坪井 直毅

Acute lung injury (ALI), which occurs in association with sepsis, trauma, and coronavirus disease 2019 (COVID-19), is a serious clinical condition with high mortality. Excessive platelet-leukocyte aggregate (PLA) formation promotes neutrophil extracellular trap (NET) release and thrombosis, which are involved in various diseases, including ALI. Macrophage-1 antigen (Mac-1, CD11b/CD18), which is expressed on the surface of leukocytes, is known to promote NET formation. This study aimed to elucidate the role of Mac-1 in extracellular histone-induced ALI. Exogenous histones were administered to Mac-1-deficient mice and wild-type (WT) mice with or without neutrophil or platelet depletion, and several parameters were investigated 1 h after histone injection. Depletion of neutrophils or platelets improved survival time and macroscopic and microscopic properties of lung tissues, and decreased platelet-leukocyte formation and plasma myeloperoxidase levels. These improvements were also observed in Mac-1-/- mice. NET formation in Mac-1-/- bone marrow neutrophils (BMNs) was significantly lower than that in WT BMNs. In conclusion, our findings suggest that Mac-1 is associated with exacerbation of histone-induced ALI and the promotion of NET formation in the presence of activated platelets.

INTRODUCTION: Coronary artery and heart valve calcification is a risk factor for cardiovascular death in haemodialysis patients, so calcification prevention should be started as early as possible. Treatment with concomitant calcimimetics and low-dose vitamin D receptor activators (VDRAs) is available, but not enough evidence has been obtained on the efficacy of this regimen, particularly in patients with short dialysis duration. Therefore, this study will evaluate the efficacy and safety of early intervention with upacicalcet, a calcimimetic used to prevent coronary artery calcification in this patient population. METHODS AND ANALYSIS: This multicentre, open-label, randomised, parallel-group controlled study will compare an early intervention group, which received upacicalcet and a low-dose VDRA, with a conventional therapy group, which received a VDRA. The primary endpoint is a change in log coronary artery calcium volume score from baseline to 52 weeks. The main inclusion criteria are as follows: (1) age 18 years or older; (2) dialysis is planned or dialysis duration is less than 60 months; (3) intact parathyroid hormone (PTH) >240 pg/mL or whole PTH level>140 pg/mL; (4) serum-corrected calcium≥8.4 mg/dL and (5) Agatston score >30. The main exclusion criteria are as follows: (1) history of parathyroid intervention or fracture in the past 12 weeks; (2) history of myocardial infarction, stroke or leg amputation in the past 12 weeks; (3) history of coronary angioplasty and (4) heart failure of New York Heart Association class III or worse. ETHICS AND DISSEMINATION: The study will comply with the Declaration of Helsinki and the Japanese Clinical Trials Act. The study protocol has been approved by the Fujita Health University Certified Review Board (file no. CR22-052). Written informed consent will be obtained from all participants. Study results will be presented in academic meetings and peer-reviewed academic journals. TRIAL REGISTRATION NUMBER: jRCTs041220126.

Objective The objective of this study was to estimate the humoral immune response evaluated by immunoglobulin G (IgG) against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD-IgG) following the third mRNA COVID-19 vaccination in patients with kidney disease who received immunosuppressive treatment. Methods The primary outcome was RBD-IgG levels after the third SARS-CoV-2 vaccination. The primary comparison was the RBD-IgG levels between patients with kidney disease who received immunosuppressive treatment (n=124) and those who did not (n=33). Results The RBD-IgG levels were significantly lower in the patients with kidney disease who received immunosuppressive treatment than in those who did not receive immunosuppressive treatment. The RBD-IgG levels were lower in patients treated with glucocorticoid monotherapy than in those who did not receive immunosuppressive treatment. Even in patients who received ≤ 5 mg prednisolone, the RBD-IgG levels were significantly lower. Nine of the 10 patients who received rituximab within one year before the first vaccination did not experience seroconversion after the third vaccination. Meanwhile, all nine patients who received rituximab only after the second vaccination experienced seroconversion, even if B cell recovery was insufficient. Patients treated with mycophenolate mofetil plus glucocorticoid plus belimumab had significantly lower RBD-IgG levels than those treated with mycophenolate mofetil plus glucocorticoid. Conclusions The RBD-IgG levels were lower in patients with kidney disease who received immunosuppressive treatment than in those who did not receive immunosuppressive treatment. Low-dose glucocorticoid monotherapy affected the humoral immune response following the third mRNA COVID-19 vaccination.

