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Abstract Background The underlying mechanism of human umbilical-derived mesenchymal stem cells (hUC-MSCs) therapy for renal senescence in post-acute kidney injury (post-AKI) remains unclear. Unopposed mitochondrial fusion-based mitochondrial elongation is required for cellular senescence. This study attempted to dissect the role of hUC-MSCs therapy in modulating mitochondrial elongation-related senescence by hUC-MSCs therapy in post-AKI. Methods Initially, a unilateral renal ischemia–reperfusion (uIRI) model was established in C57 mice. Subsequently, lentivirus-transfected hUC-MSCs were given by subcapsular injection. Two weeks after transplantation, histochemical staining, and transmission electron microscopy were used to assess the efficacy of hUC-MSCs in treating renal senescence, fibrosis, and mitochondrial function. To further investigate the mitochondrial regulation of hUC-MSCs secretion, hypoxic HK-2 cells were built. Finally, antibodies of HGF and its receptor were used within the hUC-MSCs supernatant. Results Unopposed mitochondrial fusion, renal senescence, and renal interstitial fibrosis were successively identified after uIRI in mice. Then, the efficacy of hUC-MSCs after uIRI was confirmed. Subsequently, inhibiting hUC-MSCs-derived HGF significantly compromises the efficacy of hUC-MSCs and leads to ineffectively curbing mitochondrial elongation, accompanying insufficient control of elevated PKA and inhibitory phosphorylation of drp1 (Drp1pSer637). As a result, the treatment efficacy of renal senescence and fibrosis alleviation was also weakened. Furthermore, similar results were obtained with antibodies blocking HGF or cMet in hypoxic HK-2 cells treated with hUC-MSCs-condition medium for further proving. Uncurbed mitochondrial elongation induced by PKA and Drp1pSer637 was inhibited by hUC-MSCs derived HGF but reversed in the activation or overexpression of PKA. Conclusions The research concluded that hUC-MSCs-derived HGF can inhibit PKA-Drp1pSer637-mitochondrial elongation via its receptor cMet to alleviate renal senescence and fibrosis in post-AKI.

Abstract Background Although mesenchymal stem cells (MSCs) have been proven to be appropriate candidates for the treatment of AKI-CKD, their efficacy is limited and variable. Astilbin (AST) had a protective effect on MSCs from oxidative stress via ROS-scavenging, however, whether it can improve MSCs’ renoprotection and the underlying mechanism need to be elucidated. Methods AST-pretreated MSCs were administered intravenously into the ischemia–reperfusion injury mice models and the renal function, pathological changes and inflammation. Were evaluated. In addition, DARTS, molecular docking, surface plasma resonance(SPR), dual-luciferase reporter gene assay and the ChIP-PCR were utilized to explore the potential signaling pathways through which AST exert renal protective effects on MSCs. Results AST-pretreated MSCs markedly improved kidney function, reduced kidney pathological injury and inflammation in AKI and AKI-CKD mice. RNA-seq results showed that PTGS2 related pathway was significantly up-regulated in MSCs after AST pretreatment. DARTS assay, molecular docking and SPR assay revealed that AST could bind with the transcriptional factor of Kruppel-Like Factor 4(KLF4) protein. The promoter of PTGS2 had the binding and transcriptional activation by KLF4. Furthermore, AST pretreatment promoted the secretion of PGE2 in MSCs. And then the westren blot results showed that the protein levels of CD163 and CD206 were upregulated after coculture in AST-pretreated MSCs, indicating that the polarization of RAW264.7 cells towards M2-like macrophages was induced. Knockdown of PTGS2 reversed the ability of AST-pretreated MSCs in converting macrophages to M2 phenotype and reducing their therapeutic effects on AKI-CKD mice. Conclusion AST pretreatment enhances the efficacy of MSCs on AKI and AKI-CKD mice by inducing of M2-like phenotype polarization in macrophages through the PTGS2-mediated pathway. This approach not only provides a novel strategy to strengthen the capability of MSCs but also helps elucidate the beneficial effects of the Chinese herbal medicine AST.

Abstract Background We investigated the associations between IgM, IgG, IgA, and IgE levels and all-cause mortality risk in Chinese centenarians. Methods All participants were from the China Hainan Centenarian Cohort Study. Eligible participants were divided into quartiles based on their IgM, IgG, IgA, and IgE levels. We used restricted cubic spline analyses, Cox regression analyses, and Kaplan–Meier survival curves to analyze associations between IgM, IgG, IgA, and IgE and all-cause mortality risk. Results A total of 906 centenarian participants were included in this study (81.2% female; median age, 102 years). During a median follow-up of 30.1 months, 838 (92.5%) participants died. Restricted cubic spline analysis revealed a nonlinear relationship (“L” type) between serum IgM level and all-cause mortality. Compared with the higher three quartiles of serum IgM level, the lowest quartile was associated with a higher risk of death (Q1 versus Q2-Q4: HR, 1.365; 95% CI, 1.166–1.598; P

Abstract Background Lupus nephritis (LN) is the most common cause of kidney injury in systemic lupus erythematosus (SLE) patients and is associated with increased mortality. DNA methylation, one of the most important epigenetic modifications, has been reported as a key player in the pathogenesis of SLE. Hence, our article aimed to explore DNA methylation in CD4+ T cells from LNs to identify additional potential biomarkers and pathogenic genes involved in the progression of LN. Methods Our study enrolled 46 SLE patients with or without kidney injury and 23 healthy controls from 2019 to 2022. CD4+ T cells were sorted for DNA methylation genotyping and RNA-seq. Through bioinformatics analysis, we identified the significant differentially methylated CpG positions (DMPs) only in the LN group and validated them by Bisulfite PCR. Integration analysis was used to screen for differentially methylated and expressed genes that might be involved in the progression of LN, and the results were analyzed via cell experiments and flow cytometry. Results We identified 243 hypomethylated sites and 778 hypermethylated sites only in the LN cohort. Three of these DMPs, cg08332381, cg03297029, and cg16797344, were validated by Bisulfite PCR and could be potential biomarkers for LN. Integrated analysis revealed that the expression of BCL2L14 and IFI27 was regulated by DNA methylation, which was validated by azacytidine (5-aza) treatment. The overexpression of BCL2L14 in CD4+ T cells might induce renal fibrosis and inflammation by regulating the differentiation and function of Tfh cells. Conclusion Our study identified novel aberrant DMPs in CD4+ T cells only in LN patients and DNA methylation-regulated genes that could be potential LN biomarkers. BCL2L14 is likely involved in the progression of LN and might be a treatment target.

With the development of nanomedicine, nanomaterials have been widely used, offering specific drug delivery to target sites, minimal side effects, and significant therapeutic effects. The kidneys have filtration and reabsorption functions, with various potential target cell types and a complex structural environment, making the strategies for kidney function protection and recovery after injury complex. This also lays the foundation for the application of nanomedicine in kidney diseases. Currently, evidence in preclinical and clinical settings supports the feasibility of targeted therapy for kidney diseases using drug delivery based on nanomaterials. The prerequisite for nanomedicine in treating kidney diseases is the use of carriers with good biocompatibility, including nanoparticles, hydrogels, liposomes, micelles, dendrimer polymers, adenoviruses, lysozymes, and elastin-like polypeptides. These carriers have precise renal uptake, longer half-life, and targeted organ distribution, protecting and improving the efficacy of the drugs they carry. Additionally, attention should also be paid to the toxicity and solubility of the carriers. While the carriers mentioned above have been used in preclinical studies for targeted therapy of kidney diseases both in vivo and in vitro, extensive clinical trials are still needed to ensure the short-term and long-term effects of nano drugs in the human body. This review will discuss the advantages and limitations of nanoscale drug carrier materials in treating kidney diseases, provide a more comprehensive catalog of nanocarrier materials, and offer prospects for their drug-loading efficacy and clinical applications.

