Yu Zhang

Background: Immunoglobulin A nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide and a leading cause of end-stage renal disease, posing a significant threat to human health. Modified Huangqi Chifeng decoction (MHCD) has shown efficacy in ameliorating IgAN; however, its underlying regulatory mechanisms remain incompletely understood. Objective: To evaluate the anti-inflammatory and anti-fibrotic effects of MHCD on IgAN and elucidate its molecular mechanisms through in vivo and in vitro experiments. Methods: An IgAN rat model was established. The therapeutic effects of MHCD were assessed by measuring 24-hour urinary protein, Gd-IgA1, serum biochemistry, renal pathological damage, IgA deposition, inflammatory mediators, and fibrosis levels after 8 weeks of MHCD administration. ELISA was used to quantify inflammatory mediators; Western blot and immunohistochemistry were employed to analyze protein expression; PCR was performed to determine miR-146a levels. Subsequently, lipopolysaccharide-stimulated mesangial cells were used in vitro . Mesangial cell proliferation and the expression of TLR4/NF-κB signaling pathway components and downstream inflammatory factors was examined to verify the anti-inflammatory and anti-fibrotic mechanism of MHCD by overexpressing or silencing miR-146a. Results: MHCD reduced urinary protein and serum Gd-IgA1 in IgAN rats, and alleviated renal IgA deposition, pathological injury, inflammation and fibrosis. Furthermore, MHCD inhibited renal expression of TLR4, MyD88, NF-κB p65 and NF-κB p-p65, and increased the level of miR-146a. Mechanistically, in vitro experiments demonstrated that MHCD exerted anti-inflammatory and anti-fibrotic effects by upregulating miR-146a and inhibiting the TLR4/NF-κB signaling pathway. Conclusion: MHCD alleviates IgA nephropathy inflammation and renal fibrosis partially through upregulating miR-146a and subsequently suppressing the TLR4/NF-κB signaling pathway.

Background: Chronic kidney disease (CKD) is a major global health burden with substantial morbidity and mortality. Proteinuria is strongly associated with adverse renal outcomes, and podocyte pyroptosis is increasingly recognized as a key driver of glomerular filtration barrier disruption. Objective: This study sought to elucidate how Modified Huangqi Chifeng Decoction (MHCD) mitigates renal and podocyte injury by modulating the Arid5a/AIM2-dependent pyroptosis pathway. Materials and methods: An adriamycin-induced nephropathy (ADR) rat model and an in vitro podocyte injury model were established. Twenty-four-hour urinary protein levels, serum biochemical indices, and renal histopathology were assessed. Expression of Arid5a, AIM2, and downstream pyroptosis-related molecules (Caspase-1, ASC oligomerization, GSDMD, IL-1β, and IL-18) was quantified. Mutagenesis of Arid5a binding sites in the AIM2 promoter, along with electrophoretic mobility shift assays (EMSA) and dual-luciferase reporter assays, were used to validate Arid5a’s promoter binding and its transcriptional regulation of AIM2. Results: MHCD markedly reduced proteinuria, alleviated renal histopathological damage, and improved podocyte viability in ADR rats. These protective effects coincided with downregulation of Arid5a, AIM2, and downstream pyroptosis mediators—including Caspase-1, ASC oligomers, GSDMD, IL-1β, and IL-18. Mechanistically, Arid5a functioned as a transcription factor that binds to the AIM2 promoter to regulate AIM2 expression. Conclusions: MHCD mitigates renal and podocyte injury by suppressing inflammasome activation and pyroptosis through Arid5a-mediated transcriptional activation of the AIM2 signaling axis.