Extracellular histones induce endothelial damage, resulting in lung haemorrhage; however, the underlying mechanism remains unclear. Factor XIII, as a Ca2+-dependent cross-linking enzyme in blood, mediates fibrin deposition. As another isozyme, transglutaminase 2 (TG2) has a catalytic activity distributing in most tissues. Herein, we investigated whether TG2 promotes fibrin deposition and mediates the adhesion of platelets to ECs in histone-induced acute lung injury (ALI). We evaluated the lung histology and the adhesion of platelets to endothelial cells (ECs) after injecting histones to wild-type (WT) C57BL/6J and TG2 knockout (TG2-/-) mice, and administered a TG2 inhibitor (NC9) to WT mice. Pulmonary haemorrhage was more severe in TG2-/- mice than that in WT mice. The area of fibrin deposition and the proportion of CD41+CD31+ cells were lower in TG2-/- mice than in WT mice. Pre-treatment of NC9 decreased the area of fibrin deposition and the proportion of CD41+CD31+ cells in WT mice. These results suggest that TG2 prevents from pulmonary haemorrhage in ALI by promoting the adhesion of platelets to ECs and the fibrin deposition.

BACKGROUND: Sodium zirconium cyclosilicate, a non-absorbed non-polymer zirconium silicate, is a new potassium binder for hyperkalemia. A previous report showed that administering sodium zirconium cyclosilicate to patients with hyperkalemia allows a higher continuation rate of renin-angiotensin-aldosterone system inhibitors. However, no studies have compared sodium zirconium cyclosilicate with existing potassium binders for renin-angiotensin-aldosterone system inhibitor continuity. The purpose of this study was to evaluate the effect of sodium zirconium cyclosilicate on angiotensin-converting enzyme inhibitor /angiotensin receptor blocker continuation in patients with hyperkalemia compared to that of calcium polystyrene sulfonate. METHODS: Patients on angiotensin-converting enzyme inhibitors/angiotensin receptor blockers who were newly prescribed sodium zirconium cyclosilicate or calcium polystyrene sulfonate to treat hyperkalemia at a tertiary referral hospital between August 2020 and April 2022 were enrolled in this single-center, retrospective observational study. The primary outcome measure was angiotensin-converting enzyme inhibitor/angiotensin receptor blocker prescription three months after initiating potassium binders. RESULTS: In total, 174 patients on angiotensin-converting enzyme inhibitors/angiotensin receptor blockers who were newly administered sodium zirconium cyclosilicate (n = 62) or calcium polystyrene sulfonate (n = 112) were analyzed. The prescription rate of angiotensin-converting enzyme inhibitors /angiotensin receptor blockers at 3 months was significantly higher in the sodium zirconium cyclosilicate group than in the calcium polystyrene sulfonate group (89 vs. 72%). Multivariate logistic regression models showed that sodium zirconium cyclosilicate was independently associated with the primary outcome (odds ratio 2.66, 95% confidence interval 1.05-7.43). The propensity score-matched comparison also showed a significant association between sodium zirconium cyclosilicate and the primary outcome. CONCLUSIONS: Our study suggests that administering sodium zirconium cyclosilicate to patients with hyperkalemia allows for a higher continuation rate of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers than calcium polystyrene sulfonate. These findings suggest that sodium zirconium cyclosilicate has potential benefits for patients with chronic kidney disease receiving renin-angiotensin-aldosterone system inhibitors.

Abstract Introduction Indoxyl sulfate (IS) is a protein‐bound uremic toxin that causes uremic sarcopenia. IS has poor dialysis clearance; however, the addition of a binding competitor improves its removal efficiency. Methods Dialysis experiments were performed using N‐acetyl‐l‐tryptophan (L‐NAT) instead of l‐tryptophan (Trp) using pooled sera obtained from dialysis patients. The molecular structures of L‐NAT and Trp were similar to that of IS. Therefore, we examined whether Trp and L‐NAT were involved in muscle atrophy in the same manner as IS by performing culture experiments using a human myotube cell line. Results The removal efficiency of L‐NAT was the same as that of Trp. However, L‐NAT concentrations in the pooled sera increased at the end of the experiment. Trp (1 mM) decreased the area of human myocytes, similar to IS, whereas L‐NAT did not. Conclusion L‐NAT is a binding competitor with the ability to remove protein‐bound IS while preventing sarcopenia.