We aimed to test whether red blood cell distribution width (RDW) to monocyte percentage ratio (RMR) was associated with the acute-phase prognosis of coronavirus disease 2019 (COVID-19) in chronic kidney disease (CKD) patients. Prospective enrollment and 90-day follow-up of CKD patients with COVID-19 were conducted from December 1, 2022 to January 31, 2023. Demographics, clinical data, and laboratory and radiographic findings were collected, and multiple logistic regression, subgroup analysis, and receiver operating characteristic (ROC) curve analysis were performed. A total of 218 patients were enrolled, with a mean age of 59 years and 69.7% being male. The 90-day mortality rate was 24.8%. The lnRMR level was 5.18 (4.91-5.43) and emerged as an independent risk factor (OR: 3.01, 95% CI: 1.72-5.85). The lnRMR-mortality association was consistent across sex, age, CKD stage, COVID-19 vaccination, and comorbidity subgroups. The area under the ROC curve of lnRMR was 0.737 (95% CI: 0.655-0.819). Our findings indicate that lnRMR is a simple and practical predictor for identifying high-risk CKD patients during the acute phase of COVID-19.

CagA, a virulence factor of Helicobacter pylori (H. pylori), is known to drive inflammation in gastric epithelial cells and is typically degraded through autophagy. However, the molecular mechanism by which CagA evades autophagy-mediated degradation remains elusive. This study found that H. pylori inhibits autophagic flux by upregulating the expression of AU-rich element RNA-binding factor 1 (AUF1). We confirmed that AUF1 does not affect autophagy initiation but instead hampers lysosomal clearance, as evidenced by treatments with 3-MA, CQ and BafA1. Upregulated AUF1 stabilizes CagA protein levels by inhibiting the autolysosomal degradation of intracellular CagA in H. pylori-infected gastric epithelial cells. Knocking down AUF1 promotes CagA degradation, an effect that can be reversed by the lysosome inhibitor BafA1 and CQ. Transcriptome analysis of AUF1-knockdown gastric epithelial cells infected with H. pylori indicated that AUF1 regulates the expression of lysosomal-associated hydrolase genes, specifically CTSD, to inhibit autolysosomal degradation. Moreover, we observed that knockdown of AUF1 enhanced the stability of CTSD mRNA and identified AUF1 binding to the 3’UTR region of CTSD mRNA. AUF1-mediated downregulation of CTSD expression contributes to CagA stability, and AUF1 overexpression leads to an increase in CagA levels in exosomes, thus promoting extracellular inflammation. In clinical gastric mucosa, the expression of AUF1 and its cytoplasmic translocation are associated with H. pylori-associated gastritis, with CagA being necessary for the translocation of AUF1 into the cytoplasm. Our findings suggest that AUF1 is a novel host-positive regulator of CagA, and dysregulation of AUF1 expression increases the risk of H. pylori-associated gastritis.

Background Kidney fibrosis is the common final pathway of virtually all advanced forms of chronic kidney disease (CKD) including diabetic nephropathy (DN), IgA nephropathy (IgAN) and membranous nephropathy (MN), with complex mechanism. Comparative gene expression analysis among these types of CKD may shed light on its pathogenesis. Therefore, we conducted this study aiming at exploring the common and specific fibrosis-related genes involved in different types of CKD.Methods Kidney biopsy specimens from patients with different types of CKD and normal control subjects were analyzed using the NanoString nCounter® Human Fibrosis V2 Panel. Genes differentially expressed in all fibrotic DN, IgAN and MN tissues compared to the normal controls were regarded as the common fibrosis-related genes in CKD, whereas genes exclusively differentially expressed in fibrotic DN, IgAN or MN samples were considered to be the specific genes related to fibrosis in DN, IgAN and MN respectively. Quantitative real-time PCR (qRT-PCR) was performed to validate the expression of the selected genes.Results Protein tyrosine phosphatase receptor type C (PTPRC), intercellular cell adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), interleukin 10 receptor alpha (IL10RA) and CC chemokine receptor 2 (CCR2) were identified as the potential common genes for kidney fibrosis in different types of CKD, while peroxisome proliferator-activated receptor alpha (PPARA), lactate oxidase (LOX), secreted phosphoprotein 1 (SPP1) were identified as the specific fibrosis-associated genes for DN, IgAN and MN respectively. qRT-PCR demonstrated that the expression levels of these selected genes were consistent with the NanoString analysis.Conclusions There were both commonalities and differences in the mechanisms of fibrosis in different types of CKD, the commonalities might be used as the common therapeutic targets for kidney fibrosis in CKD, while the differences might be used as the diagnostic markers for DN, IgAN and MN respectively. Inflammation was highly relevant to the pathogenesis of fibrosis. This study provides further insight into the pathophysiology and treatment of fibrotic kidney disease.

The persistence of HBV covalently closed circular DNA (cccDNA) and HBV integration into the host genome in infected hepatocytes pose significant challenges to the cure of chronic HBV infection. Although CRISPR/Cas9-mediated genome editing shows promise for targeted clearance of viral genomes, a safe and efficient delivery method is currently lacking. Here, we developed a novel approach by combining light-induced heterodimerization and protein acylation to enhance the loading efficiency of Cas9 protein into extracellular vesicles (EVs). Moreover, vesicular stomatitis virus-glycoprotein (VSV-G) was incorporated onto the EVs membrane, significantly facilitating the endosomal escape of Cas9 protein and increasing its gene editing activity in recipient cells. Our results demonstrated that engineered EVs containing Cas9/gRNA and VSV-G can effectively reduce viral antigens and cccDNA levels in the HBV-replicating and infected cell models. Notably, we also confirmed the antiviral activity and high safety of the engineered EVs in the HBV-replicating mouse model generated by hydrodynamic injection and the HBV transgenic mouse model. In conclusion, engineered EVs could successfully mediate functional CRISPR/Cas9 delivery both in vitro and in vivo, leading to the clearance of episomal cccDNA and integrated viral DNA fragments, and providing a novel therapeutic approach for curing chronic HBV infection.

Abstract IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis, resulting in end‐stage renal disease and increased mortality rates. Prognostic biomarkers reflecting molecular mechanisms for effective IgAN management are urgently needed. Analysis of kidney single‐cell transcriptomic sequencing data demonstrated that IgAN expressed high‐expression levels of inflammatory cytokines TNFSF10, TNFSF12, CCL2, CXCL1, and CXCL12 than healthy controls (HCs). We also measured the urine proteins in 120 IgAN (57 stable and 63 progressive) and 32 HCs using the proximity extension assay (PEA), and the multivariable and least absolute shrinkage and selection operator (LASSO) logistic regression analysis both revealed that CXCL12, MCP1 were the prognostic significant variables to predict IgAN progression severity. These two proteins exhibited negative correlation with the estimated glomerular filtration rate (eGFR) and patients with higher expression levels of these two proteins had a higher probability to have poorer renal outcome. We further developed a risk index model utilizing CXCL12, MCP1, and baseline clinical indicators, which achieved an impressive area under the curve (AUC) of 0.896 for prediction of IgAN progression severity. Our study highlights the significance of the inflammatory protein biomarkers for noninvasive prediction of IgAN severity and progression, offering valuable insights for clinical management.

RationaleKidney inflammation plays a crucial role in the pathogenesis of IgA nephropathy (IgAN), yet the specific phenotypes of immune cells involved in disease progression remain incompletely understood. Utilizing joint profiling through longitudinal single-cell RNA-sequencing (scRNAseq) and single-cell assay for transposase-accessible chromatin sequencing (scATACseq) can provide a comprehensive framework for elucidating the development of cell subset diversity and how chromatin accessibility regulates transcription.ObjectiveWe aimed to characterize the dynamic immune cellular landscape at a high resolution in an early IgAN mouse model with acute kidney injury (AKI).Methods and resultsA murine model was utilized to mimic 3 immunological states –”immune stability (IS), immune activation (IA) and immune remission (IR)” in early human IgAN-associated glomerulopathy during AKI, achieved through lipopolysaccharide (LPS) injection. Urinary albumin to creatinine ratio (UACR) was measured to further validate the exacerbation and resolution of kidney inflammation during this course. Paired scRNAseq and scATACseq analysis was performed on CD45+ immune cells isolated from kidney tissues obtained from CTRL (healthy vehicle), IS, IA and IR (4 or 5 mice each). The analyses revealed 7 major cell types and 24 clusters based on 72304 single-cell transcriptomes, allowing for the identification and characterization of various immune cell types within each cluster. Our data offer an impartial depiction of the immunological characteristics, as the proportions of immune cell types fluctuated throughout different stages of the disease. Specifically, these analyses also revealed novel subpopulations, such as a macrophage subset (Nlrp1b Mac) with distinct epigenetic features and a unique transcription factor motif profile, potentially exerting immunoregulatory effects, as well as an early subset of Tex distinguished by their effector and cytolytic potential (CX3CR1-transTeff). Furthermore, in order to investigate the potential interaction between immune cells and renal resident cells, we conducted single-cell RNA sequencing on kidney cells obtained from a separate cohort of IS and IA mice without isolating immune cells. These findings underscored the diverse roles played by macrophages and CD8+ T cells in maintaining homeostasis of endothelial cells (ECs) under stress.ConclusionsThis study presents a comprehensive analysis of the dynamic changes in immune cell profiles in a model of IgAN, identifying key cell types and their roles and interactions. These findings significantly contribute to the understanding of the pathogenesis of IgAN and may provide potential targets for therapeutic intervention.

