IPNA clinical practice recommendations for the diagnosis and management of children with IgA nephropathy and IgA vasculitis nephritis.

IgA nephropathy and IgA vasculitis with nephritis, albeit rare, represent two relatively frequent glomerular conditions in childhood. Compared to adults, pediatric IgA nephropathy has a more acute presentation, most frequently with synpharyngitic macrohematuria and histologically with more intense inflammation and less intense chronic damage. Management of these conditions is controversial and supported by little high-quality evidence. The paucity of evidence is due to the disease heterogeneity, its inter-ethnic variability, and the difficulty of extrapolating data from adult studies due to the peculiarities of the condition in children. IgA vasculitis with nephritis is a kidney manifestation of a systemic disorder, typical of the pediatric age, in which both the diagnosis of kidney involvement and its management are poorly defined, and an interdisciplinary approach is crucial. Both conditions can have a profound and long-lasting impact on kidney function and the global health of affected children. The International Pediatric Nephrology Association has therefore convened a diverse international group of experts from different disciplines to provide guidance on the recommended management of these conditions in children and to establish common definitions and define priorities for future high-quality, evidence-based collaborative studies for the benefit of children.

Distribution and diversity of ticks determined by environmental factors in Ningxia, China.

Ticks are important vectors of zoonotic pathogens, and represent an increasing threat for human and animal health. Considering the complex natural environments of Ningxia Hui Autonomous Region, China, we expect the diverse tick species in this region. Here, we conduct a field survey on parasitic and host-seeking ticks. A total of 10,419 ticks were collected, which belonged to nine species of four genera. There were significant differences in terms of vegetation index, altitude, and seven climatic factors among the four tick genera -Hyalomma, Dermacentor, Haemaphysalis, and Ixodes, except between Haemaphysalis and Ixodes, where no significant differences were observed in these factors. The ecological niche modelling revealed that the suitable habitats for Hyalomma asiaticum was in the northwest Ningxia, with annual ground surface temperature as the most important factor. The suitable area for Dermacentor nuttalli was in the southwest and eastern regions of Ningxia with elevation as the highest contribution. D. silvarum was best suited to the southern Ningxia also with elevation as the most important factor. The four tick species including Haemaphysalis longicornis, Hae. qinghaiensis, Hae. japonica, and Ixodes persulcatus were best suited to the southernmost Ningxia with annual precipitation as the main factors for Hae. longicornis and elevation for the other three ticks. The results of predicted potential distribution of different tick species provide a scientific basis for the prevention and control of ticks and tick-borne diseases in the region. Furthermore, the subsequent impacts of the Greening Program to regain forests and grasslands from former agricultural lands in Ningxia on tick population dynamics deserve further investigation.

Estrogen receptor is involved in the osteoarthritis mediated by Atg16L1-NLRP3 activation.

OBJECTIVES: This study aims to explore the mechanisms of dual regulation of osteoarthritis (OA) progression by the involvement of estrogen receptor (ER) in autophagy and inflammation. MATERIALS AND METHODS: Bioinformatics methods were used to explore the relationship among associated genes. Western blot assays were used to detect related protein expression of OA in C28I2 and induced OA cellular model. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis were used to detect OA related gene expression in C28I2 and induced OA cellular model. Co-immunoprecipitation (CO-IP) analysis were used to verify the direct interaction between ER and NOD-like receptor thermal protein domain associated protein 3 (NLRP3). RESULTS: The C28I2 cellular model of OA was induced by interleukin-1ß (IL-1ß). The small interfering ribonucleic acid (SiRNA)-mediated knockdown of autophagy-related 16 like 1 (ATG16L1) in C28I2 decreased the expression of MAP1LC3B (LC3B) and NLRP3. Besides, ER-beta (ERß) agonist changed the gene expression of NLRP3 and ATG16L1. Moreover, CO-IP analysis indicated the direct interaction between ER and NLRP3. CONCLUSION: Our study results revealed that ATG16L1, NLRP3, and IL-1ß interacted closely and ERß was involved in OA process by affecting autophagy and inflammatory activation.

Application of the updated International IgA Nephropathy Prediction Tool in children one or two years post-biopsy.

