Objective To investigate the correlation between serum growth differentiation factor 15 (GDF15) and the clinicopathological characteristics of patients with IgA nephropathy (IgAN), and further explore the relationship of GDF15 with the cardiac and renal prognosis of IgAN patients. Methods It was a single-center retrospective cohort study. From January 2018 to December 2022, the relevant data were collected from patients who were diagnosed with primary IgAN at the Department of Nephrology, Beijing Anzhen Hospital Affiliated to Capital Medical University, and regularly followed up for at least 1 year. Serum samples were collected at admission and the baseline level of serum GDF15 was measured. Based on the median GDF15 level, IgAN patients were categorized into high-level GDF15 group and low-level GDF15 group, and their clinicopathological characteristics were compared. A multiple linear regression model was then constructed to identify independent factors associated with serum GDF15 level based on these comparisons. Subsequently, Kaplan-Meier survival analysis was performed to investigate the association between serum GDF15 level and the cardiorenal prognosis of IgAN patients. Results A total of 104 IgAN patients were included in this study. The serum GDF15 level in these IgAN patients was 825.60 (556.84, 1 428.15) ng/L. Serum GDF15 level was positively correlated with 24 h urinary protein (r=0.405, P<0.001), negatively correlated with estimated glomerular filtration rate (eGFR)(r=-0.606, P<0.001). The serum levels of GDF15 in patients with tubular atrophy or interstitial fibrosis (overall comparison among T0, T1, and T2, H=21.866, P<0.001), crescentic lesions (overall comparison among C0, C1, and C2, H=13.787, P=0.001), or intrarenal arteriolar lesions (overall comparison among none, mild, and moderate-to-severe, H=9.856, P=0.007) were significantly different. Compared with IgAN patients without tubular atrophy or interstitial fibrosis, those with Oxford classification T1 (Z=-17.326, P=0.042) or T2 (Z=-42.933, P<0.001) had higher serum GDF15 levels. Compared with IgAN patients without crescentic lesions, those with Oxford classification C2 had higher serum GDF15 levels (Z=-45.929, P=0.001). Compared with IgAN patients without intrarenal arteriolar lesions, those with moderate-to-severe arteriolar sclerosis had higher serum GDF15 levels (Z=-26.686, P=0.005). The median GDF15 was used as the cut-off value to divide IgAN patients into a high-level GDF15 group (≥825.60 ng/L, n=52) and a low-level GDF15 group (<825.60 ng/L, n=52). Compared to low-level GDF15 group, IgAN patients in high-level GDF15 group presented with a higher proportion of diabetes mellitus (χ² =9.420, P=0.002) and cardiovascular disease (χ² =7.792, P=0.005), a higher level of systolic blood pressure (Z=-2.266, P=0.023), body mass index (Z=-2.183, P=0.031), 24 h urinary protein (Z=-3.485, P<0.001), blood total cholesterol (Z=-2.002, P=0.045) and left ventricular mass index (Z=-2.649, P=0.008), and a lower level of blood albumin (Z=-3.053, P=0.002) and eGFR (Z=6.480, P<0.001). Multiple linear regression analysis showed that serum GDF15 level was independently associated with systolic blood pressure (regression coefficient B=29.453, 95% CI 14.139–44.767, P<0.001), blood albumin (B=-81.412, 95% CI -113.084–-49.740, P<0.001) and eGFR (B=-9.797, 95% CI -17.554–-2.040, P=0.014). Moreover, IgAN patients in high-level GDF15 group exhibited significantly poorer cardiac and renal prognosis compared to low-level GDF15 group (χ² =9.955, P=0.002). Conclusion High serum GDF15 level correlates with disease severity in IgAN, and high serum GDF15 level may suggest a poorer cardiorenal prognosis in IgAN patients.