OBJECTIVES: Cardiovascular and renal diseases are closely related. Brain natriuretic peptide (BNP) and urinary albumin are established predictors for cardiac and renal morbidities, respectively. To date, no reports have investigated the combined predictive value of BNP and urinary albumin for long-term cardiovascular-renal events in patients with chronic kidney disease (CKD). The aim of this study was to investigate this theme. METHODS: Four hundred eighty-three patients with CKD were enrolled into this study and followed-up for 10 years. The endpoint was cardiovascular-renal events. RESULTS: During the median follow-up period of 109 months, 221 patients developed cardiovascular-renal events. Log-transformed BNP and urinary albumin were identified as independent predictors for cardiovascular-renal events, with a hazard ratio of 2.59 (95% confidence interval [CI], 1.81-3.72) and 2.27 (95% CI, 1.82-2.84) for BNP and urinary albumin, respectively. For the combined variables, the group with high BNP and urinary albumin had a markedly higher risk (12.41-times; 95% CI 5.23-29.42) of cardiovascular-renal events compared with that of the group with low BNP and urinary albumin. Adding both variables to a predictive model with basic risk factors improved the C-index (0.767, 0.728 to 0.814, p=0.009), net reclassification improvement (0.497, p<0.0001), and integrated discrimination improvement (0.071, p<0.0001) more than each of them alone. CONCLUSIONS: This is the first report to demonstrate that the combination of BNP and urinary albumin can stratify and improve the predictability of long-term cardiovascular-renal events in CKD patients.

OBJECTIVE: The objective of this study was to compare the ACR/EULAR 2022 criteria with the previous classification algorithm for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: We used data from two nationwide, prospective, inception cohort studies. The enrolled patients were classified as having eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA) according to the new criteria; these criteria were compared with Watts' algorithm. RESULTS: Among 477 patients, 10.7%, 9.9%, and 75.6% were classified as having EGPA, GPA, and MPA, respectively; 6.1% were unclassifiable. Three patients met both the EGPA and MPA criteria and eight patients met both the GPA and MPA criteria. Of 78 patients with GPA classified using Watts' algorithm, 27 (34.6%) patients were reclassified as having MPA. Ear, nose, and throat involvement were significantly less frequent in patients reclassified as having MPA than in those reclassified as having GPA. Of 73 patients unclassifiable using Watts' algorithm, 62 were reclassified as having MPA. All patients reclassified as having MPA were MPO-ANCA positive, and 46 had ILD. CONCLUSION: Although the ACR/EULAR 2022 criteria cause overlapping multiple criteria fulfillments in some patients, those items contribute to classifying unclassifiable patients using Watts' algorithm into MPA.

Purpose: Coronavirus disease 2019 (COVID-19) mRNA vaccines are used worldwide to prevent severe symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. IgA nephropathy (IgAN) is the most common form of glomerular injury after COVID-19 vaccination; however, because of the low frequency of such events, only a few reports have been published. A large pharmacovigilance database of real-world spontaneous adverse event (AE) reports is essential for evaluating the drug-associated safety signals regarding rare AEs. Herein, we aimed to investigate the frequency of IgAN after the COVID-19 vaccination, using the Japanese Adverse Drug Event Report (JADER) database. Methods: Data on drug-associated AEs reported between April 2004 and May 2022 were obtained from the JADER database on the Pharmaceuticals and Medical Devices Agency website. To evaluate the safety signals for the targeted AEs, reporting odds ratios (RORs), information components (ICs), and their 95% confidence intervals (CIs) were calculated using two-by-two contingency tables. Results: A total of 697,885 cases were included in the analysis. Safety signals were detected for IgAN (ROR: 6.49, 95% CI: 4.38-9.61; IC: 2.27, 95% CI: 1.70-2.83). Of 30 cases for IgAN associated with COVID-19 mRNA vaccines, 16 had information available on time to onset. Of the 16 cases, 11 occurred ≤2 days after vaccination, and two occurred >28 days after vaccination. Conclusion: These results suggest that, compared with other drugs, COVID-19 vaccination is associated with a higher frequency of IgAN. Monitoring of gross hematuria following COVID-19 vaccination should be needed.