The pediatric International IgA Nephropathy (IgAN) Prediction Tool comprises two models with and without ethnicity and is the first method to predict the risk of a 30% decline in estimated glomerular filtration rate (eGFR) or kidney failure in children at the time of biopsy using clinical risk factors and Oxford MEST histology scores. However, it is unknown if the Prediction Tool can be applied after a period of observation post-biopsy. Using an international multi-ethnic cohort of 947 children with IgAN, 38% of whom were followed into adulthood, the Prediction Tool was updated for use one year after biopsy. Compared to the original pediatric Prediction Tool, the updated post-biopsy Prediction Tool had a better model fit with higher R2D (51%/50% vs 20%), significant increase in 4-year C-statistics (0.83 vs 0.73/0.69, ΔC 0.09 [95% confidence interval 0.07-0.10] and ΔC 0.14 [0.12-0.15]) and better 4-year calibration with lower integrated calibration indices (0.74/0.54 vs 2.45/1.01). Results were similar after internal validation and when the models were applied two years after biopsy. Trajectories of eGFR after a baseline one year post-biopsy were non-linear and those at higher predicted risk started with a lower eGFR and experienced a more rapid decline over time. In children, eGFR had a variable rate of increase until 15-18 years old and then decreased linearly with a more rapid decline in higher risk groups that was similar to young adults of comparable risk. Thus, the original pediatric Prediction Tool should be used in children at the time of biopsy, and the updated pediatric Prediction Tool should be used to re-evaluate risk one or two years after biopsy.

Fabricating a high-performance anode by coating a carbon layer on a yolk-shell bimetallic selenide microsphere for enhanced lithium storage.

The rational synthesis of an electrode material with a highly active and stable architecture is very critical to achieving high-performance electrochemical energy storage. Herein, N-doped carbon restricting yolk-shell CoSe2/Ni3Se4 (CoSe2/Ni3Se4@NC) flower-like microspheres were successfully synthesized from solid CoNi-glycerate microspheres using a coating technology as an anode material for lithium-ion batteries (LIBs). The unique yolk-shell CoSe2/Ni3Se4@NC microspheres with hierarchical pores can increase the contact area with the electrolyte and provide enough transfer channels for the diffusion of Li+. The carbon layer on the surface of CoSe2/Ni3Se4@NC can not only improve the conductivity of the electrode but also provide the protective effect of active nanosheets during the process of synthesis, avoiding the overall structure collapse during the charge/discharge process of LIBs. Benefiting from the high conductivity, hollow structure, and elastic NC shell bestowed by the unique architecture, the yolk-shell CoSe2/Ni3Se4@NC anode shows excellent lithium storage performances, such as an excellent reversible specific capacity of 319 mA h g-1 at a current density of 1000 mA g-1 after 500 cycles and excellent cycling stability. This synthesis strategy provides a new way to optimize the lithium storage performance of transition metal compound electrode materials, which is helpful to the design of the next generation of high-performance LIBs.

Inhibition of receptor interacting protein kinase-1 (RIPK1) in the treatment of murine lupus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a type of autoimmune disease that involves multiple organs involved as well as cytokine dysregulation. The treatment of SLE is still challenging due to the side effects of the different drugs used. Receptor-interacting protein kinase 1 (RIPK1) is a kinase involved in T cell homeostasis and autoinflammation. Although clinical trials have shown that RIPK1 inhibition exhibits significant efficacy in different autoimmune diseases, its role in SLE remains unclear. METHODS: MRL/lpr lupus-prone mice received RIPK1 inhibitor ZJU37 or vehicle intraperitoneally for 10 weeks. A BM12-induced chronic graft-versus-host-disease (cGVHD) lupus-like model was introduced in RIPK1 D138N mice or C57BL/6 mice. Nephritis, serum autoantibody levels, dysregulation of adaptive immune response and cytokines were compared in treated and untreated mice. RESULTS: ZJU37 alleviated the clinical features of the MRL/lpr mice including nephritis and anti-dsDNA antibody production. In addition, ZJU37 treatment reduced the proportion of double-negative T cells in the spleen and the cytokines of TNFα, IFN-γ, IL-6, IL-17 and IL-1ß in the serum. Moreover, RIPK1 D138N mice were able to prevent the cGVHD lupus-like model from SLE attack, manifesting as anti-dsDNA antibody production, the proliferation of germinal centre B cells, plasma cells, and T follicular helper cells as well as IgG and C3 deposits in kidneys. CONCLUSION: RIPK1 inhibition has a protective effect in the mouse model of SLE and can potentially become a new therapeutic target for SLE in humans.

