Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease worldwide, with a highly heterogeneous clinical course. Current biopsy-based risk assessment relies largely on structured histological scores, such as the Oxford MEST-C score, which summarize selected lesions but may omit information contained in routine narrative pathology reports. Here we show that large language model-based analysis of routine biopsy reports identifies reproducible pathological subtypes with prognostic relevance in IgAN. We studied 3,078 adults with primary IgAN from two hospitals in Wenzhou, China, using the First Affiliated Hospital cohort for subtype discovery and model development and the Second Affiliated Hospital cohort for independent external validation. Unsupervised clustering identified two subtypes, low-injury and high-injury, that differed in clinical presentation, histological severity and kidney outcomes. The high-injury subtype was independently associated with a higher risk of the composite kidney endpoint after adjustment for baseline clinical factors and the complete Oxford MEST-C score set (hazard ratio, 2.57; 95% confidence interval, 1.25-5.29). Interpretability analyses indicated that subtype separation was driven mainly by chronic tubulointerstitial injury and inflammatory burden. Exploratory analyses suggested heterogeneity in corticosteroid-associated outcome patterns across subtypes. These findings indicate that routine narrative biopsy reports contain prognostic information that complements structured pathological scoring.

Hypertensive nephropathy (HN), a significant consequence of chronic hypertension, remains a leading contributor to end-stage renal disease. Excessive Angiotensin II (Ang II)-driven inflammation, apoptosis, and fibrosis are central to its pathogenesis. Salvianolic acid A (SAA), a polyphenolic compound from Salvia miltiorrhiza, has anti-inflammatory properties, but its therapeutic potential in HN is unclear. HN was induced in mice by continuous subcutaneous infusion of Ang II (1.44 mg/kg/day) for 28 days. SAA (10 or 20 mg/kg/day) was administered orally every day during the final 14 days. Network pharmacology suggested SAA targets the TLR4/PI3K/AKT/NF-κB pathway. SAA administration improved renal function and attenuated inflammatory infiltration, tubular cell apoptosis, and interstitial fibrosis, independent of systemic blood pressure. NRK-52E cells were used in vitro. SAA inhibited PI3K and AKT phosphorylation, suppressed NF-κB P65 activation, and downregulated pro-inflammatory cytokines. The PI3K activator 740 Y-P abolished these effects. Pull-down, DARTS assays and molecular docking showed interaction between SAA and TLR4, while TLR4 overexpression reversed SAA's protective actions. These findings provide the evidence that SAA exerts protective effects against Ang II-induced HN, acting through inhibition of the TLR4/MyD88/PI3K/AKT/NF-κB axis and represents a potential TLR4-targeted therapy for hypertensive kidney injury.

BackgroundAbnormal lipid metabolism affects IgA nephropathy (IgAN) prognosis, but the prognostic value of LDL-C/HDL-C ratio in IgAN remains unclear.MethodsA bicenter retrospective cohort study enrolled 1,405 IgAN patients with a median follow-up of 50.1 months. Patients were divided into four quartiles based on LDL-C/HDL-C ratio (Q1: lowest quartile, Q4: highest quartile). Kaplan–Meier, Cox regression, and restricted cubic spline (RCS) analyses were used to explore the association between LDL-C/HDL-C ratio and end-stage renal disease (ESRD) risk.ResultsESRD occurred in 110 patients (8.45%). The ESRD-free survival rate decreased significantly with increasing LDL-C/HDL-C quartiles (log-rank p < 0.001). Multivariate Cox regression analysis demonstrated that, compared with the first quartile (Q1, reference), the hazard ratios for Q2, Q3, and Q4 were 2.542 (95% CI: 0.679–9.523, p = 0.166), 2.499 (95% CI: 0.707–8.830, p = 0.155), and 6.384 (95% CI: 1.840–22.154, p = 0.003), respectively. Each 1-unit increase in the LDL-C/HDL-C ratio was independently associated with a 45.2% elevated risk (HR = 1.452, 95% CI: 1.159–1.818, p = 0.001). Restricted cubic splines (RCS) analysis confirmed a linear dose–response relationship (overall p = 0.0196, nonlinear p = 0.2199). Subgroup analysis revealed that the association was amplified in patients with elevated serum creatinine (sCr), hypertension, hyperuricemia, M1, and T2 (all p < 0.05). However, the LDL-C/HDL-C ratio exhibited no correlation with renal IgA deposition intensity (r = 0.013, p = 0.624).ConclusionElevated LDL-C/HDL-C ratio constitutes an independent risk factor for end-stage renal disease (ESRD) in patients with IgA nephropathy (IgAN), demonstrating a linear dose–response relationship and serving as a reliable prognostic biomarker independent of IgA deposition.