There have been no investigations on the relationship between hemoglobin glycation index (HGI) and poor prognosis in patients with acute kidney injury (AKI). Patients were enrolled from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. The HGI was calculated using a linear regression model fitted to glycosylated hemoglobin and fasting plasma glucose (FPG). Kaplan-Meier survival analysis and Cox proportional hazards regression analysis were performed based on HGI quartiles to determine the independent association between HGI and mortality risk. A restricted cubic spline (RCS) was employed to assess the potential nonlinear relationship between HGI and mortality risk. A two-piecewise linear regression model was developed to identify the threshold effect. Additionally, a linear regression model was applied to evaluate the association between HGI and the length of hospital stays. A total of 3684 patients with AKI were included in this study. Among them, 486 patients died within 28 days, and 673 patients died within 90 days. Multivariate Cox regression analysis identified HGI as an independent risk factor for both 28-day mortality (hazard ratio [HR], 1.65 [95% CI 1.26 to 2.16], p < 0.001) and 90-day mortality (HR, 1.45 [95% CI 1.16 to 1.82], p < 0.001) in AKI. The RCS analysis revealed a significant L-shaped association between HGI and both 28-day (nonlinear p < 0.001) and 90-day mortality (nonlinear p < 0.001). For 28-day mortality, the inflection point was 1.09 (HR = 0.72, 95% CI: 0.65 to 0.805). For 90-day mortality, the inflection point was 1.14 (HR = 0.76, 95% CI: 0.69 to 0.84). Notably, the association between HGI and outcomes was more significant in nondiabetic patients (p < 0.05). Additionally, HGI was found to be significantly and inversely associated with the length of hospital stays. In patients with AKI, a low HGI is an independent risk factor for 28-day and 90-day mortality, exhibiting an L-shaped association. HGI may serve as a potential predictor of mortality risk.

IgA nephropathy (IgAN) is one of the most common immune-related primary glomerular diseases. The pathological mechanism of this disease is complex, and the specific pathogenesis is still unclear. To obtain a comprehensive understanding of its molecular mechanism and to provide new perspectives regarding the detection and treatment of the disease, this study investigated the role of immune cells in IgAN, as well as the role of autophagy-related biomarkers in IgAN development. The original datasets GSE93798, GSE35487, GSE58539, GSE116626 and GSE115857 were downloaded from Gene Expression Omnibus (GEO) and were further integrated and analyzed. The differentially expressed genes (DEGs) between IgAN and healthy control (HC) group were identified by the “limma” R package. The gene ontology (GO) function, Kyoto Encyclopedia of Genes and Genome (KEGG) pathway, GeneSet Enrichment Analysis (GSEA) and DisGeNet enrichment were adopted to analyze the genes from the intersection of DEGs. The hub genes were screened by the square least absolute shrinkage and selection operator (LASSO) and cross validation. Immune cell infiltration was analyzed using CIBERSORT. The correlation between hub genes and infiltrating immune cells was calculated by R software. For the purpose of exploring the value of hub genes for diagnosing IgAN, a receiver operating characteristic (ROC) curve was constructed. Finally, Real-time quantitative polymerase chain reaction (qRT-PCR) was used to verify the relative mRNA level of the AT-DEGs. 12 DEGs were screened out. Enrichment analysis revealed that autophagy-related DEGs (AT-DEGs) were mainly related to intrinsic apoptotic signaling pathway, cellular response to external stimulus, transcription repressor complex and other cellular functions, KEGG pathways enriched by AT-DEGs mainly included biological metabolic pathways related to autophagy, while DisGeNET analysis showed that these AT-DEGs were mainly related to immunological diseases. The optimal six hub genes were obtained by lasso analysis as potential biomarkers for IgAN. ROC curve analysis showed that 4 of the 6 HUB genes had great diagnostic value. Immune infiltration results showed B cells memory, macrophages M2, NK cells activated, T cells CD4⁺ memory resting, and monocytes are the predominant immune cells with the development of IgAN. The qRT-PCR results showed that, compared to the NC group, SIRT1 mRNA expression in PBMCs from IgAN patients was significantly reduced, while BAG3, CDKN1A, and FOS mRNA levels were markedly elevated. SIRT1, BAG3, COKN1A and FOS can be considered as effective biomarkers related to autophagy for the diagnosis of IgAN. These findings suggest some potential new serum biomarkers for IgAN diagnosis.