Insights into the Roles of Natural Killer Cells in Osteoarthritis.

Osteoarthritis (OA) is now widely acknowledged as a low-grade inflammatory condition, in which the intrinsic immune system plays a significant role in its pathogenesis. While the involvement of macrophages and T cells in the development of OA has been extensively reviewed, recent research has provided mounting evidence supporting the crucial contribution of NK cells in both the initiation and advancement of OA. Accumulated evidence has emerged in recent years indicating that NK cells play a critical role in OA development and progression. This review will outline the ongoing understanding of the utility of NK cells in the etiology of OA, focusing on how NK cells interact with chondrocytes, synoviocytes, osteoclasts, and other immune cells to influence the course of OA disease.

Deep learning model to predict lupus nephritis renal flare based on dynamic multivariable time-series data.

OBJECTIVES: To develop an interpretable deep learning model of lupus nephritis (LN) relapse prediction based on dynamic multivariable time-series data. DESIGN: A single-centre, retrospective cohort study in China. SETTING: A Chinese central tertiary hospital. PARTICIPANTS: The cohort study consisted of 1694 LN patients who had been registered in the Nanjing Glomerulonephritis Registry at the National Clinical Research Center of Kidney Diseases, Jinling Hospital from January 1985 to December 2010. METHODS: We developed a deep learning algorithm to predict LN relapse that consists of 59 features, including demographic, clinical, immunological, pathological and therapeutic characteristics that were collected for baseline analysis. A total of 32 227 data points were collected by the sliding window method and randomly divided into training (80%), validation (10%) and testing sets (10%). We developed a deep learning algorithm-based interpretable multivariable long short-term memory model for LN relapse risk prediction considering censored time-series data based on a cohort of 1694 LN patients. A mixture attention mechanism was deployed to capture variable interactions at different time points for estimating the temporal importance of the variables. Model performance was assessed according to C-index (concordance index). RESULTS: The median follow-up time since remission was 4.1 (IQR, 1.7-6.7) years. The interpretable deep learning model based on dynamic multivariable time-series data achieved the best performance, with a C-index of 0.897, among models using only variables at the point of remission or time-variant variables. The importance of urinary protein, serum albumin and serum C3 showed time dependency in the model, that is, their contributions to the risk prediction increased over time. CONCLUSIONS: Deep learning algorithms can effectively learn through time-series data to develop a predictive model for LN relapse. The model provides accurate predictions of LN relapse for different renal disease stages, which could be used in clinical practice to guide physicians on the management of LN patients.

Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus Nephritis.

The Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Management of Glomerular Diseases was published in 2021. Since then, the pace of drug development for glomerular diseases has accelerated, due in large part to rapidly accumulating insights into disease pathogenesis from genetic and molecular studies of afflicted patients. To keep the Glomerular Diseases Guideline as current as possible, KDIGO made a commitment to the nephrology community to provide periodic updates, based on new developments for each disease. After the 2021 guideline was published, two novel drugs received regulatory approval for the management of lupus nephritis, leading to the first KDIGO guideline update. Herein, an executive summary of the most important guideline changes from the Lupus Nephritis chapter is provided as a quick reference.

Combined ATAC-seq, RNA-seq, and GWAS analysis reveals glycogen metabolism regulatory network in Jinjiang oyster ( Crassostrea ariakensis).