Chronic kidney disease (CKD) poses a significant global health challenge due to its high prevalence, low awareness, poor prognosis, and substantial medical costs. High-risk factors such as severe proteinuria and hypertension exacerbate CKD progression, leading to adverse kidney outcomes, cardiovascular diseases, hospitalizations, and increased mortality. Despite existing CKD registries in China, comprehensive data on patients at high-risk of CKD progression, such as patient with CKD and high proteinuria (CKD-HP) or hypertension (CKD-HTN) are lacking, highlighting the need for a dedicated registry to amass comprehensive patient data, thereby enhancing disease understanding. The China Chronic Kidney Disease Registry Platform Study (C-INSIGHT) is a national-wide, multicenter, prospective, observational study designed to enroll approximately 5,000 patients at high risk of CKD progression, including severe proteinuria (urine albumin-to-creatinine ratios (UACR) ≥ 700 mg/g or urine protein-to-creatinine ratio (UPCR) ≥ 1000 mg/g) or hypertension (systolic blood pressure (SBP) ≥ 130 mmHg), from 37 clinical centers across China between November 2023 and December 2026. Data collected will include demographic and clinical characteristics, CKD etiology and staging, diagnosis and treatment patterns, clinical outcomes, healthcare resource utilization, and lifestyle factors. Patients will be followed up annually until study end, withdrawal, loss to follow-up, or death. The study will utilize both traditional chart reviews and electronic medical records for data collection, with data governance methods employed at selected centers to enhance efficiency and accuracy of patient screening and data collection. The outcomes of this registry include both disease progression and clinical outcomes. The disease progression refers to the progressive deterioration of renal function, including decline in estimated Glomerular Filtration Rate (eGFR) category and rapid progression. The clinical outcomes are renal outcomes, cardiovascular outcomes, cardio-kidney composite outcomes, and all-cause mortality. C-INSIGHT is the first nationwide initiative in China dedicated to characterizing CKD patients at high-risk for progression, focusing on the unique disease profiles, risk factors, and clinical outcomes of CKD-HP and CKD-HTN subgroups. This registry study will develop predictive models for CKD progression and clinical outcomes and identify gaps between real-world management and guideline-based care of CKD. Large-scale, detailed data on diagnosis, treatment, and outcomes may support the development of enhanced strategies for early intervention, risk stratification, and long-term management, ultimately improving clinical outcomes. This study aims to fill crucial evidence gaps in China, and the findings may provide a reference for CKD management within China or regions with similar populations. First submitted: 2023-10-31; First submitted that met QC criteria: 2023-10-31; First posted: 2023-11-07. NCT06117852 ( ClinicalTrials.gov ).

BACKGROUND:IgA nephropathy (IgAN) presents a challenging spectrum of outcomes, often complicated by intrarenal arterial/arteriolar lesions (IALs) in affected individuals. Despite their clinical relevance, existing criteria for classifying and assessing the severity of these lesions remain undefined. This study aimed to establish semi-quantitative assessment criteria for grading IALs and to evaluate their prognostic significance in patients with IgAN. METHOD:We conducted a retrospective cohort study of 417 cases of primary IgAN in which IALs were meticulously scored in individual biopsies. Kaplan-Meier survival analysis was employed to compare the time to the renal composite endpoint between different IALs severity groups. The association between the severity of IALs and clinical outcomes was further evaluated using multivariate Cox regression models to control for potential confounders. RESULTS:Among the 417 patients studied, 230 (55.2%) exhibited IALs. Kaplan-Meier curve analysis showed a higher cumulative incidence of the composite endpoint in patients with IALs (p < 0.001). In a compelling multivariate analysis, we identified IALs and its subclassifications, including moderate to severe intimal fibrosis and hyalinosis, as strong independent risk factors for poor prognosis (IALs: HR = 2.15, p = 0.009; moderate to severe hyalinosis: HR = 3.58, p = 0.001; moderate to severe intimal fibrosis: HR = 3.56, p = 0.001). CONCLUSION:Our findings underscore the prognostic significance of IALs in IgAN, particularly moderate to severe intimal fibrosis and hyalinosis and highlight the urgent need for novel therapeutic strategies specifically designed to mitigate the impact of IALs in high-risk IgAN patients.