Abstract A promising new therapy option for acute kidney injury (AKI) is mesenchymal stem cells (MSCs). However, there are several limitations to the use of MSCs, such as low rates of survival, limited homing capacity, and unclear differentiation. In search of better therapeutic strategies, we explored all-trans retinoic acid (ATRA) pretreatment of MSCs to observe whether it could improve the therapeutic efficacy of AKI. We established a renal ischemia/reperfusion injury model and treated mice with ATRA-pretreated MSCs via tail vein injection. We found that AKI mice treated with ATRA-MSCs significantly improved renal function compared with DMSO-MSCs treatment. RNA sequencing screened that hyaluronic acid (HA) production from MSCs promoted by ATRA. Further validation by chromatin immunoprecipitation experiments verified that retinoic acid receptor RARα/RXRγ was a potential transcription factor for hyaluronic acid synthase 2. Additionally, an in vitro hypoxia/reoxygenation model was established using human proximal tubular epithelial cells (HK-2). After co-culturing HK-2 cells with ATRA-pretreated MSCs, we observed that HA binds to cluster determinant 44 (CD44) and activates the PI3K/AKT pathway, which enhances the anti-inflammatory, anti-apoptotic, and proliferative repair effects of MSCs in AKI. Inhibition of the HA/CD44 axis effectively reverses the renal repair effect of ATRA-pretreated MSCs. Taken together, our study suggests that ATRA pretreatment promotes HA production by MSCs and activates the PI3K/AKT pathway in renal tubular epithelial cells, thereby enhancing the efficacy of MSCs against AKI.

Abstract Kidney diseases pose a significant threat to human health due to their high prevalence and mortality rates. Worryingly, the clinical use of drugs for kidney diseases is associated with more side effects, so more effective and safer treatments are urgently needed. Oleanolic acid (OA) is a common pentacyclic triterpenoid that is widely available in nature and has been shown to have protective effects in kidney disease. However, comprehensive studies on its role in kidney diseases are still lacking. Therefore, this article first explores the botanical sources, pharmacokinetics, derivatives, and safety of OA, followed by a summary of the anti-inflammatory, immunomodulatory, anti-oxidative stress, autophagy-enhancing, and antifibrotic effects of OA and its analogues in renal diseases, and an analysis of the molecular mechanisms, aiming to provide further insights for the development of novel drugs for the treatment of kidney diseases.

Abstract Background Nonmalignant pleural effusion (NMPE) is common and remains a definite health care problem. Pleural effusion was supposed to be a risk factor for acute kidney injury (AKI). Incidence of AKI in NMPE patients and whether there is correlation between the size of effusions and AKI is unknown. Objective To assess the incidence of AKI in NMPE inpatients and its association with effusion size. Study design and method We conducted a retrospective cohort study of inpatients admitted to the Chinese PLA General Hospital with pleural effusion from 2018-2021. All patients with pleural effusions confirmed by chest radiography (CT or X-ray) were included, excluding patients with diagnosis of malignancy, chronic dialysis, end-stage renal disease (ESRD), community-acquired AKI, hospital-acquired AKI before chest radiography, and fewer than two serum creatinine tests during hospitalization. Multivariate logistic regression and LASSO logistic regression models were used to identify risk factors associated with AKI. Subgroup analyses and interaction tests for effusion volume were performed adjusted for the variables selected by LASSO. Causal mediation analysis was used to estimate the mediating effect of heart failure, pneumonia, and eGFR

BackgroundExisting studies investigating the impact of serum calcium (Ca), phosphate (P), 25 hydroxyvitamin D (25[OH]D), and parathyroid hormone (PTH) levels on kidney function have produced inconsistent results. Further research is needed to establish the direct causal relationship between these factors and kidney function.MethodsThe study used genome-wide association study datasets for exposure and outcome, mainly derived from the UK Biobank and CKDGen Consortium, with sample sizes ranging from 3,310 to 480,699 individuals of European ancestry. Heritability and genetic correlations among these phenotypes were assessed using linkage disequilibrium score regression (LDSC) and phenotypes with a heritability z-score

Background & Aims: The expression of HBsAg from integrated HBV DNA limits the achievement of functional cure for chronic hepatitis B. Thus, characterising the unique expression and secretion of HBsAg derived from integrated HBV DNA is of clinical significance. Methods: A total of 563 treatment-naive patients and 62 functionally cured patients were enrolled, and HBsAg and HBcAg immunohistochemistry of their liver biopsy tissues was conducted followed by semi-quantitative analysis. Then, based on stratified analysis of HBeAg-positive and -negative patients, long-read RNA sequencing analysis, as well as an in vitro HBV integration model, we explored the HBsAg secretion characteristics of integrated HBV DNA and underlying mechanisms. Results: In contrast to the significantly lower serum HBsAg levels, no significant decrease of intrahepatic HBsAg protein was observed in HBeAg-negative patients, as compared with HBeAg-positive patients. The results of long-read RNA sequencing of liver tissues from patients with chronic HBV infection and in vitro studies using integrated HBV DNA mimicking dslDNA plasmid revealed that, the lower HBsAg secretion efficiency seen in HBeAg-negative patients might be attributed to an increased proportion of preS1 mRNA derived from integrated HBV DNA instead of covalently closed circular DNA. The latter resulted in an increased L-HBsAg proportion and impaired HBsAg secretion. Enhancer 1 (EnhI) in integrated HBV DNA could retarget preS1 (SP1) and preS2 (SP2) promoters to disrupt their transcriptional activity balance. Conclusions: The secretion of HBsAg originating from integrated HBV DNA was impaired. Mechanistically, functional deficiency of core promoter leads to retargeting of EnhI and thus uneven activation of the SP1 over the SP2 promoter, resulting in an increase in the proportion of L-HBsAg. Impact and implications: Integrated hepatitis B virus (HBV) DNA can serve as an important reservoir for HBV surface antigen (HBsAg) expression, and this limits the achievement of a functional cure. This study revealed that secretion efficiency is lower for HBsAg derived from integrated HBV DNA than HBsAg derived from covalently closed circular DNA, as determined by the unique sequence features of integrated HBV DNA. This study can broaden our understanding of the role of HBV integration and shed new light on antiviral strategies to facilitate a functional cure. We believe our results are of great general interest to a broad audience, including patients and patient organisations, the medical community, academia, the life science industry and the public.

Introduction: Shenhua Tablet (SH), a traditional Chinese medicine (TCM) formulation with seven herbs, is widely used in the clinical treatment of Immunoglobulin A (IgA) nephropathy. Despite its effectiveness, the specific active components of SH in vivo remain unidentified, presenting a challenge for further research on its pharmacodynamic material basis. Methods: A rat model of IgA nephropathy was treated with Shenhua Tablet (SH) to evaluate its potential in protecting kidney function. UHPLC-Q/Orbitrap/LTQ MS was utilized to identify active components of SH in vivo under the active condition for intervening IgA. Results: SH significantly ameliorated Thy-1 antibody-induced IgA nephropathy by decreasing glomerular injury, suppressing pro-inflammatory factor secretion, and inhibiting mesangial cell proliferation. 83 kinds of prototypal compounds absorbed into the blood were comprehensively characterized, along with 145 metabolites arising from Phase I and Phase II metabolic reactions. and the metabolic pathways of these metabolites were elucidated for the first time. 10 active components were found to be correlated with the effectiveness of SH, including Atractylenolide I, chlorogenic acid, ferulic acid, salidroside+SO3, calycosin+O, furanodiene, paeoniflorin-H2, germacron+O, formononetin+C6H8O6, and calycosin. Discussion: The results fill the current research gap on the active components of SH and examine its potential renoprotective effects on IgA nephropathy. This study provides valuable references and insights for elucidating the active components and mechanisms of action of SH in treating IgA nephropathy.