Glycogen serves as the principal energy reserve for metabolic processes in aquatic shellfish and substantially contributes to the flavor and quality of oysters. The Jinjiang oyster ( Crassostrea ariakensis) is an economically and ecologically important species in China. In the present study, RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) were performed to investigate gene expression and chromatin accessibility variations in oysters with different glycogen contents. Analysis identified 9 483 differentially expressed genes (DEGs) and 7 215 genes with significantly differential chromatin accessibility (DCAGs) were obtained, with an overlap of 2 600 genes between them. Notably, a significant proportion of these genes were enriched in pathways related to glycogen metabolism, including "Glycogen metabolic process" and "Starch and sucrose metabolism". In addition, genome-wide association study (GWAS) identified 526 single nucleotide polymorphism (SNP) loci associated with glycogen content. These loci corresponded to 241 genes, 63 of which were categorized as both DEGs and DCAGs. This study enriches basic research data and provides insights into the molecular mechanisms underlying the regulation of glycogen metabolism in C. ariakensis.

Hybrid Ascharite/Reduced Graphene Oxide with Polysulfide Adsorption Host for Advanced Lithium-Sulfur Batteries.

Balancing the adsorption of lithium-polysulfide intermediates on polar host material surfaces and the effect of their electronic conductivity in the subsequent oxidation and reduction kinetics of electrochemical reactions is necessary and remains a challenge. Herein, we have evaluated the role of polarity and conductivity in preparing a series of ascharite/reduced graphene oxide (RGO) aerogels by dispersing strong polar ascharite nanowires of varying mass into the conductive RGO matrix. When severed as Li-S battery cathodes, the optimized S@ascharite/RGO cathode with a sulfur content of 73.8 wt % demonstrates excellent rate performance and cycle stability accompanied by a high-capacity retention for 500 cycles at 1.0 C. Interesting advantages including the enhanced adsorption ability by the formation of the Mg-S and Li bonds, the continuous and quick electron/ion transportations assembled conductive RGO framework, and the effective deposition of Li2S are combined in the ascharite/RGO aerogel hosts. The electrochemical results further demonstrate that the polarity of ascharite components for the S cathode plays a dominant role in the improvement of electrochemical performance, but the absence of a conductive substrate leads to serious capacity attenuation, especially the rate performance. The balanced design protocol provides a universal method for the synthesis of multiple S hosts for high-performance LSBs.

Histologic and Clinical Factors Associated with Kidney Outcomes in IgA Vasculitis Nephritis.

BACKGROUND: Nephritis is a common manifestation of IgA vasculitis and is morphologically indistinguishable from IgA nephropathy. While MEST-C scores are predictive of kidney outcomes in IgA nephropathy, their value in IgA vasculitis nephritis has not been investigated in large multiethnic cohorts. METHODS: Biopsies from 262 children and 99 adults with IgA vasculitis nephritis ( N =361) from 23 centers in North America, Europe, and Asia were independently scored by three pathologists. MEST-C scores were assessed for correlation with eGFR/proteinuria at biopsy. Because most patients ( N =309, 86%) received immunosuppression, risk factors for outcomes were evaluated in this group using latent class mixed models to identify classes of eGFR trajectories over a median follow-up of 2.7 years (interquartile range, 1.2-5.1). Clinical and histologic parameters associated with each class were determined using logistic regression. RESULTS: M, E, T, and C scores were correlated with either eGFR or proteinuria at biopsy. Two classes were identified by latent class mixed model, one with initial improvement in eGFR followed by a late decline (class 1, N =91) and another with stable eGFR (class 2, N =218). Class 1 was associated with a higher risk of an established kidney outcome (time to ≥30% decline in eGFR or kidney failure; hazard ratio, 5.84; 95% confidence interval, 2.37 to 14.4). Among MEST-C scores, only E1 was associated with class 1 by multivariable analysis. Other factors associated with class 1 were age 18 years and younger, male sex, lower eGFR at biopsy, and extrarenal noncutaneous disease. Fibrous crescents without active changes were associated with class 2. CONCLUSIONS: Kidney outcome in patients with biopsied IgA vasculitis nephritis treated with immunosuppression was determined by clinical risk factors and endocapillary hypercellularity (E1) and fibrous crescents, which are features that are not part of the International Study of Diseases of Children classification.

Etiological classification and manifestation of pulmonary artery dissection: A literature review and case analysis.

