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Development of a novel agent against life-threatening sepsis requires the in-depth understanding of the relevant pathophysiology and therapeutic targets. Given the function of microRNAs (miRNAs) as potent oligonucleotide therapeutics, here we investigated the pathophysiological role of exogenously applied miRNA in sepsis-induced multiple organ injury. In vitro, miR-16, miR-126, miR-146a, and miR-200b suppressed the production of pro-inflammatory cytokines in RAW264.7 macrophage cells after lipopolysaccharide (LPS) stimulation. Of these, miR-146a displayed the most highly suppressive effect, wherein the transcriptional activity of nuclear factor kappa B (NF-κB) was decreased via targeting of interleukin 1 receptor-associated kinase 1 and tumor necrosis receptor-associated factor 6. Sepsis was induced in mice via cecal ligation and puncture (CLP) and an intravenous injection of a complex of miR-146a-expressing plasmid and polyethyleneimine. Treatment with this complex significantly decreased the level of serum inflammatory cytokines, attenuated organ injury including kidney injury, and led to increased survival from polymicrobial sepsis induced by CLP. miR-146a-expressing plasmid was abundantly distributed in splenic macrophages, but not in renal parenchymal cells. CLP mice treated with miR-146a displayed significantly decreased NF-κB activation and splenocyte apoptosis. Splenectomy diminished the anti-inflammatory effects of miR-146a. The collective results support the conclusion that the induction of miR-146a expression in splenic macrophages prevents excessive inflammation and sepsis-induced multiple organ injury. This study establishes a novel and critical pathophysiological role for splenic macrophage interference in sepsis-related organ injury.

Lupus nephritis (LN) is a life-threatening complication of systemic lupus erythematosus. The 2003 pathological classification of LN was revised in 2016; it quantitatively evaluates the interstitium in addition to the glomeruli. We performed a retrospective multi-centre cohort study and investigated the utility of the 2016 classification—including the activity index (AI), chronicity index (CI), and each pathological component to predict complete remission or renal function decline, defined as 1.5-fold increase in serum creatinine levels—and compare with that of the 2003 classification. Ninety-one consecutive adult patients with first-onset class III/IV LN who were newly prescribed any immunosuppressants were enrolled and followed up for a median of 51 months from January 2004. Cox regression analysis demonstrated the subclasses based on the 2003 classification, which mainly evaluate glomerular lesions, were not associated with clinical outcomes. After adjustments for estimated glomerular filtration rate and urinary protein levels, higher CI and higher interstitial fibrosis and lower hyaline deposit scores were associated with renal functional decline. Similarly, higher CI and interstitial inflammation scores were associated with failure to achieve complete remission. Therefore, the 2016 classification can predict the clinical outcomes more precisely than the 2003 classification.

Presepsin is highlighted as a diagnostic and prognostic marker of sepsis. Little information is available regarding the accurate association between presepsin levels and the degree of kidney function. We analyzed presepsin levels in patients with a glomerular filtration rate (GFR) in the categories G1 to G5, evaluated via inulin renal clearance test, and receiving hemodialysis (HD). Patients who were not receiving HD were included if they had undergone inulin renal clearance measurements for the accurate measurement of GFR (measured GFR), and patients who were receiving hemodialysis (HD) were included if they had anuria. Exclusion criteria were infection, cancer, liver disease, autoimmune disorders, or steroid or immunosuppressant use. GFR category was defined as follows; G1: GFR ≥ 90 ml/min/1.73 m2, G2: GFR = 60 to 90 ml/min/1.73 m2, G3: GFR = 30 to 60 ml/min/1.73 m2, G4: GFR = 15 to 30 ml/min/1.73 m2, G5: GFR ≤ 15 ml/min/1.73 m2. Seventy-one patients were included. The median (IQR) presepsin values of patients in each GFR category were as follows: G1 + G2: 69.8 (60.8-85.9) pg/ml; G3: 107.0 (68.7-150.0) pg/ml; G4: 171.0 (117.0-200.0) pg/ml; G5: 251.0 (213.0-297.5) pg/ml; and HD: 1160.0 (1070.0-1400.0) pg/ml. The log-transformed presepsin values, excluding patients receiving HD, inversely correlated with the measured GFR (Pearson's correlation coefficient = -0.687, P < 0.001). The multivariate analysis revealed that measured GFR and hemoglobin levels significantly correlated with elevated presepsin levels. Presepsin levels were markedly high in patients receiving HD, similar to values seen in patients with severe sepsis or septic shock. In patients who were not receiving HD, presepsin levels increased as GFR decreased. Thus, the evaluation of presepsin levels in patients with chronic kidney disease requires further consideration, and a different cutoff value is needed for diagnosing sepsis in such patients.