IgA Nephropathy (IgAN) is a glomerular disorder characterized by proteinuria, hematuria, and chronic renal impairment. Patients with IgAN often experience recurrent renal inflammation and progressive disease deterioration, underscoring the critical need for early diagnosis and intervention to improve outcomes. This study analyzed medical records of primary IgAN patients with mild proteinuria from the 1st Affiliated Hospital of Wenzhou Medical University, spanning from January 1, 2004, to July 31, 2022. Using this dataset, we propose a novel variant of the Harris Hawks Optimization (HHO) algorithm, named MGHHO, which integrates the Modified Rosenbrock Method (MRM) and Gorilla Troops Optimizer (GTO). The MGHHO algorithm’s optimization ability was initially validated using IEEE CEC2017 benchmark functions, illustrating the efficacy of the fusion strategy in balancing global exploration and local exploitation. Subsequently, we combined the MGHHO algorithm with the K-Nearest Neighbor (KNN) algorithm to develop the MGHHO-KNN prediction framework designed explicitly for IgAN prognosis. Feature selection experiments were conducted on high-dimensional datasets from the UCI repository and the hospital’s records to substantiate the framework’s effectiveness further. The experimental results demonstrate that the proposed MGHHO-KNN model outperforms comparable methods in accuracy, sensitivity, and precision. Specifically, the MGHHO-KNN model achieved an accuracy of 98.75% and a sensitivity of 96.82% in feature selection for mild proteinuria. These findings suggest that the MGHHO-KNN model has significant potential as an auxiliary prognosis tool for IgAN. The model’s feature selection process, which highlights variables such as Systolic Blood Pressure (SBP), Oxford-E, and Oxford-T, is particularly valuable in assisting physicians with IgAN risk assessment.

BACKGROUND:Cisplatin-induced acute kidney injury (CKI) represents a severe renal dysfunction characterized by DNA damage and tubular injury. Fraxetin, derived from the Chinese herb Qinpi (Fraxinus bungeana A.DOC), is recognized for its neuroprotective effects and has been used for the prevention of various diseases. METHODS:This study investigated the renoprotective effects and molecular mechanisms of fraxetin in CKI. A mouse CKI model and a cisplatin-induced tubule epithelial cell (TEC) injury model were established to evaluate fraxetin's effects by measuring diverse parameters associated with kidney injury, focusing on DNA damage and inflammation. Additionally, network pharmacology and cellular sequencing analysis were employed to identify altered pathways or targets after fraxetin treatment. Subsequent experiments involved siRNA and pharmacological regulation to identify fraxetin targets, alongside molecular docking to unravel binding mechanisms. RESULTS:Fraxetin pretreatment significantly ameliorated CKI, with a 45% reduction in in tubular damage compared to the cisplatin-only group. Additionally, fraxetin notably enhanced DNA repair. Fraxetin pretreatment reduced cisplatin-induced DNA damage in HK-2 cells by 42.8% in comet assays. Fraxetin also mitigated inflammation, with pro-inflammatory cytokine levels decreasing by approximately 20-30% in both mouse and cell models. Notable changes were observed in the FoxO pathway. Specifically, manipulating Forkhead box O1 (FoxO1), a transcription factor involved in stress responses and longevity, influenced fraxetin's protective effect. Molecular docking revealed that fraxetin binds to the Forkhead (FH) domain of FoxO1, promoting its nuclear localization. CONCLUSIONS:Fraxetin protects against CKI by activating FoxO1, providing a foundation for novel therapeutic strategies and underscoring fraxetin's potential in treating kidney injury.