Objective To screen bile acid-related characteristic genes in IgA nephropathy (IgAN) based on the feature gene selection algorithm in the machine learning method, aiming to exploring the molecular biological mechanisms and biomarkers of IgAN. Methods The gene expression data and sample grouping information of GSE93798, GSE116626 and GSE35487 were downloaded from the Gene Expression Omnibus (GEO). Bile acid-related gene sequences were obtained from the Molecular Signatures Database (MSigDB). R language was used to identify differentially expressed genes between IgAN samples and healthy control samples. Candidate genes were obtained by intersecting differentially expressed genes and bile acid-related genes. The least absolute shrinkage and selection operator (LASSO) algorithm in machine learning was used to screen the feature genes in the candidate genes as biomarkers, and the feature genes in the training set and validation set were analyzed by the rate of change index. Receiver operating characteristic curve (ROC) method was used to evaluate the diagnostic value of identified bile acid related characteristic genes for IgAN. Gene set enrichment analysis (GSEA) was used to analyze the Spearman correlation between the characteristic genes and all other genes and their related metabolic pathways. The expression of disease-characteristic genes in the kidney tissues of IgAN rats was validated by real-time PCR. Results Gene expression information from kidney tissue samples of 20 IgAN cases and 22 healthy controls were obtained from GEO database. A total of 204 bile acid-related genes including 24 pathways were obtained from MSigDB. The results of gene differential expression analysis showed that 333 genes in the kidney tissues of IgAN patients were differentially expressed compared with those of healthy controls, including 102 up-regulated genes and 231 down-regulated genes, among which 12 differentially expressed genes were related to bile acid genes, as follows: NR1H4,SLC23A1, ALDH8A1, FABP1, ALB, SLC27A2, DIO1, CYP8B1, BBOX1, PIPOX, AKR1C1 and SLC10A2. Five characteristic genes (NR1H4, SLC23A1, FABP1, ALB and AKR1C1) were screened by LASSO regression algorithm.ROC analysis results showed that in GSE93798 cohort genes, the AUC of NR1H4, SLC23A1, FABP1 and ALB genes with differential expression was >0.95 respectively in diagnosing IgAN, and that of AKR1C1 genes with differential expression was >0.85 in diagnosing IgAN. The gene expression data of SLC23A1 in GSE35487 cohort was missing. ROC analysis results of other four genes showed that the AUC of differential expression of ALB gene for IgAN was >0.95 respectively, that of NR1H4 gene was >0.70, and that of both FABP1 and AKR1C1 gene was >0.60. In the GSE116626 cohort genes, the AUC of five disease characteristic genes (NR1H4, SLC23A1, FABP1, ALB, AKR1C1) for diagnosing IgAN was >0.60, respectively. These results suggested that 5 characteristic genes have certain distinguishing ability between IgAN group and control group. GSEA results were displayed that the characteristic genes were related to butyric acid metabolism, propionic acid metabolism, arginine and proline metabolism, valine leucine and isoleucine degradation, fatty acid metabolism, etc. These results suggested that five characteristic genes might be related to IgAN through the above metabolic mechanisms. The verification results of five bile acid characteristic genes in the rat model of IgAN in the kidney tissue showed that the expressions of four genes, NR1H4, SLC23A1, FABP1 and ALB, were higher than those of the control group, and there was no statistical significance in the expression of AKR1C1 gene between the two groups. Conclusions The expression of bile acid-related characteristic genes is abnormal in the kidney tissue of IgAN patients. Four bile acid-related differentially expressed genes, NR1H4, SLC23A1, FABP1 and ALB, are expected to be biomarkers for non-invasive diagnosis and therapeutic targets.

Objective To investigate the different clinical characteristics and prognosis of patients with diabetic nephropathy (DN) accompanied by IgA deposition diagnosed by renal biopsy. Methods The study was a retrospective cohort study. Clinical and pathological data of patients diagnosed with DN through renal biopsy in Beijing Anzhen Hospital affiliated to Capital Medical University from January 1, 2010 to March 31, 2023 were retrospectively collected. The clinical and pathological characteristics and prognosis of DN patients with IgA deposition and DN control group patients without IgA deposition were compared. Immunofluorescence staining was used to detect the intensity of galactose?deficient IgA1 (Gd?IgA1) staining in renal tissue of DN patients with DN IgA deposition, and grouping was performed according to whether the staining intensity was≥2+. Enzyme linked immunosorbent assay was used to detect the serum level of Gd?IgA1 in patients. A 