disease (CKD). Among them, 64 patients had AS. The prevalence rates of AS were 28.9% and 15.7% in MPO-AAV and control patients, respectively (p = 0.006). The multivariable logistic regression analysis showed that MPO-AAV, dialysis dependence, and hypertension were independently associated factors for AS. In MPO-AAV patients, systolic blood pressure was positively significantly associated with AS, whereas glucocorticoid dose of induction therapy was negatively significantly associated. The use of cyclophosphamide tended to be negatively associated with AS. The survival rate was significantly lower for patients with AS than for those without AS.ConclusionsThe AS prevalence rate was significantly higher in MPO-AAV patients at more than 1 year after the onset of vasculitis than in control CKD patients. Therefore, regular monitoring of echocardiography during MPO-AAV treatment is suggested.

Background The benefits of vitamin D receptor activators (VDRAs) for patients with chronic kidney disease are well recognized. However, the optimal criteria for patient selection, dosage forms, and duration providing the highest benefit and the least potential risk remain to be confirmed. Materials and methods The study population was derived from the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis, a multicenter prospective cohort study of 1520 incident dialysis patients. According to the VDRA usage status in March 2015 (interim report), the 967 patients surviving after March 2015 were classified into three groups: without VDRA (NV, n = 177), oral VDRA (OV, n = 447), and intravenous VDRA (IV, n = 343). Mortality rates were compared using the log-rank test, and factors contributing to all-cause mortality were examined using both univariate and multivariate Cox proportional hazard regression analyses. Results There were 104 deaths (NV, n = 27; OV, n = 53; IV, n = 24) during the follow-up period (1360 days, median), and significant differences in cumulative survival rates were observed between the three groups (p = 0.010). Moreover, lower all-cause mortality was associated with IV versus NV (hazard ratio, 0.46 [95% confidence interval 0.24–0.89]; p = 0.020). Conclusion This study demonstrated the impact of the VDRA dosage form on the short-term survival of incident hemodialysis patients during the introduction period. Our results suggest that relatively early initiation of intravenous VDRA in patients beginning hemodialysis may have some clinical potential.

application/pdf, (Pro)renin receptor [(P)RR] has a role in various diseases, such as cardiovascular and renal disorders and cancer. Aberrant (P)RR expression is prevalent in pancreatic ductal adenocarcinoma (PDAC) which is the most common pancreatic cancer. Here we show whether aberrant expression of (P)RR directly leads to genomic instability in human pancreatic ductal epithelial (HPDE) cells. (P)RR-expressing HPDE cells show obvious cellular atypia. Whole genome sequencing reveals that aberrant (P)RR expression induces large numbers of point mutations and structural variations at the genome level. A (P)RR-expressing cell population exhibits tumour-forming ability, showing both atypical nuclei characterised by distinctive nuclear bodies and chromosomal abnormalities. (P)RR overexpression upregulates SWItch/Sucrose Non-Fermentable (SWI/SNF)-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 5 (SMARCA5) through a direct molecular interaction, which results in the failure of several genomic stability pathways. These data reveal that aberrant (P)RR expression contributes to the early carcinogenesis of PDAC.

Treatment of eosinophilic granulomatosis with polyangiitis (EGPA) remains a challenge because currently available therapies, corticosteroids and immunomodulators, do not always control symptoms and are often associated with significant morbidity and relapse. Mepolizumab has been demonstrated to be an effective add-on therapy with steroid-sparing effect in cases of relapsing or refractory EGPA. Intravenous immunoglobulin (IVIG) therapy is effective against mononeuritis multiplex or heart failure in patients with EGPA who do not respond to corticosteroid-cyclophosphamide treatment. We present two cases of EGPA in which earlier add-on administration of adjunct mepolizumab and IVIG led to significant improvement in EGPA symptoms and prevention of flare-up of the disease. We suggested that earlier add-on combination administration of IVIG and mepolizumab might be a useful adjunct treatment to induce clinical remission of EGPA and improve the rate of remission, decrease relapse rate, and allow for reduced glucocorticoid use without any serious adverse drug effects.