IntroductionThe impact of coronavirus disease 2019 (COVID-19) on diabetic kidney disease (DKD) patients in China is not fully understood. This study aimed to investigate infection status in a DKD cohort post-renal biopsy and analyze vaccination and infection rates, as well as symptom severity, across various renal pathologies in DKD patients.MethodsThis epidemiological survey, centered on COVID-19, employed a Chinese DKD and renal puncture follow-up cohort. A customized questionnaire enabled standardized data gathering. It collected data on clinical characteristics, vaccination and infection statuses, and diverse pathological types. The study analyzed the relationship between vaccination and infection statuses across various pathological types, evaluating characteristics and treatment outcomes in patients with infections.ResultsIn total, 437 patients with DKD from 26 Chinese provinces were followed up for a median of 44.6 ± 20 months. COVID-19 infection, vaccination, and novel coronavirus pneumonia (NCP) rates were 73.68%, 59.3%, and 6.63%, respectively. Ten patients with NCP had severe pneumonia or died of COVID-19. Renal pathology revealed that 167 (38.22%) patients had diabetic nephropathy (DN), 171 (39.13%) had non-diabetic renal disease (NDRD), and 99 had DN and NDRD (22.65%). The DN group had the lowest vaccination (54.5%), highest all-cause mortality (3.6%), and highest endpoint rates (34.10%). Compared to patients who were not vaccinated pre-infection (117 cases), vaccinated patients (198 cases) had reduced NCP (6.6% vs. 13.7%), severity (1.0% vs. 3.4%), and endpoint (9.10% vs. 31.60%) rates.ConclusionVaccination can prevent infection and diminish COVID-19 severity in patients with DKD; therefore, increasing vaccination rates is particularly important.Clinical Trial registrationClinicalTrails.gov, NCT05888909.

Diabetic kidney disease (DKD) is one of the leading causes of end-stage renal disease worldwide and significantly increases the risk of premature death due to cardiovascular diseases. Elevated urinary albumin levels are an important clinical feature of DKD. Effective control of albuminuria not only delays glomerular filtration rate decline but also markedly reduces cardiovascular disease risk and all-cause mortality. New drugs for treating DKD proteinuria, including sodium-glucose cotransporter two inhibitors, mineralocorticoid receptor antagonists, and endothelin receptor antagonists, have shown significant efficacy. Auxiliary treatment with proprietary Chinese medicine has also yielded promising results; however, it also faces a broader scope for development. The mechanisms by which these drugs treat albuminuria in patients with DKD should be described more thoroughly. The positive effects of combination therapy with two or more drugs in reducing albuminuria and protecting the kidneys warrant further investigation. Therefore, this review explores the pathophysiological mechanism of albuminuria in patients with DKD, the value of clinical diagnosis and prognosis, new progress and mechanisms of treatment, and multidrug therapy in patients who have type 2 diabetic kidney disease, providing a new perspective on the clinical diagnosis and treatment of DKD.

Objective Non-malignant pleural effusions (NMPE) are common in hospitalised patients. Data on NMPE inpatients are scarce and the factors influencing the prognosis are unknown.Design This was a retrospective cohort study.Setting and participants We conducted a retrospective cohort of inpatients (n=86 645) admitted to the Chinese PLA General Hospital from 2018 to 2021, based on electronic medical records. The observations of 4934 subjects with effusions confirmed by chest radiological tests (CT or X-ray) without a diagnosis of malignancy were followed during admission. Logistic regression was used to analyse organ damage and other factors associated with in-hospital death. Patients were clustered according to their laboratory indicators, and the association between the clustering results and outcomes was studied.Outcome The outcome of this study was in-hospital mortality.Results Among 4934 patients, heart failure + pneumonia + renal dysfunction was the most common (15.12%) among 100 different diagnostic groups. 318 (6.4%) patients died during hospitalisation. Lung (OR 3.70, 95% CI 2.42 to 5.89), kidney (OR 2.88, 95% CI 2.14 to 3.90) and heart (1.80, 95% CI 1.29 to 2.55) damage were associated with in-hospital mortality. Hierarchical clustering of laboratory indicators (estimated glomerular filtration rate, white blood cell count, platelet count, haemoglobin, N-terminal pro-B-type natriuretic peptide, serum albumin) demonstrated the ability to discriminate patients at high risk of in-hospital death.Conclusion Comorbidities and multiorgan failure are the prominent characteristics of NMPE patients, which increase the risk of in-hospital mortality, and comprehensive intervention for specific comorbidity patterns is suggested.

BackgroundPopulation aging is a pivotal trend observed globally, and the exposure to heavy metals can exacerbate the aging process and lead to kidney damage. However, the impact of combined heavy metal exposure on renal function among older individuals remains elusive. Our study employs machine learning techniques to delve into the effects and underlying mechanisms of mixed exposure to heavy metals on the renal function of the aging population.MethodsThis study extracted comprehensive data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2015 and 2020. A total of 3,175 participants aged 60 years and above, with complete information on six metals – lead, cadmium, manganese, cobalt, mercury, and selenium, along with relevant covariates, were included in the study. To assess the impact of single or mixed metal exposure on the renal function of older adult individuals, various statistical techniques were employed: multiple logistic regression, weighted quantitative sum (WQS) regression, Bayesian kernel machine regression (BKMR), and mediation effects analysis.ResultsMultiple logistic regression revealed that selenium and manganese were protective factors for chronic kidney disease (CKD). Cobalt was a risk factor for CKD. High concentrations of lead, cadmium, and cobalt were risk factors for urinary albumin creatinine ratio (ACR). WQS analyses revealed that mixed metal exposure was positively correlated with estimated glomerular filtration rate (eGFR) but negatively correlated with CKD. Selenium and manganese can neutralize the effects of other metals on eGFR. Mixed metal exposure was positively correlated with ACR, with lead and cadmium having a substantial effect. Mediation analysis showed that uric acid (UA) had a mediating effect of 9.7% and −19.7% in the association between mixed metals exposure and proteinuria and CKD, respectively.ConclusionThe impact of heavy metals on renal function in the older adult differs from that of adolescents and adults. This study suggests that elevated levels of mixed metals exposure are linked to proteinuria and CKD, with UA serving as a mediating factor.

Abstract Preparation of kidney tissue single-cell suspensions is the basis of single-cell sequencing, flow cytometry and primary cell culture, but it is difficult to prepare high quality whole kidney single-cell suspensions because of the complex structure of the kidney. We explored a technique called stepwise enzymatic digestion (StE) method for preparing a single-cell suspension of rat whole kidney tissue which contained three main steps. The first step is to cut the kidney into a homogenate. The second step is the digestion of renal tubules using Multi Tissue Dissociation Kit 2 and the last step is the digestion of glomeruli using type IV collagenase. We also compared it with two previous techniques, mechanical grinding method and simple enzymatic digestion method. The StE method had the advantages of high intrinsic glomerular cells and immune cells harvest rate, high singlets rate and high cell viability compared with the other two techniques. In conclusion, the StE method is feasible, highly efficient, and worthy of further research and development.

Abstract Retinoid-related orphan receptor gamma t (RORγt) is the lineage-specific transcription factor for T helper 17 (Th17) cells. Our previous study demonstrated that STAT3 likely participates in the activation of RORCE2 (a novel enhancer of the RORγt gene) in Th17 cells. However, the detailed mechanism is still unclear. Here, we demonstrate that both STAT3 and SOX-5 mediate the enhancer activity of RORCE2 in vitro. Deletion of the STAT3 binding site (STAT3-BS) in RORCE2 impaired RORγt expression and Th17 differentiation, resulting in reduced severity of experimental autoimmune encephalomyelitis (EAE). Mechanistically, STAT3 and SOX-5 bind the RORCE2 region and recruit the chromatin remodeling factor BRG1 to remodel the nucleosomes positioned at this region. Collectively, our data suggest that STAT3 and SOX-5 mediate the differentiation of Th17 cells through the induction of BRG1-mediated chromatin remodeling of RORCE2 in Th17 cells.

