UNASSIGNED: IgA nephropathy (IgAN), a prevalent form of glomerulonephritis globally, exhibits complex pathogenesis. Cathepsins, cysteine proteases within lysosomes, are implicated in various physiological and pathological processes, including renal conditions. Prior observational studies have suggested a potential link between cathepsins and IgAN, yet the precise causal relationship remains unclear.
UNASSIGNED: We conducted a comprehensive bidirectional and multivariable Mendelian randomization (MR) study using publicly available genetic data to explore the causal association between cathepsins and IgAN systematically. Additionally, immunohistochemical (IHC) staining and enzyme-linked immunosorbent assay (ELISA) were employed to evaluate cathepsin expression levels in renal tissues and serum of IgAN patients. We investigated the underlying mechanisms via gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and immune cell infiltration analysis. Molecular docking and virtual screening were also performed to identify potential drug candidates through drug repositioning.
UNASSIGNED: Univariate MR analyses demonstrated a significant link between increased cathepsin S (CTSS) levels and a heightened risk of IgAN. This was evidenced by an odds ratio (OR) of 1.041 (95% CI=1.009-1.073, P=0.012) as estimated using the inverse variance weighting (IVW) method. In multivariable MR analysis, even after adjusting for other cathepsins, elevated CTSS levels continued to show a strong correlation with an increased risk of IgAN (IVW P=0.020, OR=1.037, 95% CI=1.006-1.069). However, reverse MR analyses did not establish a causal relationship between IgAN and various cathepsins. IHC and ELISA findings revealed significant overexpression of CTSS in both renal tissues and serum of IgAN patients compared to controls, and this high expression was unique to IgAN compared with several other primary kidney diseases such as membranous nephropathy, minimal change disease and focal segmental glomerulosclerosis. Investigations into immune cell infiltration, GSEA, and GSVA highlighted the role of CTSS expression in the immune dysregulation observed in IgAN. Molecular docking and virtual screening pinpointed Camostat mesylate, c-Kit-IN-1, and Mocetinostat as the top drug candidates for targeting CTSS.
UNASSIGNED: Elevated CTSS levels are associated with an increased risk of IgAN, and this enzyme is notably overexpressed in IgAN patients\' serum and renal tissues. CTSS could potentially act as a diagnostic biomarker, providing new avenues for diagnosing and treating IgAN.

BACKGROUND: The effects of tonsillectomy combined with steroid pulse (TSP) therapy for IgA nephropathy (IgAN) are little known. Therefore, we examined the effects of TSP therapy on the kidney outcomes of IgAN in a large, nationwide cohort study in Japan.
METHODS: Between 2002 and 2004, 632 IgAN patients with ≥ 0.5 g/day proteinuria at diagnosis were divided into three groups with mild (0.50-0.99 g/day; n = 264), moderate (1.00-1.99 g/day, n = 216), or severe (≥ 2.00 g/day; n = 153). Decline in kidney function and urinary remission were compared among the three groups after TSP therapy, corticosteroid (ST) therapy, or conservative therapy during a mean follow-up of 6.2 ± 3.3 years. 10.6% and 5.9% of patients in the ST and conservative therapy group underwent tonsillectomy.
RESULTS: The rate of urinary remission at the final observation was significantly higher in the TSP therapy group than in the ST or conservative therapy groups (mild proteinuria: 64%, 43%, and 41%; moderate proteinuria: 51%, 45%, and 28%; severe proteinuria: 48%, 30%, and 22%, respectively). In contrast, the rate of a 50% increase in serum creatinine was lower in groups TSP therapy, than ST or conservative therapy (mild proteinuria: 2.1%, 10.1% and 16.7%; moderate proteinuria: 4.8%, 8.8% and 27.7%; severe proteinuria: 12.0%, 28.9% and 43.1%, respectively). In multivariate analysis, TSP therapy significantly prevented a 50% increase in serum creatinine levels compared with conservative therapy in groups with moderate and severe proteinuria (hazard ratio, 0.12 and 0.22, respectively).
CONCLUSIONS: TSP significantly increased the rate of proteinuria disappearance and urinary remission in IgAN patients with mild-to-moderate urinary protein levels. It may also reduce the decline in kidney function in patients with moderate-to-severe urinary protein levels.

IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis, and serum Helicobacter pylori (H. pylori) antibody levels are increased in patients with IgA N, but the role of H. pylori infection in the pathogenesis of IgAN is unclear. In this study, we investigated whether there is a causal relationship and reverse causality between IgAN and H. pylori infection by using a bidirectional two-sample Mendelian randomization (MR) analysis. This study was estimated using inverse variance weighted (IVW), MR-Egger and weighted median methods, with the IVW method having the strongest statistical efficacy. Seven common serum H. pylori antibodies were selected as exposure factors for positive MR analysis. The results showed that there was no evidence of a causal relationship between H. pylori infection and IgAN. Reverse MR analysis showed that there was also no evidence that the occurrence of IgAN leads to an increased risk of H. pylori infection.

OBJECTIVE: Little is known regarding the association between chronic tonsillitis and the onset of IgA nephropathy (IgAN). In the present study, we examined the potential relationship between chronic tonsillitis and a subsequent risk of developing IgAN.
METHODS: Observational cohort study.
METHODS: & Participants: 4,311,393 individuals without a history of IgAN identified between January 2005 to May 2022 within a Japanese nationwide epidemiological database, the JMDC Claims Database, representing health claims to over 60 insurers.
METHODS: Comorbid chronic tonsillitis based on diagnosis codes.
RESULTS: IgAN occurrence.
METHODS: Cause-specific Cox proportional hazards analysis adjusting for potential confounding factors were employed to estimate hazard ratios (HRs).
RESULTS: Comorbid chronic tonsillitis was identified in 12,842 individuals, constituting 0.3% of the cohort. The cohort had a median age of 44 years (interquartile range: 36-53), and males accounted for 57.9%, with a follow-up of 1,089 days (interquartile range: 532-1,797), during which 2,653 cases of IgAN developed. Cumulative incidence curve showed a higher cumulative incidence of IgAN in individuals with chronic tonsillitis compared to their counterparts without this condition. Multivariable cause-specific analysis further demonstrated that individuals with chronic tonsillitis had an elevated risk of developing IgAN, with a HR of 2.72 (95% confidence interval: 1.79-4.14).
CONCLUSIONS: Potential residual confounders, and lack of consideration for ethnic distinctions.
CONCLUSIONS: Using a largescale epidemiological dataset, these findings suggest a relationship between chronic tonsillitis and an elevated risk of IgAN development in the general Japanese population.

BACKGROUND: Tonsillectomy with steroid pulse therapy (TSP) and tonsillectomy monotherapy (T) have improved the prognosis of patients with immunoglobulin A nephropathy (IgAN). However, a consensus has not been reached on the best treatment for these patients. This study aimed to compare the efficacies of TSP and T.
METHODS: Data of patients with IgAN who received TSP or T were retrospectively analyzed. The exclusion criterion was a serum creatinine level > 1.5 mg/dL. The clinical remission and renal survival rates were compared.
RESULTS: Patients were divided into groups based on the treatment method: the TSP (n = 82) and T groups (n = 41). No significant differences were observed in patient characteristics, except for the observation period (TSP: 60 months, T: 113 months). The log-rank test revealed that the clinical remission rate was significantly higher in the TSP group than in the T group (p < 0.05). The superiority of TSP was also observed in the urinary protein excretion (> / = or < 1 g/day) of the two subgroups. According to the Cox proportional-hazards model, the treatment method and daily urinary protein extraction were independent factors affecting clinical remission. The 10-year renal survival rates in the TSP and T groups were 100% and 92.5%, respectively. The log-rank test revealed a tendency for a higher renal survival rate in the TSP group than in the T group (p = 0.09).
CONCLUSIONS: The clinical remission rate was significantly higher with TSP than with T, regardless of urinary protein levels. TSP tended to have a better renal survival rate than T.