50% decrease in estimated glomerular filtration rate (eGFR) from baseline or progression to end-stage renal disease within 5 years was defined as a renal endpoint event, and Kaplan?Meier survival analysis and Log?rank test were used to compare the difference in cumulative incidence of renal endpoint events between two groups of patients. Results A total of 101 DN patients were enrolled in this study, including 68 males (67.3%) and 33 females (32.7%), with age of (52.2±10.3) years and a median follow-up time of 13.5(4.8, 26.3) months. There were 44 patients with IgA deposition (43.6%) and 57 patients without IgA deposition (56.4%). Compared with DN control group, Kaplan-Meier analysis showed that DN patients with IgA deposition had a higher cumulative incidence of renal endpoint within 5 years (χ²=6.473, P=0.011). The proportion of positive glomerular Gd?IgA1 (KM55) staining in the DN patients with IgA deposition was 54.5% (24/44), and immunofluorescence examination showed consistent distribution of Gd?IgA1 and IgA in the glomerular mesangial and capillary regions. The serum level of Gd?IgA1 in the glomerular Gd?IgA1 positive patients was significantly higher than that in those negative patients [(6 296.4± 1 535.4) μg/L vs. (4 057.4±1 082.0) μg/L, t=-3.037, P=0.010]. In DN patients with IgA deposition, the age of the subgroup with endpoint events was younger [(42.8±6.9) years vs. (53.3±9.4) years, t=-3.440, P=0.002], the duration of proteinuria was shorter [6.0(1.0, 22.0) months vs. 12.0(10.0, 36.0) months, Z=-2.150, P=0.032], and the proportion of patients with glomerular Gd?IgA1 staining intensity ≥2+ was higher [Fisher'exact test, 30.8%(4/13) vs. 0(0/20), P=0.017]. Kaplan-Meier survival analysis showed that patients with glomerular Gd?IgA1 staining intensity≥2+ had a significantly higher cumulative incidence of renal endpoint events (χ²=4.846, P=0.028). Conclusion DN patients with glomerular IgA deposition and Gd?IgA1 positivity may be associated with worse prognosis.

Objective To report two cases of anti-glomerular basement membrane (GBM) disease with IgA nephropathy (IgAN), and summarize the clinical characteristics of these patients through systematic literature review, for providing clinical data for the diagnosis and treatment of this disease. Methods It was a case-series analysis. Clinical data of two cases with anti-GBM disease and IgAN diagnosed in the First Affiliated Hospital of Guangxi Medical University were collected. The course of their diagnosis and treatment was described. Besides, the relevant literature of anti-GBM disease with IgAN cases reported in PubMed and CNKI databases from the establishment of the database to June 30, 2024 were retrived, and the relevant clinical data were extracted for analysis and summary. Patients were divided into end?stage renal disease (ESRD) group and non-ESRD group according to renal outcome, and the differences in age, gender, hemoglobin, creatinine at diagnosis, proportion of hypuria/anuria, qualitative grade of urinary protein, and proportion of renal crescent were compared between the two groups. Results Two patients were both young women. The pathology of renal tissue suggested crescentic glomerulonephritis. The pathological manifestations were linear deposition of IgG along GBM and deposition of immune complex dominated by IgA in mesangial region. At the initial diagnosis, the renal function damage of the case one was not severe. After plasma exchange, glucocorticoid and cyclophosphamide treatment, the renal function recovered. The kidney function of the case two was obviously impaired at the initial diagnosis, and was improved after the above treatment, but aggravated due to infection, and continued to progress into ESRD. Twenty-six literates involving 40 cases of anti-GBM disease with IgAN were retrieved. A total of 42 cases of anti-GBM disease with IgAN, including 2 cases in this report, were analyzed and summarized. The age was (41.3±17.5) years old, 45.2% were male, 39 cases (92.9%) were from Asia. The hemoglobin was (94.4±15.1) g/L, the serum creatinine was 450.8 (284.4, 755.8) μmol/L, 83.3% (35/42) patients had crescent ratio greater than 50% and 37 patients (88.1%) patients were treated with intravenous methylprednisolone and cytotoxic immunosuppressive drugs. Plasma exchange was performed in 34 patients (81.0%) patients, 23 patients (54.8%) had renal function recovered and 17 patients (40.5%) entered ESRD. Compared with the non-ESRD group, the serum creatinine in the ESRD group was higher at initial diagnosis (P<0.01), and the proportion of hypuria/anuria was higher (P=0.03). There were no statistically significant differences in age, sex, hemoglobin, urinary protein and crescent proportion between the two groups (all P>0.05). Conclusions Compared with anti-GBM disease, anti-GBM with IgAN has a smoother course and a better prognosis. Infection should be actively prevented during treatment.