Background: Pulmonary artery dissection (PAD) is an uncommon condition associated with high mortality rates. To date, a comprehensive examination of various underlying causes of PAD remains unexplored. Methods: We used the search words "pulmonary artery dissection," "pulmonary artery dilatation," and "pulmonary artery rupture" in the public database, and examined the medical records of PAD patients treated in our hospital. Data on demographics, aetiology, PAD locations, histopathology, treatments, and outcomes, were collected. Results: A total of 145 patients with PAD (135 cases from the literature and 10 cases from our hospital) were analysed. PAD aetiology was categorized into four groups: congenital heart diseases (CHD) associated with pulmonary arterial hypertension (PAH), non-CHD associated with pulmonary hypertension (PH), aortic dissection-related, and miscellaneous causes. The most frequent cause, accounting for 32.4 % of PAD cases, was congenital heart disease, followed by idiopathic PAH (13 %) and chronic obstructive pulmonary disease (6 %). Patients with CHD were typically younger at the time of PAD diagnosis (median age: 35 years old) when compared with those suffering from aortic dissection, PH-associated conditions, or other causes (median age: 45, 55, and 56 years old, respectively). Imaging of the pulmonary artery proved effective in diagnosing PAD. The outcomes were generally poor. 44.7 % (21/47) of patients with CHD associated with PAH and 47.7 % (21/44) of non-CHD PH-associated diseases died during follow-up. Multidisciplinary team consultations are crucial when making decisions on management of PAD. Characteristic PAD histopathology features included thickened intima and hypertrophied media with atheromatous degeneration, disrupted elastic fibres, and lymphocytic infiltration. Conclusions: PAD aetiology can be divided into four main categories, with CHD associated with PAH being the leading cause. Despite the similar histopathology features, clinical manifestations and outcomes vary according to the aetiology.

Improved surgical exposure and early clinical outcomes using a femoral-release-first technique in direct anterior approach during total hip arthroplasty.

BACKGROUND: Total hip arthroplasty (THA) performed using the direct anterior approach (DAA) has demonstrated favourable early-, mid-, and long-term outcomes. However, the traditional femoral release technique remains technically demanding and is associated with challenges and a heightened risk of complications. This study aimed to compare the clinical outcomes of patients who underwent THA with DAA performed using either the femoral-release-first (FRF) or the traditional approach (TA) strategy. METHODS: A retrospective analysis of demographics, clinical and radiological outcomes, and occurrence of complications was performed using data from 106 patients between 2018 and 2019. The patients were categorised into two groups: FRF (44 hips) and TA (69 hips). RESULTS: The FRF group showed a reduced operative time, haemoglobin (Hb) drop, postoperative hospital stay, and more optimal acetabular cup anteversion angles. Furthermore, during the first 2 months postoperatively, the FRF group demonstrated superior visual analogue scale, Harris Hip, and Oxford Hip scores. In the TA group, two hips experienced greater trochanter fractures, and one experienced delayed incision healing. CONCLUSIONS: Compared with the TA, employing the FRF strategy during THA with DAA resulted in improved outcomes within the first 2 months postoperatively and comparable functional recovery beyond this period. The FRF method exhibited advantages such as favourable acetabular exposure and alignment and a reduced risk of complications. Therefore, the FRF strategy may be a favourable option.

Genome-Wide Association Analysis of Protein-Coding Variants in IgA Nephropathy.

SIGNIFICANCE STATEMENT: Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility. BACKGROUND: Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated. METHODS: We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression. RESULTS: We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03). CONCLUSIONS: Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.

Hsa-miR-379 down-regulates Rac1/MLK3/JNK/AP-1/Collagen I cascade reaction by targeting connective tissue growth factor in human alveolar basal epithelial A549 cells.