WHAT IS KNOWN AND OBJECTIVE Hypertension (HTN) and chronic kidney disease (CKD) are recognized as silent killers because they are asymptomatic conditions that contribute to the burden of multiple comorbidities. The achievement of a blood pressure (BP) goal can dramatically reduce the risks of CKD. In this study, we aimed to assess the effectiveness of pharmacist intervention on BP control in patients with CKD and evaluate the usefulness of home-based BP telemonitoring. METHODS The terms "chronic kidney disease," "pharmacist," "BP" and "randomized controlled trial (RCT)" were used five databases to search for information regarding pharmacist intervention on BP control in patients with CKD. The inclusion criteria were as follows: (a) studies for adult patients with uncontrolled HTN and (b) studies with adequate data for meta-analysis. The primary outcome was an evaluation of achievement of BP goal in patients with CKD. The secondary outcome was usefulness of home-based BP telemonitoring by pharmacists in patients with CKD. RESULTS AND DISCUSSION Six RCTs were identified and included in the meta-analysis with a total of 2573 patients (mean age 66.0 years and 63.9% male). Pharmacist interventions resulted in significantly better BP control vs usual care (OR = 1.53, 95% CI = 1.15-2.04, P

The glomerulus primarily comprises mesangial cells, glomerular microvascular endothelial cells, and podocytes. IgA nephropathy is the most common primary glomerulonephritis worldwide and has a risk of progression to end-stage renal disease. IgA nephropathy is characterized by predominant IgA deposition in the glomerular mesangial area, where TG2 is significantly enhanced. Therefore, identification of glomerular TG2 substrates is the first step in elucidating the role of TG2 as a crosslinking enzyme during disease progression. To clarify potential glomerular TG2 substrates, and to establish a procedure for substrate identification, we attempted to identify those molecules using normal mouse glomeruli. Extracts from mouse glomerular and non-glomerular fractions were treated with our established biotin-labeled substrate peptide, which specifically crosslinks to the lysine-donor substrates depending on TG2 activity. Peptide-incorporated proteins were then purified using avidin resin and identified via mass spectrometry. In parallel, we performed the identification using corresponding samples from TG2 knockout mice. Consequently, potential TG2 substrates were separately identified in glomerular and non-glomerular fractions. They were mainly identified as novel TG2 substrates and partly include the well-known substrates. These results potentially provide novel insights into the mechanism underlying IgA nephropathy and may help elucidate the physiological functions of TG2.

Extracellular histones induce lethal thrombosis by promoting platelet aggregation, neutrophil migration, and cell injuries. Heparin, which has negative charges, can bind to extracellular histones; however, heparin strongly inhibits the activation of coagulation. Since chondroitin sulfate (CS) shows less effect on the coagulation system than heparin does, CS has the potential to become an effective drug for lethal thrombosis with high risk of bleeding. To elucidate the therapeutic mechanisms of CS in lethal thrombosis, we investigated the interaction between CS and extracellular histones. Mouse vascular endothelial cells were incubated with histones in the presence of heparin or CS, and the expression of caspase-3/7 was measured. The interactions between histones and heparin or CS were measured by surface plasmon resonance analysis. Vascular permeability, platelet counts, liver and renal functions, and coagulation times were evaluated in an in vivo assay. The apoptosis induced by histones was inhibited by treatment with heparin or CS. Heparin and CS showed strong binding to histones and inhibited vascular hyperpermeability. The platelet counts as well as liver and renal functions were not decreased by the treatment with heparin or CS. Moreover, CS showed less effect on the coagulation system than heparin did. These results suggested that CS can be a novel agent for lethal thrombosis with the risk for hemorrhage. Since vascular endothelial cell injuries occur at an early stage of lethal thrombosis, administration of CS might be a useful approach.

Aim Some observational studies of the general population showed that resting heart rate was associated with mortality. However, the relationship was unclear in dialysis patients. Methods The study was a multicenter prospective cohort analysis including 1,102 patients. Patients were classified into four groups based on resting heart rate just before starting the first dialysis session

Aortic stenosis (AS) is common in patients on dialysis as well as in the general population. AS leads to difficulty with dialysis therapy because of unstable conditions such as intradialytic hypotension due to low cardiac output. However, the precise morbidity rates and risk factors of AS in patients on dialysis are unknown. Moreover, there are no large-scale observational studies regarding the association between AS in patients on dialysis and mortality. Therefore, we will investigate whether morbidity of AS in patients on dialysis is associated with mortality. This is a multicenter prospective cohort analysis in the Tokai region of Japan. The 75 participating centers in this study will enroll approximately 2400 patients during 12 months, with or without AS. We started enrollment in July 2017 and will follow patents until June 2023. Transthoracic echocardiography will be performed to evaluate aortic valve. Parameters used for evaluation of aortic valve are mean pressure gradient between left ventricle and ascending aorta, aortic valve area, and maximum aortic jet velocity. We will diagnose AS using the criteria based on the 2014 American Heart Association/ American College of Cardiology Guideline. We will also perform transthoracic echocardiography at 12, 24, 36, 48, and 60 months. Survival prognosis and CV events will be determined at the end of June 2019, 2020, 2021, 2022, and 2023. Development of AS will be also evaluated as new onset or annual change in AS parameters. We will classify patients based on the presence or absence of AS and the stages of AS and will compare outcomes. Study outcomes will include the following: 1) all-cause mortality rates; 2) incidence of cardiovascular (CV) events; 3) CV-related mortality rates; 4) infection-related mortality rates; 5) new onset or development of AS. We will consider the following hypotheses in this study, among others: The prevalence of AS is higher in dialysis patients; new onset and development of AS are associated with factors that are specific for dialysis, such as hyperphosphatemia, hyperparathyroidism, and medication; and outcomes in AS patients are poorer than in patients without AS at baseline. UMIN000026756 , Registered March 29 2017.