Objective To analyze the target signaling pathway of histone H3K27 methylation-induced podocyte injury, verify the regulatory effect of histone H3K27 methylation on podocyte injury in focal segmental glomerulosclerosis (FSGS) mice through target signaling pathway, and explore the mechanism of abnormal methylation of histone H3K27-induced podocyte injury in FSGS mice. Methods (1) Cell experiments: primary cultured immortalized mouse podocytes MPC5 were cultured in vitro, and divided into control group, adriamycin (ADR) group, ADR+GSK-J4 (histone demethylase, KDM6B inhibitor) group, ADR+coumarin A1 (C-A1, JAK2 agonist) group and ADR+GSK-J4+C-A1 group. The transmission electron microscope was used to observe ultrastructure of podocytes. Immunofluorescence was used to detect the protein expression of H3K27me3 and nephrin in podocytes. The whole genome sequence of podocytes was obtained, the differentially expressed genes were screened, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used for enrichment analysis. Real time-quantitative PCR and Western blotting were used to detect the gene and protein expression of JAK2-STAT3 signaling pathway in podocytes respectively. Enzyme-linked immunosorbent assay was used to detect interleukin 6 (IL?6), monocyte chemotactic protein 1 (MCP?1), α?smooth muscle actin (α?SMA) and transforming growth factor β1 (TGF?β1). (2) Animal experiments: EZH2 gene knock out(EZH2^podKo)-FSGS (tail vein injection of ADR) mouse models were established, and divided into EZH2^ctrl+control group (n=20), EZH2^ctrl+FSGS (n=20), EZH2^podKo+control group (n=30) and EZH2^podKo+FSGS group (n=30). HE staining was used to observe the morphology of kidney tissues. Immunohistochemistry was used to detect the H3K27me3 protein expression in podocytes. Real time-quantitative PCR and Western blotting were used to verify the gene and protein expression of JAK2-STAT3 signaling pathway respectively. Enzyme-linked immunosorbent assay was used to detect IL?6, MCP?1, α?SMA and TGF?β1 of kidney tissues. Results (1) Cell experiments: Compared with control group, the nucleus shrank and ruptured, the cytoplasm showed vacuole, and mitochondria and endoplasmic reticulum swelled in ADR group, which verified that the podocyte injury model of ADR nephropathy was successfully established. Compared with control group, the protein expression level of H3K27me3 in ADR group was significantly lower (P<0.05). Compared with ADR group, the protein expression level of H3K27me3 in podocytes in ADR+GSK-J4 group was significantly higher (P<0.05), and there were 502 increased genes and 443 decreased genes. GO enrichment analysis showed that the differentially enriched peaks were mainly in ribonucleoprotein complex biogenesis, ribosome biogenesis, establishment of protein localization to organelle, and involved in regulation of receptor signaling pathway via JAK-STAT and receptor signaling pathway via JAK-STAT. Differential expressed genes were Irf1, Tnfrsf1a, Socs1, Notch1, Gadd45a, Hes1 and Socs3, involving in the regulation of JAK-STAT signaling pathway. KEGG enrichment analysis showed that the differentially enriched peaks were mainly in amyotrophic lateral sclerosis, and the target genes were Mcl1, Egfr, Socs1, Cdkn1a, Pdgfa and Socs3, involving in the regulation of JAK-STAT signaling pathway. Compared with ADR group, the mRNA and protein expression levels of JAK2 and STAT3 in the ADR+GSK-J4 group were significantly lower, and the downstream inflammatory factors of IL?6, MCP-1 and α?SMA were significantly higher (all P<0.05). Compared with ADR group, the protein expression level of nephrin in ADR+GSK-J4 group was higher (P<0.05), and the protein expression level of nephrin in ADR+C-A1 group was lower (P<0.05). Compared with ADR+GSK-J4 group, the protein expression level of nephrin in ADR+GSK-J4+C-A1 group was lower (P<0.05). (2) Animal experiments: Compared with EZH2^ctrl+FSGS group, EZH2^podKo+FSGS group showed obvious renal tissue damage, matrix hyperplasia in mesangial area with massive homogeneous substance deposition, apoptosis and necrosis of renal tubular epithelial cells, obvious thickening and extensive fusion of glomerular epithelial cells, basement membrane collapse, and compression and narrowing of capillary structure. Compared with EZH2^ctrl+FSGS group, the protein expression level of H3K27me3 in EZH2^podKo+FSGS group was significantly lower, and the mRNA and protein expression levels of JAK2 and STAT3, and the levels of IL?6, MCP-1, α?SMA and TGF?β1 were higher (all P<0.05). Conclusions Abnormal methylation modification of H3K27 leads to change of target gene expression, activation of JAK2-STAT3 signaling pathway, podocyte injury, glomerulosclerosis and renal tubular injury, participating in the development of FSGS.