Background and Objectives: To evaluate the value of the postvascular phase of contrast-enhanced ultrasound (CEUS) in differentiating between benign and metastatic lymph nodes (LNs) in patients with breast cancer (BC). Materials and Methods: This study retrospectively analyzed 96 suspicious LNs in the lymphatic drainage area of the breast from 90 patients with BC. All LNs were assessed by conventional ultrasound (US) and CEUS following intravenous Sonazoid injection. All LNs underwent puncture biopsy, and pathological results were obtained. The correlations between US and CEUS indicators of LNs and LN metastasis (LNM) were analyzed. Results: Of the 96 LNs, 66 were metastatic. Overall, 80.00% (24/30) of the benign LNs exhibited relative hyper-enhancement in the postvascular phase, whereas 96.97% (64/66) of the metastatic LNs exhibited relative hypo-enhancement (p < 0.001). This CEUS finding was highly predictive of metastasis, with a sensitivity of 96.97%, specificity of 80.00%, positive predictive value of 91.43%, negative predictive value of 92.31%, and accuracy of 91.67%. The mean postvascular phase intensity (MPI) was significantly lower for malignant (median MPI, 12 dB) than for benign (median MPI, 75 dB) LNs. The postvascular phase was more sensitive, specific, and accurate than conventional US or the vascular phase of CEUS for the diagnosis of LNM, with an area under the curve of 0.95 (95% confidence interval: 0.89–0.99). Conclusions: Qualitative and quantitative indicators of the postvascular phase of CEUS provide a reliable diagnostic approach to differentiate benign and metastatic LNs in patients with BC.

BackgroundSodium/glucose cotransporter-2 inhibitors (SGLT2i) are associated with cardiovascular benefits. The aim of this systematic review and meta-analysis is to summarize the influence of SGLT2i on the incidence of acute kidney injury (AKI), and to ascertain whether it is affected by confounding variables such as age, baseline renal function and concurrent use of renin-angiotensin-aldosterone system inhibitors (RAASi) or mineralocorticoid receptor antagonists (MRA).MethodsPubMed, Embase, and Cochrane Library databases were searched for randomized controlled trials comparing the influence of SGLT2i versus placebo/blank treatment on AKI in the adult population. A fixed-effect model was used if the heterogeneity was not significant; otherwise, a randomized-effect model was used.ResultsEighteen studies comprising 98,989 patients were included. Compared with placebo/blank treatment, treatment with SGLT2i significantly reduced the risk of AKI (risk ratio [RR]: 0.78, 95% confidence interval [CI]: 0.71 to 0.84, p < 0.001; I2 = 0%). Subgroup analysis suggested consistent results in patients with diabetes, chronic kidney disease, and heart failure (for subgroup difference, p = 0.32). Finally, univariate meta-regression suggested that the influence of SGLT2i on the risk of AKI was not significantly modified by variables such as age (coefficient: 0.011, p = 0.39), baseline estimated glomerular filtration rate (coefficient: −0.0042, p = 0.13) or concomitant use of RAASi (coefficient: 0.0041, p = 0.49) or MRA (coefficient: −0.0020, p = 0.34).ConclusionSGLT2i may be effective in reducing the risk of AKI, and the effect might not be modified by age, baseline renal function and concurrent use of RAASi or MRA.

Summary: Aging is closely associated with inflammation, which affects renal function reserve (RFR) in the kidneys. This study aims to investigate the impact of reduced RFR reduction on kidney aging and the influence of renal inflammation and RFR reduction on this process. Natural aging rats and those subjected to unilateral nephrectomy (UNX), 1/6 nephrectomy (1/6NX), and unilateral ureteral obstruction (UUO) were observed at 6, 12, 18, and 21 months. Our findings suggest that RFR reduction and renal inflammation can accelerate kidney aging, and inflammation contributes more. Metabolomics analysis revealed alterations in amino acid metabolism contribute to RFR decline. Furthermore, experiments in vitro confirmed the involvement of pentose phosphate pathway (PPP) in promoting aging though inflammation. Our research provides novel insights into for the mechanism of kidney aging and provides indirect support for clinical treatment decisions, such as addressing kidney inflammation, stones, or tumors that may necessitate partial or complete nephrectomy.

IntroductionCardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). This study aimed to develop CVD risk prediction models using machine learning to support clinical decision making and improve patient prognosis.MethodsElectronic medical records from patients with CKD at a single center from 2015 to 2020 were used to develop machine learning models for the prediction of CVD. Least absolute shrinkage and selection operator (LASSO) regression was used to select important features predicting the risk of developing CVD. Seven machine learning classification algorithms were used to build models, which were evaluated by receiver operating characteristic curves, accuracy, sensitivity, specificity, and F1-score, and Shapley Additive explanations was used to interpret the model results. CVD was defined as composite cardiovascular events including coronary heart disease (coronary artery disease, myocardial infarction, angina pectoris, and coronary artery revascularization), cerebrovascular disease (hemorrhagic stroke and ischemic stroke), deaths from all causes (cardiovascular deaths, non-cardiovascular deaths, unknown cause of death), congestive heart failure, and peripheral artery disease (aortic aneurysm, aortic or other peripheral arterial revascularization). A cardiovascular event was a composite outcome of multiple cardiovascular events, as determined by reviewing medical records.ResultsThis study included 8,894 patients with CKD, with a composite CVD event incidence of 25.9%; a total of 2,304 patients reached this outcome. LASSO regression identified eight important features for predicting the risk of CKD developing into CVD: age, history of hypertension, sex, antiplatelet drugs, high-density lipoprotein, sodium ions, 24-h urinary protein, and estimated glomerular filtration rate. The model developed using Extreme Gradient Boosting in the test set had an area under the curve of 0.89, outperforming the other models, indicating that it had the best CVD predictive performance.ConclusionThis study established a CVD risk prediction model for patients with CKD, based on routine clinical diagnostic and treatment data, with good predictive accuracy. This model is expected to provide a scientific basis for the management and treatment of patients with CKD.

Abstract The pregenomic RNA (pgRNA) of hepatitis B virus (HBV) serves not only as a bicistronic message RNA to translate core protein (Cp) and DNA polymerase (Pol), but also as the template for reverse transcriptional replication of viral DNA upon packaging into nucleocapsid. Although it is well known that pgRNA translates much more Cp than Pol, the molecular mechanism underlying the regulation of Cp and Pol translation efficiency from pgRNA remains elusive. In this study, we systematically profiled HBV nucleocapsid- and pgRNA-associated cellular proteins by proteomic analysis and identified TIA-1-related protein (TIAR) as a novel cellular protein that binds pgRNA and promotes HBV DNA replication. Interestingly, loss- and gain-of-function genetic analyses showed that manipulation of TIAR expression did not alter the levels of HBV transcripts nor the secretion of HBsAg and HBeAg in human hepatoma cells supporting HBV replication. However, Ribo-seq and PRM-based mass spectrometry analyses demonstrated that TIAR increased the translation of Pol but decreased the translation of Cp from pgRNA. RNA immunoprecipitation (RIP) and pulldown assays further revealed that TIAR directly binds pgRNA at the 5’ stem-loop (ε). Moreover, HBV replication or Cp expression induced the increased expression and redistribution of TIAR from the nucleus to the cytoplasm of hepatocytes. Our results thus imply that TIAR is a novel cellular factor that regulates HBV replication by binding to the 5’ ε structure of pgRNA to tip the balance of Cp and Pol translation. Through induction of TIAR translocation from the nucleus to the cytoplasm, Cp indirectly regulates the Pol translation and balances Cp and Pol expression levels in infected hepatocytes to ensure efficient viral replication.