Idiopathic membranous nephropathy (IMN) complicated with focal segmental glomerulosclerosis (FSGS) is not rare, but the impact of variant pathological manifestations of FSGS (tip variant vs non-tip variant) on the clinical and prognosis of IMN patients remains to be further studied. A total of 536 eligible IMN patients were enrolled in the study and divided into three groups based on the variant histopathological presence of FSGS: 387 patients without FSGS (IMN group), 67 patients with tip variant FSGS (tpFSGS group), and 82 patients with non-tip variant FSGS (ntpFSGS group). IMN patients with FSGS had significantly lower serum albumin (IMN vs. tpFSGS vs. ntpFSGS, 21.20 [17.15, 25.25] vs. 18.60 [16.05, 22.10] vs. 17.90 [15.40, 22.03], p < 0.001) and higher 24-hour proteinuria (5.65 [3.60, 7.69] vs. 6.11 [3.97, 8.46] vs. 6.98 [4.77, 8.49], p = 0.003). Additionally, the ntpFSGS group exhibited more advanced histopathological manifestations (pathological stage, p < 0.05). Otherwise, a lower complete remission rate was observed in the ntpFSGS group. Furthermore, multivariate Cox regression analysis demonstrated significantly lower remission in tpFSGS [HR = 0.69, p = 0.029] and ntpFSGS [HR = 0.66, p = 0.014] groups. Adjusted by the immunosuppressive therapy, a worse prognosis was observed in the ntpFSGS group [KM curve, log-rank, p < 0.05], but no significant difference in the IMN group and the tpFSGS group [KM curve, log-rank, p = 0.74]. Our cohort study suggests that idiopathic membranous nephropathy patients with secondary variant FSGS indicated different clinical significance.

Background: Peritoneal fibrosis is a significant complication arising from long-term peritoneal dialysis (PD), primarily due to the loss of peritoneal mesothelial cells (PMCs). Recent studies have implicated periostin (POSTN) in the progression of various fibrotic diseases; however, its specific role in PD-induced peritoneal fibrosis remains unclear. Sodium alginate (SA) microgels have emerged as promising carriers for cell encapsulation in tissue engineering and regenerative medicine. This study investigated the therapeutic potential of PMCs encapsulated in SA microgels (SA/PMC) for reducing PD-induced peritoneal fibrosis, with a focus on the modulation by the periostin/nuclear factor kappa-B (NF-κB)/CXCL8 signaling pathway. Methods: Primary human peritoneal mesothelial cells (PHPMCs) were isolated from the PD effluent of patients. The effect of SA encapsulation on PMCs proliferation was evaluated using a Cell Counting Kit 8 (CCK-8) assay. The expression levels of POSTN, NF-κB p65, and CXCL8, as well as fibrosis markers, including α-smooth muscle actin (α-SMA), collagen I, transforming growth factor-β (TGF-β), and fibronectin, were evaluated in patients undergoing PD and a PD mouse model. Results: Patients undergoing PD for 1 year exhibited elevated levels of POSTN, NF-κB p65, CXCL8, and fibrosis markers compared with those undergoing PD for 1 week. Conclusions: Consistent results from in vivo and in vitro models demonstrated that PD and hyperglycemic conditions upregulated the expression of POSTN, NF-κB p65, CXCL8, and profibrotic markers, leading to peritoneal thickening and fibrotic progression. Treatment with SA/PMC microgels ameliorated these effects. By modulating the POSTN/NF-κB/CXCL8 pathway and enhancing PMCs survival, SA/PMC microgels may have therapeutic potential in mitigating peritoneal fibrosis in PD patients.

Background:Systemic immune inflammation index (SII) is a potential marker that can reflect the systemic inflammatory response. However, the clinical significance of SII for immunoglobulin A nephropathy (IgAN) has yet to be determined. Methods:This was a retrospective analysis, covering January 2011 to December 2023, involving 1,399 IgAN patients confirmed through renal biopsy. The low TASII (L-TASII) group comprised patients with a time-average SII (TASII) below the top third of the cohort, whereas the high TASII (H-TASII) group included all remaining patients. All patients were matched 1:1 according to age, sex, follow-up time, and baseline estimated glomerular filtration rate (eGFR). Clinical pathology and prognosis were assessed and compared between the two groups. Results:After matching, the L-TASII and H-TASII groups each feature 556 cases. Patients in the H-TASII group had lower albumin levels (36.88 ± 6.24 g/L vs. 37.93 ± 5.45 g/L, p = 0.01) and higher proteinuria levels (2.19 ± 2.25 g/day vs. 1.75 ± 2.07 g/day, p = 0.003). With an eGFR ≥30% when compared with the baseline or end-stage renal disease as the composite endpoint events, Kaplan-Meier curve analysis revealed that after an average follow-up of 59.91 ± 32.42 months, the survival rate was markedly lower in the H-TASII group than in L-TASII group (log-rank p < 0.01). Analysis revealed that TASII levels are independent predictors for the occurrence of endpoint events (hazard ratio, 1.02; 95% confidence interval, 1.01-1.04; p = 0.001). Conclusion:IgAN patients with a high TASII have more serious clinical manifestations such as creatinine, urinary protein, and inflammatory markers, while there is a worse prognosis for patients with low TASII. Thus, the TASII score represents a significant risk factor for adverse renal outcomes in IgAN patients and serves as a reliable predictor of renal survival.