Background: Several human studies reported that the combined use of renin-angiotensin system blockers (RASBs) and vitamin D receptor activators (VDRAs) resulted in decreased urinary protein excretion. However, it is unknown whether this combination therapy influences the incidence of cardiovascular (CV) events in dialysis patients. Methods: The study was a multicenter nonrandomized prospective cohort analysis including 1,518 patients. Patients were classified into 4 groups based on medications prescribed before dialysis initiation: those who did not receive RASBs or oral VDRAs (N group), those receiving only RASBs, those receiving only VDRAs, and those receiving a combination of RASBs and VDRAs (RD group). CV events after dialysis initiation were compared using the log-rank test. Factors contributing to the incidence of CV events were examined using multivariate Cox proportional hazard regression analysis. Results: Significant differences were observed in the incidence of CV events and all-cause mortality between the 4 groups (p = 0.021 and p = 0.001, respectively). Cox proportional hazard analysis revealed that the incidence of CV events was significantly lower in the RD group than in the N group (hazard ratio [HR] = 0.65, 95% confidence interval [CI]: 0.50-0.86, p = 0.002). Multivariate analysis revealed that the incidence of CV events was significantly lower in the RD group than in the N group (HR = 0.66, 95% CI: 0.47-0.93, p = 0.016). Conclusion: Combination therapy with RASBs and VDRAs in patients before dialysis initiation was associated with a reduction in CV events during maintenance dialysis.

Some studies have shown that the estimated glomerular filtration rate (eGFR) at the time of initiating dialysis was associated with mortality. However, the relationship between ratio of blood urea nitrogen to serum creatinine (BUN/Cr) and mortality is unknown. The study was a multicenter, prospective cohort analysis including 1520 patients. Patients were classified into four quartiles based on the BUN/Cr ratio at the dialysis initiation, with Q1 having the lowest ratio and Q4 the highest. All-cause mortality after initiating dialysis was compared using the log-rank test. All-cause mortality of Q1, Q2, and Q3 was compared with that of Q4 using multivariate Cox proportional hazard regression analysis. Moreover, we compared the renal parameters including BUN/Cr ratio, eGFR, and creatinine clearance for sensitivity and specificity using receiver operative characteristic (ROC) curve. Significant differences were observed in all-cause mortality among the four groups (p

Background Usage of vitamin D receptor activator (VDRA) for chronic kidney disease (CKD) including patients on dialysis patients has been controversial yet. It is unknown when to begin or discontinue VDRA therapy, the type of VDRA to administer, and the method of delivery, intravenous or oral for survival in CKD patients. Therefore, we examined whether intravenous or oral VDRA early after dialysis initiation affected mortality in incident dialysis patients. Methods The study database was derived from the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis (AICOPP), a multicenter, prospective, cohort analysis of 1,520 consecutive patients who began dialysis at the 17 AICOPP group centers between October 2011 and September 2013. We excluded the 262 patients who died by March 2015, 15 patients were lost to follow-up, 241 patients with unconfirmed information about use of VDRA in March 2015, and 35 patients who discontinued VDRA between dialysis initiation and March 2015. Finally, 967 patients participated in the present study. We classified the participating patients into three groups according to the usage of VDRA in March 2015: no use of VDRA (NV group), oral VDRA (OV group), and intravenous VDRA (IV group) and compared their all-cause mortality. Results There were 104 deaths during the follow-up period (NV group, 27 cases; OV group, 53 cases; IV group, 24 cases). Significant differences between the cumulative survival rates were observed for the three groups (p = 0.010). The IV group was associated with low all-cause mortality compared to the NV group (Hazard ratio = 0.46, 95% CI = 0.24−0.89, p = 0.020) by multivariate Cox proportional hazard analysis using the stepwise method. Conclusions Our study shows that early introduction of intravenous VDRA to patients on hemodialysis seems to be associated with better prognosis.Trial Registration The trial registration no. is UMIN 000007096, registered on January 18, 2012. 298words, Text: 2967 words