Stress hyperglycemia ratio (SHR) has been associated with increased mortality from various cerebrovascular events and a higher incidence of acute kidney injury (AKI) in certain patient populations. However, the relationship between SHR and the mortality risk in patients with AKI has not been fully elucidated. Our study sought to comprehensively investigate the association and potential mediating effects between SHR and 28-day and 90-day mortality in patients with AKI. 3703 patients with AKI were included in this study. Feature importance variables were screened by a random forest algorithm, and the independent association of SHR with mortality risk was determined by Kaplan ‒ Meier survival analysis with Cox regression analysis. Restricted cubic spline (RCS) was conducted to assess the non-linear relationship between SHR and mortality risk. Mediation analysis was deployed to investigate the indirect effect of SHR on respiratory failure (RF) -mediated mortality risk. Among the patients with AKI included in this study, the 28-day mortality was 13.6% and the 90-day mortality was 18.7%. Fully adjusted Cox regression demonstrated that SHR was an independent risk factor for 28-day mortality (HR, 1.77 [95% CI 1.38–2.27], P < 0.001) and 90-day mortality (HR, 1.69 [95% CI 1.36–2.11], P < 0.001) in patients with AKI. RCS analysis revealed a linear relationship between SHR and outcome events. Additionally, the effect of SHR on 28-day and 90-day mortality risk were mediated by an increased RF risk in 6.62% and 6.54%, respectively. High SHR is an independent risk factor for 28-day and 90-day mortality in patients with AKI, and its effect is partly mediated by an increased risk of RF.

Background: The triglyceride glucose (TyG) index is a novel and reliable alternative marker for insulin resistance. Previous studies have shown that TyG index is closely associated with cardiovascular outcomes in cardiovascular diseases and coronary revascularization. However, the relationship between TyG index and renal outcomes of coronary revascularization is unclear. The purpose of this study was to investigate the correlation between TyG index and the risk of acute kidney injury (AKI) in patients with coronary revascularization. Methods: A retrospective cohort study was conducted to select eligible patients with coronary revascularization admitted to ICU in the medical information mart for intensive care IV (MIMIC-IV). According to the TyG index quartile, these patients were divided into four groups (Q1-Q4). The primary endpoint was the incidence of AKI, and secondary endpoints included 28-day mortality and the rate of renal replacement therapy (RRT) use in the AKI population. Multivariate Cox regression analysis and restricted cubic splines (RCS) were used to analyze TyG index association with AKI risk. Kaplan-Meier survival analysis was performed to assess the incidence of endpoints in the four groups. Results: In this study, 790 patients who underwent coronary revascularization surgery were included, and the incidence of AKI was 30.13%. Kaplan-Meier analysis showed that patients with a high TyG index had a significantly increased incidence of AKI (Log-rank P = 0.0045). Multivariate Cox regression analysis showed that whether TyG index was a continuous variable (HR 1.42, 95% CI 1.06–1.92, P = 0.018) or a categorical variable (Q4: HR 1.89, 95% CI 1.12–3.17, P = 0.017), and there was an independent association between TyG index and AKI in patients with coronary revascularization. The RCS curve showed a linear relationship between higher TyG index and AKI in this particular population (P = 0.078). In addition, Kaplan-Meier analysis showed a significantly increased risk of RRT application in a subset of AKI patients based on quartiles of TyG index (P = 0.029). Conclusion: TyG index was significantly associated with increased risk of AKI and adverse renal outcomes in patients with coronary revascularization. This finding suggests that the TyG index may be useful in identifying people at high risk for AKI and poor renal outcomes in patients with coronary revascularization.