OBJECTIVE: This study was aimed to screen and identify miRNAs that could regulate human CTGF gene and downstream cascade reaction Rac1/MLK3/JNK/AP-1/Collagen I by bioinformatics and experimental means. METHODS: TargetScan and Tarbase were used to predict miRNAs that may have regulatory effects on human CTGF gene. The dual-luciferase reporter gene assay was employed to verify the results obtained in bioinformatics. Human alveolar basal epithelial A549 cells were exposed to silica (SiO2) culture medium for 24 h to establish an in vitro model of pulmonary fibrosis, and bleomycin (BLM) of 100 ng/mL was used as a positive control. The miRNA and mRNA expression levels were determined by RT-qPCR, and the protein levels were measured by western blot in hsa-miR-379-3p overexpression group or not. RESULTS: A total of 9 differentially expressed miRNAs that might regulate the human CTGF gene were predicted. Hsa-miR-379-3p and hsa-miR-411-3p were selected for the subsequent experiments. The results of the dual-luciferase reporter assay showed that hsa-miR-379-3p could bind to CTGF, but hsa-miR-411-3p could not. Compared with the control group, SiO2 exposure (25 and 50 µg/mL) could significantly reduce the expression level of hsa-miR-379-3p in A549 cells. SiO2 exposure (50 µg/mL) could significantly increase the mRNA expression levels of CTGF, Collagen I, Rac1, MLK3, JNK, AP1, and VIM in A549 cells, while CDH1 level was significantly decreased. Compared with SiO2 + NC group, the mRNA expression levels of CTGF, Collagen I, Rac1, MLK3, JNK, AP1, and VIM were significantly decreased, and CDH1 level was significantly higher when hsa-miR-379-3p was overexpressed. At the same time, overexpression of hsa-miR-379-3p improved the protein levels of CTGF, Collagen I, c-Jun and phospho-c-Jun, JNK1 and phospho-JNK1 significantly compared with SiO2 + NC group. CONCLUSION: Hsa-miR-379-3p was demonstrated for the first time that could directly target and down-regulate human CTGF gene, and further affect the expression levels of key genes and proteins in Rac1/MLK3/JNK/AP-1/Collagen I cascade reaction.

Outcomes with Finerenone in Participants with Stage 4 CKD and Type 2 Diabetes: A FIDELITY Subgroup Analysis.

Background Patients with stage 4 chronic kidney disease (CKD) and type 2 diabetes have limited treatment options to reduce their persistent cardiovascular and kidney risk. In FIDELITY, a prespecified pooled analysis of FIDELIO-DKD and FIGARO-DKD, finerenone improved heart-kidney outcomes in participants with CKD and type 2 diabetes. Methods This FIDELITY subgroup analysis investigated the effects of finerenone in participants with stage 4 CKD (estimated glomerular filtration rate [eGFR] <30 ml/min/1.73 m2). Efficacy outcomes included a cardiovascular composite (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and a kidney composite (kidney failure, sustained ≥57% decrease in eGFR from baseline, or kidney disease death). Results Of 13,023 participants, 890 (7%) had stage 4 CKD. The hazard ratio for risk of cardiovascular composite outcome with finerenone versus placebo was 0.78 (95% confidence interval 0.57-1.07). The kidney composite outcome proportional hazards assumption was not met for the overall study period, with a protective effect only shown up to 2 years, after which the direction of association was inconsistent and an observed loss of precision over time incurred on finerenone versus placebo risk differences. Nonetheless, albuminuria and rate of eGFR decline were consistently reduced with finerenone versus placebo. Adverse events were balanced between treatment arms. Hyperkalemia was the most common AE reported (stage 4 CKD: 26% and 13% for finerenone versus placebo, respectively) however, the incidence of hyperkalemia leading to permanent discontinuation was low (stage 4 CKD: 3% and 2% for finerenone versus placebo, respectively). Conclusions The cardiovascular benefits and safety profile of finerenone in participants with stage 4 CKD were consistent with the overall FIDELITY population; this was also the case for albuminuria and the rate of eGFR decline. The effects on the composite kidney outcome were not consistent over time.

Empagliflozin in Patients with Chronic Kidney Disease.

BACKGROUND: The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. METHODS: We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m2 of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m2 with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to <10 ml per minute per 1.73 m2, a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from cardiovascular causes. RESULTS: A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P<0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P = 0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. CONCLUSIONS: Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo. (Funded by Boehringer Ingelheim and others; EMPA-KIDNEY ClinicalTrials.gov number, NCT03594110; EudraCT number, 2017-002971-24.).