Aim Some reports claim that intravenous iron supplements reduce serum phosphate levels in patients with chronic kidney disease (CKD), including those on dialysis. However, whether divalent oral iron supplements influence serum phosphate levels in patients with CKD remains unclear; thus, this study aimed to address this topic. Materials and methods The study database was derived from the Aichi Cohort Study of Prognosis in Patients Newly Initiated into Dialysis (AICOPP), which is a multicenter, prospective, cohort study. Patients were classified into two groups: those who received iron orally (iron group, n = 255) from pre-dialysis to dialysis initiation and those who did not receive iron supplements (no-iron group, n = 1,261). Moreover, patients were classified into two groups (255 patients in each) by propensity score (PS) matching. We compared serum phosphate level at dialysis initiation and all-cause mortality. Multivariate regression analysis was used to extract factors contributing to serum phosphate level at dialysis initiation through a stepwise method. Results Serum phosphate levels at dialysis initiation were significantly lower in the iron group (all cohort, 6.0 ± 1.6 vs. 6.4 ± 1.9 mg/dL, p = 0.001; PS-matched cohort, 6.0 ± 1.6 vs. 6.5 ± 1.7 mg/dL, p = 0.001). Multivariate regression analysis revealed that oral iron supplementation was significantly correlated to serum phosphate level (p = 0.023). There were no significant differences in all-cause mortality after dialysis initiation. Conclusion This study showed that oral ferrous citrate or ferrous sulfate use during predialysis was associated with differences in serum phosphate level at dialysis initiation.

IgA nephropathy (IgAN), the most common primary glomerular disease worldwide, is characterized by glomerular deposition of IgA1-containing immune complexes. The IgA1 hinge region (HR) has up to six clustered O-glycans consisting of Ser/Thr-linked N-acetylgalactosamine usually with β1,3-linked galactose and variable sialylation. Circulating levels of IgA1 with abnormally O-glycosylated HR, termed galactose-deficient IgA1 (Gd-IgA1), are increased in patients with IgAN. Current evidence suggests that IgAN is induced by multiple sequential pathogenic steps, and production of aberrantly glycosylated IgA1 is considered the initial step. Thus, the mechanisms of biosynthesis of aberrantly glycosylated IgA1 and the involvement of aberrant glycoforms of IgA1 in disease development have been studied. Furthermore, Gd-IgA1 represents an attractive biomarker for IgAN, and its clinical significance is still being evaluated. To elucidate the pathogenesis of IgAN, it is important to deconvolute the biosynthetic origins of Gd-IgA1 and characterize the pathogenic IgA1 HR O-glycoform(s), including the glycan structures and their sites of attachment. These efforts will likely lead to development of new biomarkers. Here, we review the IgA1 HR O-glycosylation in general and the role of aberrantly glycosylated IgA1 in the pathogenesis of IgAN in particular.

Hiroyuki Onodera,1 Takeru Urayama,2 Kazue Hirota,3 Kazuhiro Maeda,3 Ritsuko Kubota-Koketsu,3,4 Kazuo Takahashi,5 Katsuro Hagiwara,6 Yoshinobu Okuno,3 Kazuyoshi Ikuta,3,4 Mikihiro Yunoki,2,4,6 1Medical Information Department, 2Research and Development Division, Japan Blood Products Organization, Tokyo, 3Research and Development Division, The Research Foundation for Microbial Diseases of Osaka University, Kagawa, 4Former Department of Virology, Research Institute for Microbial Diseases, Osaka University, 5Virology Division, Department of Infectious Diseases, Osaka Prefectural Institute of Public Health, Osaka, 6Pathogenic Risk Evaluation, Graduate School of Veterinary Medicine, Rakuno Gakuen University, Hokkaido, Japan Abstract: Influenza viruses A/H1N1, A/H3N2, and B are known seasonal viruses that undergo annual mutation. Intravenous immunoglobulin (IVIG) contains anti-seasonal influenza virus globulins. Although the virus-neutralizing (VN) titer is an indicator of protective antibodies, changes in this titer over extended time periods have yet to be examined. In this study, variations in hemagglutination inhibition (HI) and VN titers against seasonal influenza viruses in IVIG lots over extended time periods were examined. In addition, the importance of monitoring the reactivity of IVIG against seasonal influenza viruses with varying antigenicity was evaluated. A/H1N1, A/H3N2, and B influenza virus strains and IVIG lots manufactured from 1999 to 2014 were examined. The HI titer was measured by standard methods. The VN titer was measured using a micro-focus method. IVIG exhibited significant HI and VN titers against all investigated strains. Our results suggest that the donor population maintains both specific and cross-reactive antibodies against seasonal influenza viruses, except in cases of pandemic viruses, despite major antigen changes. The titers against seasonal influenza vaccine strains, including past strains, were stable over short time periods but increased slowly over time. Keywords: IVIG, influenza, seasonal, neutralization, vaccine