Renal interstitial fibrosis (RIF) is a common feature of chronic kidney diseases (CKD), with epithelial-mesenchymal transition (EMT) being one of its important mechanisms. S100A2 is a protein associated with cell proliferation and differentiation, but its specific functions and molecular mechanisms in RIF remain to be determined. S100A2 levels were evaluated in three mouse models, including unilateral ureteral obstruction (UUO), ischemia-reperfusion injury (IRI), and aristolochic acid nephropathy (AAN), as well as in TGF-β1- treated HK-2 cells and in kidney tissue samples. Furthermore, the role of S100A2 and its interaction with FoxO1 was investigated using RT-qPCR, immunoblotting, immunofluorescence staining, co-immunoprecipitation (Co-IP), transcriptome sequencing, and gain- or loss-of-function approaches in vitro. Elevated expression levels of S100A2 were observed in three mouse models and TGF-β1-treated HK2 cells, as well as in kidney tissue samples. Following siRNA silencing of S100A2, exposure to TGF-β1 in cultured HK-2 cells suppressed EMT process and extracellular matrix (ECM) accumulation. Conversely, Overexpression of S100A2 induced EMT and ECM deposition. Notably, we identified that S100A2-mediated EMT depends on FoxO1. Immunofluorescence staining indicated that S100A2 and FoxO1 colocalized in the nucleus and cytoplasm, and their interaction was verified in Co-IP assay. S100A2 knockdown decreased TGF-β1-induced phosphorylation of FoxO1 and increased its protein expression, whereas S100A2 overexpression hampered FoxO1 activation. Furthermore, pharmacological blockade of FoxO1 rescued the induction of TGF-β1 on EMT and ECM deposition in S100A2 siRNA-treated cells. S100A2 activation exacerbates interstitial fibrosis in kidneys by facilitating FoxO1-mediated EMT. A schematic diagram of the underlying mechanisms by which S100A2 regulates EMT and renal fibrosis. Following injury, the cytoplasmic expression of S100A2 in renal tubular epithelial cells is markedly elevated. This increase promotes the phosphorylation of FoxO1, preventing its translocation into the nucleus and enhances EMT and extracellular matrix ECM deposition, thereby exacerbating renal interstitial fibrosis.

Objectives To evaluate the differences in efficacy and safety between lupus nephritis (LN) patients who received belimumab plus standard therapy and those who received only standard therapy in real world practice.Methods Patients diagnosed with LN at the First Affiliated Hospital of Wenzhou Medical University from November 2012 to July 2023 were identified, and eligible cases were divided into two groups according to whether they received additional treatment with belimumab during the course of the disease.Results A total of 1169 LN patients were identified from our follow-up database. In total, 112 patients receiving add-on treatment with belimumab (BLM group) and 112 control patients matched for relevant baseline characteristics were enrolled in this study. The median duration of treatment with belimumab was 13.82 [7.24, 20.29] months. Compared with the control group, the BLM group had more significant improvement in disease activity indicators such as serum albumin and complement levels, significantly lower B-cell count, immunoglobulin, and earlier first attainment of renal remission, but there was no significant improvement in renal function and kidney-related events or death during the 2-year follow-up period. In the BLM group, the treatment effect of belimumab was more prominent in patients with lower levels of proteinuria. The safety profile of belimumab treatment was favorable, with a lower incidence of respiratory tract infection in the BLM group than in the control group during the follow-up period (P = 0.015).Conclusions This real-world study revealed that add-on treatment with belimumab provided better disease remission, and the therapeutic effect was more significant in patients with lower proteinuria levels. In addition, it had a favorable safety profile and reduced the risk of respiratory tract infection.