BACKGROUND/AIM: Sepsis is a life-threatening biological condition that induces systemic tissue and organ dysfunction and confers a high mortality risk. Although the use of hydrocortisone in combination with ascorbic acid and thiamine (HAT therapy) significantly reduced mortality from sepsis or septic shock in a previous study, it did not improve mortality in subsequent randomized controlled trials (RCTs). Therefore, no definitive conclusion has been established on the benefits of HAT therapy for sepsis or septic shock. We performed a meta-analysis to assess the treatment outcomes of HAT therapy in patients with sepsis or septic shock. PATIENTS AND METHODS: We searched databases (PubMed/MEDLINE, Embase, Scopus and Cochrane Library) for RCTs using the terms "ascorbic acid", "thiamine", "sepsis", "septic shock", and "RCT". The primary outcome of this meta-analysis was the mortality rate, and the secondary outcomes were the incidence of new-onset acute renal injury (AKI), intensive care unit (ICU) length of stay (ICU-LOS), change in the Sequential Organ Failure Assessment (SOFA) score within 72 hours, and duration of vasopressor use. RESULTS: Nine RCTs were identified and included in the outcome evaluation. HAT therapy did not improve the 28-day and ICU mortality, new-onset AKI, ICU-LOS, or SOFA scores. However, HAT therapy significantly shortened the duration of vasopressor use. CONCLUSION: HAT therapy did not improve mortality, the SOFA score, renal injury, or ICU-LOS. Further studies are needed to confirm whether it shortens the duration of vasopressor use.

Abstract Perivascular mesenchymal cells (PMCs), which include pericytes, give rise to myofibroblasts that contribute to chronic kidney disease progression. Several PMC markers have been identified; however, PMC heterogeneity and functions are not fully understood. Here, we describe a novel subset of renal PMCs that express Meflin, a glycosylphosphatidylinositol-anchored protein that was recently identified as a marker of fibroblasts essential for cardiac tissue repair. Tracing the lineage of Meflin⁺ PMCs, which are found in perivascular and periglomerular areas and exhibit renin-producing potential, showed that they detach from the vasculature and proliferate under disease conditions. Although the contribution of Meflin⁺ PMCs to conventional α-SMA⁺ myofibroblasts is low, they give rise to fibroblasts with heterogeneous α-SMA expression patterns. Genetic ablation of Meflin⁺ PMCs in a renal fibrosis mouse model revealed their essential role in collagen production. Consistent with this, human biopsy samples showed that progressive renal diseases exhibit high Meflin expression. Furthermore, Meflin overexpression in kidney fibroblasts promoted bone morphogenetic protein 7 signals and suppressed myofibroblastic differentiation, implicating the roles of Meflin in suppressing tissue fibrosis. These findings demonstrate that Meflin marks a PMC subset that is functionally distinct from classic pericytes and myofibroblasts, highlighting the importance of elucidating PMC heterogeneity.

Galactose (Gal)-deficient IgA1 (Gd-IgA1) is involved in IgA nephropathy (IgAN) pathogenesis. To reflect racial differences in clinical characteristics, we assessed disease- and race-specific heterogeneity in the O-glycosylation of the IgA1 hinge region (HR). We determined serum Gd-IgA1 levels in Caucasians (healthy controls [HCs], n = 31; IgAN patients, n = 63) and Asians (HCs, n = 20; IgAN patients, n = 60) and analyzed profiles of serum IgA1 HR O-glycoforms. Elevated serum Gd-IgA1 levels and reduced number of Gal residues per HR were observed in Caucasians. Reduced number of N-acetylgalactosamine (GalNAc) residues per HR and elevated relative abundance of IgA1 with three HR O-glycans were common features in IgAN patients; these features were associated with elevated blood pressure and reduced renal function. We speculate that the mechanisms underlying the reduced GalNAc content in IgA1 HR may be relevant to IgAN pathogenesis.

Adipose-derived mesenchymal stem cells (ASCs) have shown therapeutic potentials against refractory diseases. However, the detailed therapeutic mechanisms remain unclear. Here, we report the therapeutic actions of human ASCs in nephritis, focusing on cellular dynamics and multi-organ networks. Intravenously-administered ASCs accumulated in spleen but not kidneys. Nevertheless, ASCs increased M2 macrophages and Tregs in kidneys and drove strong renoprotection. Splenectomy abolished these therapeutic effects. ASC-derived extracellular vesicles (EVs) were transferred to M2 macrophages, which entered the bloodstream from spleen. EVs induced the transcriptomic signatures of hyperpolarization and PGE2 stimulation in M2 macrophages and ameliorated glomerulonephritis. ASCs, ASC-derived EVs, and EV-transferred M2 macrophages enhanced Treg induction. These findings suggest that EV transfer from spleen-accumulated ASCs to M2 macrophages and subsequent modulation of renal immune-environment underlie the renoprotective effects of ASCs. Our results provide insights into the therapeutic actions of ASCs, focusing on EV-mediated modulation of macrophages and the spleen-kidney immune network.