Cold atmospheric pressure plasma (CAP) has potential to be utilized as an alternative method for sterilization in food industries without thermal damage or toxic residues. In contrast to the bactericidal effects of CAP, information regarding the efficacy of CAP against eukaryotic microorganisms is very limited. Therefore, herein we investigated the effects of CAP on the budding yeast Saccharomyces cerevisiae, with a focus on the cellular response to CAP. The CAP treatment caused oxidative stress responses including the nuclear accumulation of the oxidative stress responsive transcription factor Yap1, mitochondrial fragmentation, and enhanced intracellular oxidation. Yeast cells also induced the expression of heat shock protein (HSP) genes and formation of Hsp104 aggregates when treated with CAP, suggesting that CAP denatures proteins. As phenomena unique to eukaryotic cells, the formation of cytoplasmic mRNP granules such as processing bodies and stress granules and changes in the intracellular localization of Ire1 were caused by the treatment with CAP, indicating that translational repression and endoplasmic reticulum (ER) stress were induced by the CAP treatment. These results suggest that the fungicidal effects of CAP are attributed to the multiple severe stresses.

Mikihiro Yunoki,1-3 Takeshi Kurosu,2 Ritsuko Kubota Koketsu,2,4 Kazuo Takahashi,5 Yoshinobu Okuno,4 Kazuyoshi Ikuta2,4 1Research and Development Division, Japan Blood Products Organization, Tokyo, 2Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka, 3Pathogenic Risk Evaluation, Graduate School of Veterinary Medicine, Rakuno Gakuen University, Hokkaido, 4Research and Development Division, The Research Foundation for Microbial Diseases of Osaka University, Kagawa, 5Osaka Prefectural Institute of Public Health, Osaka, Japan Abstract: Japanese encephalitis virus (JEV), West Nile virus (WNV), and dengue virus (DenV) are causal agents of Japanese encephalitis, West Nile fever, and dengue fever, respectively. JEV is considered to be indigenized and widespread in Japan, whereas WNV and DenV are not indigenized in Japan. Globulin products seem to reflect the status of the donor population according to antivirus neutralization activity. However, the anti-JEV, -WNV, and -DenV neutralization activities of globulin products derived from donors in Japan have not been clarified. Furthermore, potential candidates for the development of an effective immunotherapeutic drug for encephalitis caused by JEV, WNV, or DenV have also not been identified. Therefore, the aim of this study was to determine the overall status of the donor population in Japan based on globulin products by evaluating anti-JEV, -WNV, and -DenV neutralizing activities of intravenous immunoglobulin. Overall, intravenous immunoglobulin products showed stable neutralizing activity against JEV but showed no or only weak activity against WNV or DenV. These results suggest that the epidemiological level against WNV and DenV in the donor population of Japan is still low, suggesting that these viruses are not yet indigenized. In addition, JEV vaccinations and/or infections in the donor population do not induce a cross-reactive antibody against WNV. Keywords: Japanese encephalitis virus, West Nile virus, dengue virus, intravenous immunoglobulin, neutralization

1. Definition and background IgA nephropathy (IgAN, also known as Berger’s disease) is a disease characterized by urinary findings suggesting glomerulonephritis; predominantly, IgA is deposited in the glomeruli, with no evidence of other underlying disease. Glomerular hematuria and proteinuria are urinary findings that suggest glomerulonephritis. Renal biopsy findings, which are required for confirming the diagnosis of glomerulonephritis, include IgA deposits mainly in the glomerular mesangium and occasionally in the capillary loops. In many cases, C3 is also co-deposited. The rate of progression to end-stage renal disease (ESRD) is approximately 40 % at 20 years after diagnosis. Treatment may include therapy with renin-angiotensin system (RAS) blockers, antiplatelet agents, oral corticosteroids, fish oil, or non-steroidal immunosuppressive agents; steroid pulse therapy; or tonsillectomy. The therapeutic effects of each have been examined, but an effective treatment regimen is yet to be established.