Cisplatin-induced kidney injury (CKI) is a common complication of chemotherapy. Fraxetin, derived from Fraxinus bungeana A. DC. bark, has antioxidant, anti-inflammatory, and anti-fibrotic effects. This study aims to investigate fraxetin's effects on CKI and its underlying mechanism in vivo and in vitro. Tubular epithelial cells (TECs) and mice were exposed to cisplatin with and without fraxetin preconditioning assess fraxetin's role in CKI. TECs autophagy was observed using transmission electron microscopy. Apoptosis levels in animal tissues were measured using TUNEL staining. The protective mechanism of fraxetin was explored through pharmacological and genetic regulation of mTORC1. Molecular docking was used to identify potential binding sites between fraxetin and mTORC1. The results indicated that fraxetin pretreatment reduced cisplatin-induced kidney injury in a time- and concentration-dependent way. Fraxetin also decreased autophagy in TECs, as observed through electron microscopy. Tissue staining confirmed that fraxetin pretreatment significantly reduced cisplatin-induced apoptosis. Inhibition of mTORC1 using rapamycin or siRNA reversed the protective effects of fraxetin on apoptosis and autophagy in cisplatin-treated TECs, while activation of mTORC1 enhanced fraxetin's protective effect. Molecular docking analysis revealed that fraxetin can bind to HEAT-repeats binding site on mTORC1 protein. In summary, fraxetin pretreatment alleviates CKI by antagonizing autophagy and apoptosis via mTORC1 activation. This provides evidence for the potential therapeutic application of fraxetin in CKI.

BACKGROUND:The difference of the outcomes of primary membranous nephropathy (PMN) with renal vascular lesions treated with cyclophosphamide (CTX) compared to calcineurin inhibitors (CNIs) remains undetermined. METHODS:872 patients with PMN finished CNIs or CTX-based therapy between 2003 and 2018 from three centers in China were followed up at most to 120 months. A propensity-score matched (PSM) method was used to analyze the difference of outcomes between those receiving CTX- and CNIs-based therapy. Primary endpoints were defined as a composite of a 50 % decline in eGFR, progression to end-stage renal disease, or all-cause mortality. Dual immunohistochemical staining of CD31 and α-smooth muscle action were applied to detect pathological vascular lesions. RESULTS:A total of 761 patients were included in the study. After PSM, no significant difference of proteinuria complete remission rate was found between 126 paired patients (HR, 1.32; 95 % CI, 0.95 to 1.83; p = 0.10). However, CTX-based therapy was associated with significantly better renal survival compared to CNI-based therapy. (median, 156 months vs. 108 months; hazard ratio [HR], 0.31; 95 % confidence interval [CI]0.16 to 0.61; p = 0.001). Subgroup analyses showed that CTX-based therapy was superior to CNIs-based therapy among patients with hyalinosis damage (HR, 0.16; 95 % CI 0.05 to 0.50; p = 0.002;), arteriosclerosis (HR, 0.31; 95 % CI 0.15 to 0.62; p = 0.001), or hypertension (HR, 0.21; 95 % CI 0.08 to 0.53; p = 0.001). CONCLUSIONS:CTX-based therapy exhibited a significantly improved composite endpoint of PMN patients with vascular lesions compared to CNIs-based regime.

Backgrounds Past epidemiological and experimental studies in rodents have demonstrated that chronic kidney disease (CKD) leads to cognitive impairment. However, the underlying mechanism requires further investigation. Herein, a mouse model of CKD was established using conventional 5/6 nephrectomy. We aimed to examine the relationship between CKD and cognitive impairment and elucidate the underlying mechanisms.Methods Cognitive behavior was assessed using the Morris water maze, novel object recognition test, and fear conditioning test. Further experiments were also conducted to investigate the underlying molecular mechanisms.Results Our clinical data revealed a decrease in cognitive function among patients with CKD, accompanied by elevated plasma levels of pro-inflammatory cytokines. A positive correlation between cytokine concentrations and serum creatinine levels, as well as a significant positive correlation with cognitive dysfunction, were observed. Correlation analyzes demonstrated that hippocampal cytokine levels were positively correlated with serum creatinine levels and cognitive dysfunction in CKD model mice. Furthermore, 20 mg/mL interleukin-6 (IL-6) significantly decreased HT22 cell activity in vitro. Further, HT22 cells treated with IL-6 showed increased expression levels of toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88), thereby inducing the nuclear factor kappa-B p65 inflammatory pathway and mitochondria-dependent apoptosis. The CKD mouse model showed increased expression of TLR4 and cytokines in the hippocampus. TLR4 knockdown antagonized the IL-6-mediated pro-inflammatory and pro-apoptotic effects in HT22 cells. TLR4 knockdown in the CKD model mice decreased hippocampal inflammation and increased the number of neuron dendrites, thus ameliorated cognitive impairment.Conclusion These results suggest that IL-6 triggers TLR4 activation to induce neuroinflammation and neurodegeneration in CKD, ultimately culminate in cognitive impairment.