Information on immune checkpoint inhibitor-induced vasculitides is limited, and predictors for this condition have not been identified. Therefore, we have examined the frequency of immune checkpoint inhibitor-induced vasculitides by analyzing the data recorded in the Japanese Adverse Drug Event Report database. Data from April 2004 to March 2020 were extracted, and vasculitides as an immune-related adverse event was defined according to the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Adverse event signals were recognized as significant when the reporting odds ratio estimates and lower limits of the corresponding 95% confidence intervals exceeded 1. The use of nivolumab showed a significant signal for vasculitides. Furthermore, significant signals of polymyalgia rheumatica were found when the patients were treated with nivolumab, pembrolizumab, and ipilimumab. In addition, the frequencies of nivolumab- and pembrolizumab-induced polymyalgia rheumatica were higher in patients aged ≥70 years and female patients, respectively. Polymyalgia rheumatica was reported in 38 patients treated with nivolumab; 31 (82%) of these were either in recovery or in remission. Further, polymyalgia rheumatica was reported in 17 patients treated with pembrolizumab; 13 (76%) of these were in recovery or remission, while three (18%) were not. Polymyalgia rheumatica was reported in 12 patients treated with ipilimumab; seven (58%) of these were in recovery or remission. Our study highlights that careful monitoring for the symptom of PMR (e.g., bilateral pain in shoulder and pelvic girdles) is required when the patients are aged &amp;gt;70 years and have been treated with nivolumab and when the patients are women and have been treated with pembrolizumab.

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.

BACKGROUND: Early detection and prediction of cisplatin-induced acute kidney injury (Cis-AKI) are essential for the management of patients on chemotherapy with cisplatin. This study aimed to evaluate the performance of a prediction model for Cis-AKI. METHODS: Japanese patients, who received cisplatin as the first-line chemotherapy at Fujita Health University Hospital, were enrolled in the study. The main metrics for evaluating the machine learning model were the area under the curve (AUC), accuracy, precision, recall, and F-measure. In addition, the rank of contribution as a predictive factor of Cis-AKI was determined by machine learning. RESULTS: A total of 1,014 and 226 patients were assigned to the development and validation data groups, respectively. The current prediction model showed the highest performance in patients 65 years old and above (AUC: 0.78, accuracy: 0.77, precision: 0.38, recall: 0.70, F-measure: 0.49). The maximum daily cisplatin dose and serum albumin levels contributed the most to the prediction of Cis-AKI. CONCLUSION: Our prediction model for Cis-AKI performed effectively in older patients.

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.

Background: We previously identified tissue inhibitor of metalloproteinase 1 (TIMP-1) as a biomarker of disease activity that distinguished mildly or highly active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) from remission 6 months after the initiation of remission-induction therapy. In the present study, we investigated whether TIMP-1 is clinically useful as a predictor of relapse and sustained remission in AAV patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) during maintenance therapy. Methods: The relationship between serum TIMP-1 levels and clinical outcomes in AAV patients receiving maintenance therapy was assessed using the follow-up data of a Japanese large-cohort study (the RemIT-JAV-RPGN study) and data collected from AAV patients on maintenance therapy in our hospital (the MAAV-EU study). Results: In the RemIT-JAV RPGN study, serum levels of TIMP-1 were significantly higher in mildly active AAV patients with MPA and GPA 6 months after the initiation of remission-induction therapy than in patients in remission. Regarding maintenance therapy, elevated levels of TIMP-1 in patients in remission were associated with relapse and/or difficulty reducing the glucocorticoid dosage after 6 to 12 months. In the MAAV-EU study, serum levels of TIMP-1 were elevated in relapsed patients 6 months before relapse, earlier than the increase in serum levels of CRP. Analyses of both studies revealed that approximately 30% of patients in remission with a serum TIMP-1 level ≥ 150 ng/mL relapsed after 6 to 12 months, while the majority of patients with a TIMP-1 level < 150 ng/mL sustained remission for at least 12 months. Conclusion: We herein demonstrated that TIMP-1 is more useful as a predictive biomarker of sustained remission than as a predictor of relapse in maintenance therapy for AAV. TIMP-1 levels < 150 ng/mL are important for the long-term maintenance of remission and may be an indicator for the tapering or cessation of treatment.