Background: Successive observational studies have highlighted low-density lipoprotein cholesterol (LDL-C) as a standalone risk factor for the progression of chronic kidney disease (CKD) to end-stage renal disease. Lowering LDL-C levels significantly reduces the incidence of atherosclerotic events in patients with progressive CKD. Recent research indicates that proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors not only effectively lower LDL-C levels in CKD patients but also exhibit therapeutic potential for autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and ulcerative colitis. However, the role of PCSK9 inhibitors (PCSK9i) in treating CKD beyond lowering LDL-C levels remains uncertain. Therefore, this study employs drug-targeted Mendelian randomization (MR) to investigate the causal impact of PCSK9i on primary glomerular diseases such as IgA nephropathy (IgAN), membranous nephropathy (MN), and nephrotic syndrome (NS).Methods: Single-nucleotide polymorphisms (SNPs) linked to LDL-C were sourced from the Global Lipids Genetics Consortium genome-wide association study (GWAS). Genes situated in proximity to 3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), and PCSK9 served as proxies for therapeutic inhibition of these targets. The causal link between PCSK9i and the risk of primary glomerular disorders was discovered using drug-target MR studies. The HMGCR inhibitor, a drug target of statins, was utilized for comparative analysis with PCSK9i. Primary outcomes included the risk assessment for IgAN, MN, and NS, using the risk of coronary heart disease as a positive control.Results: The inhibition of PCSK9, as proxied genetically, was found to significantly reduce the risk of IgAN [odds ratio, OR (95% confidence interval, CI) = 0.05 (−1.82 to 1.93), p = 2.10 × 10⁻³]. Conversely, this inhibition was associated with an increased risk of NS [OR (95% CI) = 1.78 (1.34–2.22), p = 0.01]. Similarly, HMGCR inhibitors (HMGCRi) demonstrated a potential reduction in the risk of IgAN [OR (95%CI) = 0.0032 (−3.58 to 3.59), p = 1.60 × 10⁻³⁾.Conclusions: PCSK9i markedly decreased the risk of IgAN, suggesting a potential mechanism beyond their primary effect on LDL-C. However, these inhibitors were also associated with an increased risk of NS. On the other hand, HMGCRi appears to serve as a protective factor against IgAN. Conversely, PCSK9i may pose a risk factor for NS, suggesting the necessity for cautious application and further research into their impacts on various glomerular diseases.

Background: This study aims to investigate the relationship between blood urea nitrogen to serum albumin ratio (BAR) and all-cause mortality in patients with acute kidney injury (AKI) and evaluate the effect of BAR on the prognosis of AKI.Methods: Adult patients with AKI admitted to the ICU in the Medical Information Mart for Intensive Care IV (MIMIC-IV) were selected in a retrospective cohort study. BAR (mg/g) was calculated using initial blood urea nitrogen (mg/dl)/serum albumin (g/dl). According to the BAR, these patients were divided into quartiles (Q1–Q4). Kaplan–Meier analysis was used to compare the mortality of the above four groups. Multivariate Cox regression analysis was used to evaluate the association between BAR and 28-day mortality and 365-day mortality. The receiver operating characteristic (ROC) curve was plotted and the area under the curve (AUC) was calculated, and the subgroup analysis was finally stratified by relevant covariates.Results: A total of 12,125 patients with AKI were included in this study. The 28-day and 365-day mortality rates were 23.89 and 39.07%, respectively. Kaplan–Meier analysis showed a significant increase in all-cause mortality in patients with high BAR (Log-rank p < 0.001). Multivariate Cox regression analysis showed that BAR was an independent risk factor for 28-day mortality (4.32 < BAR≤7.14: HR 1.12, 95% CI 0.97–1.30, p = 0.114; 7.14 < BAR≤13.03: HR 1.51, 95% CI 1.31–1.75, p < 0.001; BAR>13.03: HR 2.07, 95% CI 1.74–2.47, p < 0.001; Reference BAR≤4.32) and 365-day mortality (4.32 < BAR≤7.14: HR 1.22, 95% CI 1.09–1.36, p < 0.001; 7.14 < BAR≤13.03: HR 1.63, 95% CI 1.46–1.82, p < 0.001; BAR>13.03: HR 2.22, 95% CI 1.93–2.54, p < 0.001; Reference BAR ≤ 4.32) in patients with AKI. The AUC of BAR for predicting 28-day mortality and 365-day mortality was 0.649 and 0.662, respectively, which is better than that of blood urea nitrogen and sequential organ failure assessment. In addition, subgroup analysis showed a stable relationship between BAR and adverse outcomes in patients with AKI.Conclusion: BAR is significantly associated with increased all-cause mortality in patients with AKI. This finding suggests that BAR may help identify people with AKI at high risk of mortality.