Background and PurposeRenal interstitial fibrosis is a frequent pathological manifestation of lupus nephritis (LN). tRNA halves (tiRNAs) are acquired from tRNA-derived small non-coding RNAs (sncRNAs) and are associated with fibrosis. Our previous study indicated enhanced tiRNA-Gly-GCC-002 (tiRNA002) levels in kidneys were positively related to LN-related fibrosis. However, the precise molecular mechanism remains unclear.Experimental ApproachThe mimic and agomiR of tiRNA002 were introduced into tubular epithelial cells (TECs) and MRL/lpr mice by transfection. The levels of gene and protein expressions were quantified using real-time quantitative polymerase chain reaction (RT-qPCR), Western blot and immunofluorescence assays.Key ResultsIn TECs treated with LN serum, as well as in the kidneys of MRL/lpr mice, high levels of tiRNA002 directly influenced the epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) deposition. Furthermore, tiRNA002 overexpression promoted EMT in TECs and accelerated renal interstitial fibrosis in MRL/lpr mice via Smad signalling. The target gene of tiRNA002, FKBP prolyl isomerase 5 (FKBP5), improved Smad signalling by interacting with phosphorylated Smad2/3. Silencing FKBP5 alleviated LN serum- or tiRNA002-mimic-induced EMT in TECs. In addition, FKBP5 overexpression reversed the tiRNA002 knockdown-mediated reduction of EMT and ECM accumulation.Conclusions and ImplicationsThese findings indicated that tiRNA002 is markedly increased in LN, which facilitates renal fibrosis by promoting EMT via FKBP5-mediated Smad signalling. Therefore, targeting tiRNA002 may be an innovative approach to treat renal interstitial fibrosis in LN. The aberrantly upregulated tiRNA002 activates the Smad signalling pathway by upregulating FKBP5, which is essentially associated with the progression of interstitial fibrosis in LN.image

IgA Nephropathy (IgAN) is a disease of the glomeruli that may eventually lead to chronic kidney disease or kidney failure. The signs and symptoms of IgAN nephropathy are usually not specific enough and are similar to those of other glomerular or inflammatory diseases. This makes a correct diagnosis more difficult. This study collected data from a sample of adult patients diagnosed with primary IgAN at the First Affiliated Hospital of Wenzhou Medical University, with proteinuria ≥1 g/d at the time of diagnosis. Based on these samples, we propose a machine learning framework based on weIghted meaN oF vectOrs (INFO). An enhanced COINFO algorithm is proposed by merging INFO, Cauchy Mutation (CM) and Oppositional Based Learning (OBL) strategies. At the same time, COINFO and Support Vector Machine (SVM) were integrated to construct the BCOINFO-SVM framework for IgAN diagnosis and prediction. First, the proposed enhanced COINFO is tested on the IEEE CEC2017 benchmark problems, and the results prove its efficient optimization ability and convergence accuracy. Furthermore, the feature selection capability of the proposed method is verified on the UCI public medical datasets. Finally, the auxiliary diagnostic experiment was carried out through IgAN real sample data. The results demonstrate that the proposed BCOINFO-SVM can screen out essential features such as High-Density Lipoprotein (HDL), Uric Acid (UA), Cardiovascular Disease (CVD), Hypertension and Diabetes. At the same time, the accuracy of the BCOINFO-SVM model can reach 98.56%, the sensitivity reaches 96.08%, and the specificity reaches 97.73%. It can become a potential auxiliary diagnostic model of IgAN.