BACKGROUND: Rapidly progressive glomerulonephritis (RPGN) can progress to end-stage kidney disease within a short period. This study is a continuation of the chronological nationwide survey conducted by the Japan-RPGN working group. METHODS: We examined a total of 2793 RPGN cases registered during four periods (1989-1998, 1999-2001, 2002-2008, 2009-2011) plus 1386 cases in 2012-2015. As potential prognostic determinants, we investigated the onset period, the clinical severity (CS) grade [classified according to age, serum creatinine (sCr) and C-reactive protein levels, and presence/absence of lung lesions], and causative disease. RESULTS: The cumulative overall RPGN patient survival at 24 months kept improving over the five periods (72.0%, 72.9%, 77.7%, 83.0%, 84.9%, p < 0.001 for trend). The cumulative renal survival also improved in the latest period (68.7%, 75.4%, 76.7%, 73.4%, 78.2%, p < 0.001 for trend). The CS grade was well stratified to predict both life and renal prognoses. Anti-glomerular basement membrane disease (aGBMD)-RPGN had a poorer renal prognosis than other diseases. In anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV-RPGN, accounting for > 70% of the overall RPGN), the prognostic results were similar to that for overall RPGN. There was a much better renal prognosis for the latest period under the condition of sCr < 3 mg/dL (the 24-month cumulative renal survival: 97.9%), but not for sCr ≥ 3 mg/dL (61.5%). CONCLUSIONS: In overall RPGN as well as AAV-RPGN, both life and renal prognoses tended to improve, but the favorable renal result was substantially limited to mild cases. There was no improvement of the renal prognosis in aGBMD-RPGN.

Accumulating evidence suggests that cholesterol accumulation in leukocytes is causally associated with the development of autoimmune diseases. However, the mechanism by which fatty acid composition influences autoimmune responses remains unclear. To determine whether the fatty acid composition of diet modulates leukocyte function and the development of systemic lupus erythematosus, we examined the effect of eicosapentaenoic acid (EPA) on the pathology of lupus in drug-induced and spontaneous mouse models. We found that dietary EPA supplementation ameliorated representative lupus manifestations, including autoantibody production and immunocomplex deposition in the kidneys. A combination of lipidomic and membrane dynamics analyses revealed that EPA remodels the lipid composition and fluidity of B cell membranes, thereby preventing B cell differentiation into autoantibody-producing plasma cells. These results highlight a previously unrecognized mechanism by which fatty acid composition affects B cell differentiation into autoantibody-producing plasma cells during autoimmunity, and imply that EPA supplementation may be beneficial for therapy of lupus.

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 < .01). Pharmacist interventions using home-based BP telemonitoring were significantly superior to control/usual care (OR = 2.03, 95% CI = 1.49-2.77, P < .01), whereas pharmacist interventions without home-based BP telemonitoring did not significantly improve BP control compared to that with control/usual care (OR = 1.30, 95% CI = 0.97-1.75, P = .08). Home-based BP telemonitoring supported team-based care for HTN in these studies. In addition, patient self-monitoring with telemedicine devices might enhance patients' abilities to manage their condition by pharmacist instruction. WHAT IS NEW AND CONCLUSION: The findings of this meta-analysis showed that pharmacist interventions with home-based BP telemonitoring improve BP control among adult patients with CKD.

Objectives: Vascular calcification is common in patients with advanced chronic kidney disease (CKD) and contributes to cardiovascular disease. Accumulating evidence indicates that CKD patients often acquire subclinical vitamin K deficiency, which is associated with vascular calcification. Methods: This prospective, randomized, parallel group, multicenter trial (UMINID000011490) will include 200 dialysis patients in an open-label, two-arm design. After baseline computed tomography of the abdominal aorta, patients will be randomized to two groups that will either (1) continue receiving standard care or (2) receive additional oral supplementation with menatetrenone (45 mg/day). The treatment duration will be 24 months, and the computed tomography scan will be repeated after 12 and 24 months. The primary endpoint is the progression of abdominal aortic calcification, which is calculated as absolute changes based on the Agatston score. The secondary endpoints are the decrease in bone mineral density (measured by dual-energy X-ray absorptiometry), the biomarkers associated with vitamin K, vitamin K intake (evaluated by the food frequency questionnaire), and the biomarkers associated with vascular calcification. Conclusions: This study aims to confirm whether vitamin K has inhibitory effects on calcification that can be clinically determined. Trial registration: UMINID000011490.