A common renal disease, immunoglobulin A (IgA) nephropathy (IgAN), is associated with glomerular deposition of IgA1-containing immune complexes. IgA1 hinge region (HR) has up to six clustered O -glycans consisting of Ser/Thr-linked N -acetylgalactosamine with β1,3-linked galactose and variable sialylation. IgA1 glycoforms with some galactose-deficient (Gd) HR O -glycans play a key role in IgAN pathogenesis. The clustered and variable O -glycans make the IgA1 glycomic analysis challenging and better approaches are needed. Here, we report a comprehensive analytical workflow for IgA1 HR O -glycoform analysis. We combined an automated quantitative analysis of the HR O -glycopeptide profiles with sequential deglycosylation to remove all but Gd O -glycans from the HR. The workflow was tested using serum IgA1 from healthy subjects. Twelve variants of glycopeptides corresponding to the HR with three to six O -glycans were detected; nine glycopeptides carried up to three Gd O -glycans. Sites with Gd O -glycans were unambiguously identified by electron-transfer/higher-energy collision dissociation tandem mass spectrometry. Extracted ion chromatograms of isomeric glycoforms enabled quantitative assignment of Gd sites. The most frequent Gd site was T 236 , followed by S 230 , T 233 , T 228 , and S 232 . The new workflow for quantitative profiling of IgA1 HR O -glycoforms with site-specific resolution will enable identification of pathogenic IgA1 HR O -glycoforms in IgAN.

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.

BackgroundRapidly 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.MethodsWe 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.ResultsThe 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%).ConclusionsIn 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.

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.

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. 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. 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. Our prediction model for Cis-AKI performed effectively in older patients.

IgA nephropathy (IgAN) is characterized by glomerular deposits of IgA-containing immune complexes (IgA-ICs), which are suspected to originate from circulation. However, the composition of these ICs is not fully understood. To address this gap in knowledge, we performed label-free quantitative mass-spectrometry analyses of glomerular and circulatory IgA-ICs with a focus on complement proteins. Glomeruli of patients with IgAN compared to healthy glomeruli had greater amounts of several complement-system proteins associated with classical, alternative, and terminal pathways, including complement factor H-related (CFHR) proteins 1, 2, 3, and 5, C1q chains B and C, and properdin. Circulatory IgA-ICs of patients with IgAN vs. healthy controls had a greater abundance of complement proteins CFHR1, C1q chains A, B, and C, and properdin. Furthermore, levels of several complement proteins in circulatory IgA-ICs of IgAN patients were reduced after immunosuppressive therapy (i.e., tonsillectomy combined with pulse steroid therapy) but not in patients on comprehensive supportive therapy. CFHR1 exhibited the greatest decrease (Fold change = 48.16, P  < 0.0001). These data together revealed the complexity of complement proteome in glomerular and circulatory IgA-ICs and suggested an association of complement regulatory proteins, such as CFHR1, with pathogenic IgA-ICs.

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 >70 years and have been treated with nivolumab and when the patients are women and have been treated with pembrolizumab.