Abstract Background and Aims Sex determining region Y related high-mobility group box protein 9 (Sox9) is expressed in a subset of hepatocytes, and it is important for chronic liver injury. However, the roles of Sox9+ hepatocytes in response to the acute liver injury and repair are poorly understood. Methods In this study, we developed the mature hepatocyte-specific Sox9 knockout mouse line and applied three acute liver injury models including PHx, CCl4 and hepatic ischemia reperfusion (IR). Huh-7 cells were subjected to treatment with hydrogen peroxide (H2O2) in order to induce cellular damage in an in vitro setting. Results We found the positive effect of Sox9 deletion on acute liver injury repair. Small heterodimer partner (SHP) expression was highly suppressed in hepatocyte-specific Sox9 deletion mouse liver, accompanied by less cell death and more cell proliferation. However, in mice with hepatocyte-specific Sox9 deletion and SHP overexpression, we observed an opposite phenotype. In addition, the overexpression of SOX9 in H2O2-treated Huh-7 cells resulted in an increase in cytoplasmic SHP accumulation, accompanied by a reduction of SHP in the nucleus. This led to impaired mitochondrial function and subsequent cell death. Notably, both the mitochondrial dysfunction and cell damage were reversed when SHP siRNA was employed, indicating the crucial role of SHP in mediating these effects. Furthermore, we found that Sox9, as a vital transcription factor, directly bound to SHP promoter to regulate SHP transcription. Conclusions Overall, our findings unravel the mechanism by which hepatocyte-specific Sox9 knockout ameliorates acute liver injury via suppressing SHP signaling and improving mitochondrial function. This study may provide a new treatment strategy for acute liver injury in future. Graphical Abstract

Abstract Background Frailty and sarcopenia are prevalent in chronic kidney disease (CKD) populations and could increase the risk for adverse health outcomes. Few studies assess the correlation between frailty, sarcopenia and CKD in non‐dialysis patients. Therefore, this study aimed to determine frailty‐associated factors in elderly CKD stage I–IV patients, expected to early identify and intervene in the frailty of elderly CKD patients. Methods A total of 774 elderly CKD I–IV patients (>60 years of age) recruited from 29 clinical centers in China between March 2017 and September 2019 were included in this study. We established a Frailty Index (FI) model to evaluate frailty risk and verified the distributional property of FI in the study population. Sarcopenia was defined according to the criteria of the Asian Working Group for Sarcopenia 2019. Multinomial logistic regression analysis was used to assess the associated factors for frailty. Results Seven hundred seventy‐four patients (median age 67 years, 66.0% males) were included in this analysis, with a median estimated glomerular filtration rate of 52.8 mL/min/1.73 m2. The prevalence of sarcopenia was 30.6%. The FI exhibited a right‐skewed distribution. The age‐related slope of FI was 1.4% per year on a logarithmic scale (r2 = 0.706, 95% CI 0.9, 1.8, P

BackgroundIncreased arterial stiffness and low handgrip strength (HGS) are associated with poor health outcomes and are a severe health risk for older adults. However, there is limited evidence and mixed results on whether there is an association between them. Therefore, this study focused on the association between arterial stiffness and HGS in relatively healthy older adults in Beijing, China.MethodsIn 2016, 2,217 adult volunteers were recruited in Beijing. Brachial-ankle pulse wave velocity (baPWV) and the ankle-brachial index were measured using an automatic vascular profiling system. Carotid artery intima-media thickness and common carotid artery-internal diameter (CCAID) were evaluated using Doppler ultrasound, and HGS was measured with a dynamometer. Low HGS was determined using the Asian Sarcopenia Working Group 2019 criteria. Multivariate linear and logistic regressions evaluated the relationship between arterial stiffness and HGS.ResultsUltimately, 776 relatively healthy older adults (mean age 69.05 ± 6.46 years) were included. Based on the AWGS2019 criteria, 137 participants were defined as having low HGS. Compared to the normal HGS group, the low HGS group was older and had higher baPWV (p

IntroductionThere are no standardized assessment criteria for selecting nutritional risk screening tools or indicators to assess reduced muscle mass (RMM) in the Global Leadership Initiative on Malnutrition (GLIM) criteria. We aimed to compare the consistency of different GLIM criteria with Subjective Global Assessment (SGA) and protein-energy wasting (PEW).MethodsIn this study, nutritional risk screening 2002 first four questions (NRS-2002-4Q), Nutritional Risk Screening 2002 (NRS-2002), Malnutrition Universal Screening Tool (MUST), and Mini-Nutritional Assessment Short-Form (MNA-SF) tools were used as the first step of nutritional risk screening for the GLIM. The RMM is expressed using different metrics. The SGA and PEW were used to diagnose patients and classify them as malnourished and non-malnourished. Kappa (κ) tests were used to compare the concordance between the SGA, PEW, and GLIM of each combination of screening tools.ResultsA total of 157 patients were included. Patients with Chronic kidney disease (CKD) stage 1–3 accounted for a large proportion (79.0%). The prevalence rates of malnutrition diagnosed using the SGA and PEW were 18.5% and 19.7%, respectively. The prevalence of GLIM-diagnosed malnutrition ranges from 5.1% to 37.6%, depending on the different screening methods for nutritional risk and the different indicators denoting RMM. The SGA was moderately consistent with the PEW (κ = 0.423, p

To improve the strength of red sandstone roadbed and elevate the utilization rate of solid waste materials, this study explored the enhancement of red sandstone using three types of solid waste materials: slag-micronized powder, fly ash, and waste incineration bottom ash. The mechanical properties of various solid waste materials, including compaction, unconfined compressive strength, and disintegration test results, were evaluated to assess the enhancement of red sandstone. Additionally, scanning electron microscopy was employed to analyze the microstructural alterations induced by these materials. The results indicated that the optimal moisture content of fly ash-improved soil and slag micropowder-improved soil gradually increased, whereas the maximum dry density decreased with an increase in the solid waste material admixture. At an 11% dosage of waste incineration bottom ash, the maximum unconfined compressive strength reached 2,386 kPa. The soil–water characteristic curves for the different solid waste materials exhibited a similar overall trend. Notably, the disintegration rate significantly slowed at a 9% dosage of fly ash, whereas at 11% dosage of waste incineration bottom ash, the disintegration rate nearly reached 0%, demonstrating optimal improvement effects. This suggested that the bottom ash effectively enhanced the water stability performance of red sandstone and increased its resistance to disintegration. Microscopic analysis revealed that slag micropowder and fly ash were comparatively less effective in enhancing red sandstone. The waste incineration bottom ash efficiently generated substantial cementitious material to fill pores. In summary, employing 11% waste incineration bottom ash was recommended to enhance red sandstone in practical roadbed improvement projects.

The high-strength red sandstone in its natural state is subjected to significant strength deterioration under alternating wet and dry conditions, which can cause many catastrophic problems in the process of engineering construction. It is important to deeply understand the damage mechanism of red sandstone under the action of dry and wet cycles. Therefore, this paper explores the mechanism of red sandstone’s uniaxial deformation and failure through indoor uniaxial compression tests, studies the damage to the microstructure of red sandstone under wet–dry cycles using scanning electron microscopy, and establishes a damage variable based on fractal dimension. The results show that with the increase of wet–dry cycles, the peak stress of red sandstone shows a decreasing trend, and the minimum peak stress is 17.3 MPa, which is a 46.62% decrease compared to the sample with 0 wet–dry cycles. During the wet–dry cycle process, there are four deformation characteristics of red sandstone samples, namely, crack compression, crack extension, progressive fracture, and crack penetration. SEM images show that the porosity, pore area, and fractal dimension all show a nonlinear increase, and the maximum damage variable can reach 10.41%. The research results can provide guidance for engineering design and slope failure mechanism research in red sandstone areas.

ContextDiabetic retinopathy (DR) and diabetic nephropathy (DN), are major microvascular complications of diabetes. DR is an important predictor of DN, but the relationship between the severity of DR and the pathological severity of diabetic glomerulopathy remains unclear.ObjectiveTo investigate the relationship between severity of diabetic retinopathy (DR) and histological changes and clinical indicators of diabetic nephropathy (DN) in patients with type 2 diabetes mellitus (T2DM)MethodsPatients with T2DM (n=272) who underwent a renal biopsy were eligible. Severity of DR was classified as non-diabetic retinopathy, non-proliferative retinopathy, and proliferative retinopathy (PDR). Relationship between DN and DR and the diagnostic efficacy of DR for DN were explored.ResultsDN had a higher prevalence of DR (86.4%) and DR was more severe. The sensitivity and specificity of DR in DN were 86.4% and 78.8%, while PDR was 26.4% and 98.5%, respectively. In DN patients, the severity of glomerular lesions (p=0.001) and prevalence of KW nodules (p

The use of human aging markers, which are physiological, biochemical and molecular indicators of structural or functional degeneration associated with aging, is the fundamental basis of individualized aging assessments. Identifying methods for selecting markers has become a primary and vital aspect of aging research. However, there is no clear consensus or uniform principle on the criteria for screening aging markers. Therefore, we combine previous research from our center and summarize the criteria for screening aging markers in previous population studies, which are discussed in three aspects: functional perspective, operational implementation perspective and methodological perspective. Finally, an evaluation framework has been established, and the criteria are categorized into three levels based on their importance, which can help assess the extent to which a candidate biomarker may be feasible, valid, and useful for a specific use context.