Atractylodes lancea and Magnolia officinalis combination protects against high fructose-impaired insulin signaling in glomerular podocytes through upregulating Sirt1 to inhibit p53-driven miR-221.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Chinese medicine, a long term of improper diet causes the Dampness and disturbs Zang-Fu's functions including Kidney deficiency. Atractylodes lancea (Atr) and Magnolia officinalis (Mag) as a famous herb pair are commonly used to transform Dampness, with kidney protection. AIM OF THE STUDY: To explore how Atr and Mag protected against insulin signaling impairment in glomerular podocytes induced by high dietary fructose feeding, a major contributor for insulin resistance in glomerular podocyte dysfunction. MATERIALS AND METHODS: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyze constituents of Atr and Mag. Rat model was induced by 10% fructose drinking water in vivo, and heat-sensitive human podocyte cells (HPCs) were exposed to 5 mM fructose in vitro. Animal or cultured podocyte models were treated with different doses of Atr, Mag or Atr and Mag combination. Western blot, qRT-PCR and immunofluorescence assays as well as other experiments were performed to detect adiponectin receptor protein 1 (AdipoR1), protein kinase B (AKT), Sirt1, p53 and miR-221 levels in rat glomeruli or HPCs, respectively. RESULTS: Fifty-five components were identified in Atr and Mag combination. Network pharmacology analysis indicated that Atr and Mag combination might affect insulin signaling pathway. This combination significantly improved systemic insulin resistance and prevented glomerulus morphological damage in high fructose-fed rats. Of note, high fructose decreased IRS1, AKT and AdipoR1 in rat glomeruli and cultured podocytes. Further data from cultured podocytes with Sirt1 inhibitor/agonist, p53 agonist/inhibitor, or miR-221 mimic/inhibitor showed that high fructose downregulated Sirt1 to stimulate p53-driven miR-221, resulting in insulin signaling impairment. Atr and Mag combination effectively increased Sirt1, and decreased p53 and miR-221 in in vivo and in vitro models. CONCLUSIONS: Atr and Mag combination improved insulin signaling in high fructose-stimulated glomerular podocytes possibly through upregulating Sirt1 to inhibit p53-driven miR-221. Thus, the regulation of Sirt1/p53/miR-221 by this combination may be a potential therapeutic approach in podocyte insulin signaling impairment.

Treatment for overactive bladder: A meta-analysis of tibial versus parasacral neuromodulation.

BACKGROUND: The study aimed to assess the efficacy and safety of parasacral neuromodulation (PNS) versus tibial nerve stimulation (TNS) for patients with overactive bladder (OAB). METHODS: Databases including PubMed, Embase, clinicalTrial.gov, and Cochrane Library Central Register of Controlled Trials were systematically searched from January 1, 1999 to September 9, 2022. The improvements in a 3-day voiding diary were set as the primary outcomes. Then, the scores of overactive bladder-validated 8-question awareness tool (OAB-V8), King's health questionnaire (KHQ), and international consultation on incontinence questionnaire overactive bladder (ICIQ-OAB) were also evaluated. RESULTS: Five articles (4 randomized controlled trials [RCTs] and 1 prospective study) including 255 OAB patients were enrolled. Two kinds of neuromodulations had similar performances in the micturition (mean difference [MD] = 0.26, 95% confidence interval [CI]: -0.51 to 1.04, P = .50), urgency episodes (MD = -0.16, 95% CI: -0.64 to 0.31, P = .50), incontinence episodes (MD = 0.09, 95% CI: -0.41 to 0.59, P = .72), as well as in the nocturia episodes (MD = 0.04, 95% CI: -0.45 to 0.52, P = .89). Furthermore, there was no difference regarding ICIQ-OAB scores (P = .83), KHQ (P = .91), and OAB-V8 scores (P = .83). Importantly, included studies reported no adverse events in the 2 groups. CONCLUSION: TNS and PNS had similar effectiveness for the treatment of OAB, moreover, without any identified adverse events in both groups. However, well-designed RCTs are stilled needed to verify our results.