INTRODUCTION: Degenerative 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. METHODS: We 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. RESULTS: The 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. CONCLUSIONS: The 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 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.

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.

Accumulating evidence indicates that cell death triggers sterile inflammation and that impaired clearance of dead cells causes nonresolving inflammation; however, the underlying mechanisms are still unclear. Here, we show that macrophage-inducible C-type lectin (Mincle) senses renal tubular cell death to induce sustained inflammation after acute kidney injury in mice. Mincle-deficient mice were protected against tissue damage and subsequent atrophy of the kidney after ischemia-reperfusion injury. Using lipophilic extract from the injured kidney, we identified β-glucosylceramide as an endogenous Mincle ligand. Notably, free cholesterol markedly enhanced the agonistic effect of β-glucosylceramide on Mincle. Moreover, β-glucosylceramide and free cholesterol accumulated in dead renal tubules in proximity to Mincle-expressing macrophages, where Mincle was supposed to inhibit clearance of dead cells and increase proinflammatory cytokine production. This study demonstrates that β-glucosylceramide in combination with free cholesterol acts on Mincle as an endogenous ligand to induce cell death-triggered, sustained inflammation after acute kidney injury.

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 <6 mg/dL; G2, 6.0-8.0 mg/dL; G3, 8.0-10.0 mg/dL; G4, 10.0-12.0 mg/dL; and G5, ≥12.0 mg/dL. We created three models (Model 1: adjusted for age and sex, Model 2: adjusted for Model 1 + 12 variables, and Model 3: stepwise regression adjusted for Model 2 + 13 variables) and performed a multivariate Cox proportional hazard regression analysis to examine the association between the serum UA level and outcomes, including infection-related mortality. RESULTS: Hazard ratios (HRs) were calculated relative to the G2, because the all-cause mortality rate was the lowest in G2. For Models 1 and 2, the all-cause mortality rate was significantly higher in G5 than in G2 (HR: 1.63, 95% confidence interval [CI]: 1.14-2.33 and HR: 1.78, 95% CI: 1.19-2.68, respectively). For Models 1, 2, and 3, the infection-related mortality rate was significantly higher in G5 than in G2 (HR: 2.75, 95% CI: 1.37-5.54, HR: 3.09, 95% CI: 1.45-6.59, HR: 3.37, and 95% CI: 1.24-9.15, respectively). CONCLUSIONS: Extreme hyperuricemia (serum UA level ≥12.0 mg/dL) at dialysis initiation is a risk factor for infection-related deaths.

Background: Effective prognostic markers are needed for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study evaluated the clinical associations of serum vascular endothelial growth factor-A (sVEGF-A) and sVEGF-A&lt;sub&gt;165&lt;/sub&gt;b (an anti-angiogenic isoform of VEGF-A) levels with time to remission of AAV in a nationwide Japanese prospective follow-up cohort. Methods: We collected samples from patients with AAV who were enrolled in the nationwide Japanese cohort study (RemIT-JAV-RPGN). We measured sVEGF-A and sVEGF-A&lt;sub&gt;165&lt;/sub&gt;b levels using enzyme-linked immunosorbent assays in 57 serum samples collected 6 months before and after initiation of AAV treatment. Patients were classified based on AAV disease subtypes: microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Results: Results revealed significant reductions in sVEGF-A and sVEGF-A&lt;sub&gt;165&lt;/sub&gt;b levels in patients with MPA and EGPA, respectively. However, despite the comparable levels of sVEGF-A and sVEGF-A&lt;sub&gt;165&lt;/sub&gt;b during the 6 months of treatment in GPA patients, correlation analysis revealed that the differences in log2-transformed levels of sVEGF-A and sVEGF-A&lt;sub&gt;165&lt;/sub&gt;b were negatively correlated with time to remission in GPA patients. Conclusion: These results suggest that sVEGF-A and sVEGF-A&lt;sub&gt;165&lt;/sub&gt;b can serve as potential markers of time to remission in patients with GPA.