Abstract Background Pericyte-myofibroblast transition (PMT) has been confirmed to contribute to renal fibrosis in several kidney diseases, and transforming growth factor-β1 (TGF-β1) is a well-known cytokine that drives PMT. However, the underlying mechanism has not been fully established, and little is known about the associated metabolic changes. Methods Bioinformatics analysis was used to identify transcriptomic changes during PMT. PDGFRβ + pericytes were isolated using MACS, and an in vitro model of PMT was induced by 5 ng/ml TGF-β1. Metabolites were analyzed by ultraperformance liquid chromatography (UPLC) and tandem mass spectrometry (MS). 2-Deoxyglucose (2-DG) was used to inhibit glycolysis via its actions on hexokinase (HK). The hexokinase II (HKII) plasmid was transfected into pericytes for HKII overexpression. LY294002 or rapamycin was used to inhibit the PI3K-Akt-mTOR pathway for mechanistic exploration. Results An increase in carbon metabolism during PMT was detected through bioinformatics and metabolomics analysis. We first detected increased levels of glycolysis and HKII expression in pericytes after stimulation with TGF-β1 for 48 h, accompanied by increased expression of α-SMA, vimentin and desmin. Transdifferentiation was blunted when pericytes were pretreated with 2-DG, an inhibitor of glycolysis. The phosphorylation levels of PI3K, Akt and mTOR were elevated during PMT, and after inhibition of the PI3K-Akt-mTOR pathway with LY294002 or rapamycin, glycolysis in the TGF-β1-treated pericytes was decreased. Moreover, PMT and HKII transcription and activity were blunted, but the plasmid-mediated overexpression of HKII rescued PMT inhibition. Conclusions The expression and activity of HKII as well as the level of glycolysis were increased during PMT. Moreover, the PI3K-Akt-mTOR pathway regulates PMT by increasing glycolysis through HKII regulation.

Abstract Considering the high prevalence and the lack of targeted pharmacological management of acute kidney injury (AKI), the search for new therapeutic approaches for it is in urgent demand. Mesenchymal stem cells (MSCs) have been increasingly recognized as a promising candidate for the treatment of AKI. However, clinical translation of MSCs-based therapies is hindered due to the poor retention and survival rates as well as the impaired paracrine ability of MSCs post-delivery. To address these issues, a series of strategies including local administration, three-dimensional culture, and preconditioning have been applied. Owing to the emergence and development of these novel biotechnologies, the effectiveness of MSCs in experimental AKI models is greatly improved. Here, we summarize the different approaches suggested to optimize the efficacy of MSCs therapy, aiming at promoting the therapeutic effects of MSCs on AKI patients.

Abstract Background Fabry disease is a rare hereditary disease involving multiple organs, and there are few reports on how the initial manifestations and renal involvement of these patients with classical and late-onset phenotype evolve with sexes and ages. To improve clinicians’ understanding of Fabry disease and avoid misdiagnoses by discussing the initial manifestations, first medical specialties visited and renal involvement development in patients. Methods This study collected relevant data from 311 Chinese Fabry disease patients (200 males, 111 females) and descriptive statistical analysis was used to analyze the evolution of the initial manifestations and renal involvement of patients with classical and late-onset phenotype at different sexes and ages. Results Regarding the age at manifestation onset, age at the first medical specialty visited and age at the diagnosis of Fabry disease, males were earlier than females, and males with classical phenotype were earlier than males with late-onset and females with classical phenotype. In both male and female patients, the initial manifestations of classical patients were mainly acroparesthesia, and the first medical specialty visited were mainly pediatrics and neurology. The initial manifestations of late-onset patients were mainly renal and cardiovascular involvement, and the first medical specialty visited were mainly nephrology and cardiology. In classical patients, both male and female, the initial manifestations of the preschool and the juvenile groups were mainly acroparesthesia, and the frequency of renal and cardiovascular involvement in the young group was higher than that in the preschool and juvenile groups. There was no obvious renal involvement in the preschool group, renal involvement was most common in the young group and the middle-aged and elderly group. Proteinuria can appear in classical male patients as early as approximately 20 years, and renal insufficiency can occur at approximately 25 years. With age, over 50% of classical male patients can develop varying degrees of proteinuria at the age of 25 and renal insufficiency at the age of 40. 15.94% of the patients progressed to dialysis or kidney transplantation, mainly classical males. Conclusions The initial manifestation of Fabry disease is affected by sex, age and classical/late-onset phenotype. The initial manifestations were mainly acroparesthesia and the frequency and degree of renal involvement increased gradually with aging in classical male patients.

Abstract Thyroid cancer patients have a good prognosis, and their long survival increases the likelihood of developing a second primary tumor. Meanwhile, pancreatic cancer (PC) has a poor prognosis and therapeutic efficacy. However, the association between prior thyroid cancer and the subsequent PC prognosis is unknown. Herein, we selected pathologically diagnosed PC patients older than 17 between 2010 and 2015 from the SEER database. We used propensity score matching (PSM) to reduce confounding factors between groups and matched each PC patient with a history of thyroid cancer with 10 PC patients without a history of thyroid cancer. Finally, we selected 103 PC patients with prior thyroid cancer and 1030 PC patients without prior thyroid cancer. Then, we analyzed the factors influencing the overall survival (OS) and the cancer-specific survival (CSS) of PC patients. The median overall survival of PC patients with and without a history of thyroid cancer was 12 and 9 months, respectively. The history of thyroid cancer in PC patients reduced the PC-specific mortality (p

BackgroundChatbots have the potential to enhance health care interaction, satisfaction, and service delivery. However, data regarding their acceptance across diverse patient populations are limited. In-depth studies on the reception of chatbots by patients with chronic autoimmune inflammatory diseases are lacking, although such studies are vital for facilitating the effective integration of chatbots in rheumatology care. ObjectiveWe aim to assess patient perceptions and acceptance of a chatbot designed for autoimmune inflammatory rheumatic diseases (AIIRDs). MethodsWe administered a comprehensive survey in an outpatient setting at a top-tier rheumatology referral center. The target cohort included patients who interacted with a chatbot explicitly tailored to facilitate diagnosis and obtain information on AIIRDs. Following the RE-AIM (Reach, Effectiveness, Adoption, Implementation and Maintenance) framework, the survey was designed to gauge the effectiveness, user acceptability, and implementation of the chatbot. ResultsBetween June and October 2022, we received survey responses from 200 patients, with an equal number of 100 initial consultations and 100 follow-up (FU) visits. The mean scores on a 5-point acceptability scale ranged from 4.01 (SD 0.63) to 4.41 (SD 0.54), indicating consistently high ratings across the different aspects of chatbot performance. Multivariate regression analysis indicated that having a FU visit was significantly associated with a greater willingness to reuse the chatbot for symptom determination (P=.01). Further, patients’ comfort with chatbot diagnosis increased significantly after meeting physicians (P

Introduction Peritoneal dialysis (PD)-related peritonitis is a serious complication of PD. Improving the diagnostic rate of peritonitis pathogens may substantially benefit peritonitis patients.Methods The study was conducted in the People’s Liberation Army (PLA) General Hospital from 1 June 2021 to 31 May 2022. Information about peritonitis, culture and metagenomic next-generation sequencing (mNGS) results and so on were collected. Patients were divided into antibiotic-use and antibiotic-free groups. The culture and mNGS results were compared using the paired χ2 test.Results Data from 26 patients with peritonitis were collected. 50% of the patients had used antibiotics before samples were obtained (antibiotic-use group). The positivity rate using culture was 92.3% (12 cases) in the antibiotic-free group and 38.5% (5 cases) in the antibiotic-use group (p = 0.011). However, the positivity rate using mNGS was 92.3% (12 cases) regardless of whether antibiotics were used (p = 1.000). After revising the mNGS results, the positivity rate was 84.6% (11 cases) in both groups (p = 1.000). A significant difference between culture and mNGS results of all groups was observed (p = 0.039). The difference no matter between culture and mNGS (p = 0.016) or between culture and modified mNGS (p = 0.031) of the antibiotic-use group was observed.Conclusion For patients with PD-related peritonitis who previously received antibiotics, mNGS is suggested. For other patients, mNGS testing can be performed, but the results should be interpreted with caution. Much more research should be done to identify a powerful and ideal tool to detect pathogens underlying PD-related peritonitis.

AbstractObjectives Tracheobronchial Talaromyces marneffei (T. marneffei) infections among non-HIV-infected patients are rare. To improve understanding, we analysed the clinical features, immune mechanisms, treatment, and prognosis.Methods Data on hospitalized patients with tracheobronchial T. marneffei infections from September 2013 to May 2022 were collected. The clinical and imaging features were analysed.Results Nineteen patients were enrolled, with a median age of 52 years (45–62 years). The most common symptoms were cough, expectoration, fever, weight loss, and anaemia. The total white blood cell and neutrophil counts, erythrocyte sedimentation rate, C-reactive protein, procalcitonin and globulin were increased, and the serum albumin levels were decreased. Chest CT manifestations included patchy shadows, masses, obstructive atelectasis, cavities, pleural effusion, and hilar and mediastinal lymphadenopathy. The fibreoptic bronchoscopy findings included masses, polyps or nodules with mucosal oedema, hypertrophic bulges, lumen stenosis or obstruction, and purulent secretions. T. marneffei infection was confirmed in 10 patients by positive culture, in five by both culture and metagenomic next-generation sequencing (mNGS), in two by mNGS, in one by culture and pathology and in 1 by histopathology. BALF (15/19, 78.9%) had the highest culture positive rate, followed by sputum (3/19), bronchial mucosa (1/1), lung biopsy (1/2); 36.8% of the patients were coinfected with other pathogens. For induction therapy, 7, 6, 2, and 4 patients received voriconazole, amphotericin B, voriconazole combined with amphotericin B, and fluconazole therapy, respectively, and 26.3% received treatment combined with nebulization and/or administration of amphotericin B under fibreoptic bronchoscopy. Four patients were treated for underlying diseases or coinfection, 31.6% were cured, 42.1% improved, and 26.3% died.Conclusions T. marneffei infection is common in the tracheobronchial airway tissue or secretions, and bronchoscopy has important diagnostic and treatment value. Antifungal therapy, including systemic therapy, involves triazoles and amphotericin administration, and aerosol inhalation and administration of amphotericin B under bronchoscopy are important.

AbstractBackground The long-term mortality of kidney transplantation patients with atypical hemolytic uremic syndrome remains high, and the efficacy of the main treatment eculizumab is still controversial.Objective A comprehensive systematic review and meta-analysis of clinical trials using eculizumab in renal transplant patients with atypical hemolytic uremic syndrome was conducted to evaluate the efficacy of this therapy and its impact on renal function.Methods A comprehensive systematic search was conducted across multiple reputable databases, including Ovid (MEDLINE, EMBASE), PubMed, and the Cochrane Library (since database inception), to identify relevant studies exploring the use of eculizumab in patients with atypical hemolytic uremic kidney transplantation. Various renal function parameters, such as dialysis, rejection, glomerular filtration rate, serum creatinine, lactate dehydrogenase, and platelet count, along with patient relapse rates, were extracted and summarized using a combination of robust statistical methods, including fixed effects, random effects, and general inverse variance methods.Result Eighteen trials with 618 subjects were analyzed. Our analysis suggests that the use of eculizumab is associated with a reduced likelihood of AHUS recurrence (odds ratio (OR) = 0.05, 95% CI: 0.00–0.13), as well as a significant reduction in the need for dialysis (odds ratio (OR) = 0.13, 95% CI: 0.01–0.32). Additionally, eculizumab treatment led to lower serum creatinine levels (mean differences (MD) = 126.931μmoI/L, 95% CI: 115.572μmoI/L–138.290μmoI/L) and an improved glomerular filtration rate (mean differences (MD) = 59.571 ml/min, 95% CI: 57.876 ml/min–61.266 mL/min). Our results also indicate that the use of eculizumab reduces the likelihood of rejection (odds ratio (OR) = 0.09, 95% CI: 0.01–0.22). Furthermore, the drug was effective in improving platelet counts (×10∧9/L) (mean differences (MD) = 163.421, 95% CI: 46.998–279.844) and lactate dehydrogenase levels (mean differences (MD) = 336.608 U/L, 95% CI: 164.816 U/L–508.399 U/L).Conclusions Based on the meta-analysis, treatment with eculizumab can reduce dialysis rates and improve patients’ quality of life by enhancing renal function.

Abelmoschus manihot (A.manihot) is a herbaceous flowering medicinal plant and flavonoids are its main pharmacological active ingredients. A.manihot is listed in the 2020 edition of the Chinese Pharmacopoeia for the treatment of chronic kidney disease (CKD). A.manihot significantly reduces proteinuria in CKD, and the effectiveness and safety of A.manihot in the treatment including primary glomerulonephropathy and diabetic kidney disease (DKD) have been proved by several randomized controlled trials (RCT). Emerging pharmacological studies have explored the potential active small molecules and the underlying mechanisms in A.manihot. The active constituents of A.manihot are mainly seven flavonoids, including hibifolin, hyperoside, isoquercetin, rutin, quercetin, myricetin, and quercetin-3-O-robinobioside. The mechanisms of action mainly include alleviating renal fibrosis, reducing the inflammatory response and decreasing the apoptosis of podocytes. In this review, we summarize the updated information of active components and molecular mechanisms of A.manihot on chronic kidney disease.

Abstract With the development and introduction of immune checkpoint inhibitors (ICIs) in cancer patients, immune‐related side effects have increasingly attracted attention. However, the risks of immune‐related renal toxicity are poorly characterized. In this study, we performed a network meta‐analysis (NMA) of ICI‐related randomized clinical trials (RCTs) to elucidate the comparative risk of acute kidney injury (AKI) in cancer patients receiving different ICIs. We also sought to identify other factors potentially affecting the risk of AKI. PubMed and EMBASE were searched for peer‐reviewed trial reports published between January 2000 and May 2021. Eligible studies were RCTs studying ICIs in cancer patients and reporting AKI data. We performed a frequentist NMA to evaluate the risk ratios for grade 1‐5 and grade 3‐5 AKI between the treatment groups. We also assessed the absolute incidence of AKI in the ICI‐containing arm using traditional direct meta‐analysis. Once significant heterogeneity was detected in a traditional direct meta‐analysis, multivariable meta‐regression analysis was applied to identify factors that significantly affected the absolute incidence of AKI. A total of 85 RCTs were included in this study. In the NMA for the risk of grade 1‐5 and 3‐5 AKI, ipilimumab showed a significantly higher risk than avelumab and durvalumab, whereas 1 mg/kg nivolumab plus 3 mg/kg ipilimumab (N1I3) showed a significantly higher risk than other groups. In terms of treatment ranking, durvalumab ± low‐dose tremelimumab and avelumab were consistently among the top three safest treatments for grade 1‐5 or 3‐5 AKI, whereas N1I3, ipilimumab and tremelimumab were consistently among the top three treatments with the highest risk for grade 1‐5 or 3‐5 AKI. Compared with other cancers, renal cell carcinoma and urothelial carcinoma showed a significantly higher risk of AKI. The incidence of AKI was significantly higher with ICI+chemotherapy than with ICI monotherapy. In this NMA involving large‐scale up‐to‐date ICI trials, we demonstrated the comparative safety of existing ICI drugs for grade 1‐5 and grade 3‐5 AKI. Based on data from the ICI arms of these trials, we also revealed several potential risk factors for immune‐related AKI, including tumor type and treatment paradigm.

Chronic hepatitis B virus (HBV) infection due to perinatal mother-to-infant transmission (MTIT) remains a serious global public health problem. It has been shown that intrauterine exposure to HBV antigens might account for the MTIT-related chronic infection. However, whether hepatitis B surface antigen (HBsAg) intrauterine exposure affected the offspring’s immune response against HBV and MTIT of HBV has not been fully clarified. In this study, we investigated the effects and the potential mechanisms of the HBsAg intrauterine exposure on the persistence of HBV replication using a solely HBsAg intrauterine exposure mice model. Our results revealed that solely HBsAg intrauterine exposure significantly accelerated the clearance of HBV when these mice were hydrodynamically injected with pBB4.5-HBV1.2 plasmids after birth, which may be due to the increased number of HBs-specific CD8+ T cells and interferon-gamma secretion in the liver of mice. Mechanismly, HBsAg intrauterine exposure activated antigen-presenting dendritic cells, which led to the generation of antigen-specific cellular immunological memory. Our data provide an important experimental evidence for the activation of neonatal immune response by HBsAg intrauterine exposure.