UNASSIGNED: Observational studies have reported inconsistent results on the relationship between chronic kidney disease (CKD) and age-related macular degeneration (AMD). The primary objective of this study was to investigate the causal relationships between estimated glomerular filtration rate (eGFR), CKD, its common causes, and AMD among participants of European descent.
UNASSIGNED: Genetic variants associated with eGFR, CKD and its common causes, encompassing diabetic nephropathy (DN), immunoglobulin A nephropathy (IgAN), and membranous nephropathy (MN) were obtained from previously published genome-wide association studies (GWAS) and FinnGen database. Summary statistics for early AMD, AMD, dry AMD, and wet AMD were acquired from the GWAS and FinnGen database. Inverse-variance-weighted (IVW) method was the main MR analysis. Sensitivity analyses were performed with Cochran\'s Q, MR-Egger intercept, and leave-one-out analysis. In addition, RadialMR was utilized to identify and remove outliers.
UNASSIGNED: IVW results showed that CKD, eGFR were not associated with any type of AMD (p > 0.05). DN (OR: 1.042, 95% CI: 1.002-1.083, p = 0.037) and MN (OR: 1.023, 95% CI: 1.007-1.040, p = 0.005) were associated with an increased risk of earl AMD. DN (OR: 1.111, 95% CI: 1.07-1.154, p = 4.87 × 10-8), IgAN (OR: 1.373, 95% CI: 1.097-1.719, p = 0.006), and MN (OR: 1.036, 95% CI: 1.008-1.064, p = 0.012) were associated with an increased risk of AMD. DN (OR: 1.090, 95% CI: 1.042-1.140, p = 1.57 × 10-4) and IgAN (OR: 1.480, 95% CI: 1.178-1.858, p = 7.55 × 10-4) were associated with an increased risk of dry AMD. The risk of wet AMD was associated with DN (OR: 1.107, 95% CI: 1.043-1.174, p = 7.56 × 10-4) and MN (OR: 1.071, 95% CI: 1.040-1.103, p = 5.48 × 10-6).
UNASSIGNED: This MR study found no evidence of causal relationship between CKD and AMD. DN, IgAN, and MN may increase risk of AMD. This findings underscore the importance of ocular examinations in patients with DN, MN, and IgAN. More studies are needed to support the findings of our current study.

UNASSIGNED: Emerging research suggests that sodium-glucose cotransporter 2 (SGLT2) inhibitors may play a pivotal role in the treatment of primary glomerular diseases. This study was aimed to investigate potential pharmacological targets connecting SGLT2 inhibitors with IgA nephropathy (IgAN) and membranous nephropathy (MN).
UNASSIGNED: A univariate Mendelian randomization (MR) analysis was conducted using publicly available genome-wide association studies (GWAS) datasets. Co-localization analysis was used to identify potential connections between target genes and IgAN and MN. Then, Comparative Toxicogenomics Database (CTD) was employed to predict diseases associated with these target genes and SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin). Subsequently, phenotypic scan analyses were applied to explore the causal relationships between the predicted diseases and target genes. Finally, we analyzed the immune signaling pathways involving pharmacological target genes using the Kyoto encyclopedia of genes and genomes (KEGG).
UNASSIGNED: The results of MR analysis revealed that eight drug targets were causally linked to the occurrence of IgAN, while 14 drug targets were linked to MN. In the case of IgAN, LCN2 and AGER emerged as co-localized genes related to the pharmacological agent of dapagliflozin and the occurrence of IgAN. LCN2 was identified as a risk factor, while AGER was exhibited a protective role. KEGG analysis revealed that LCN2 is involved in the interleukin (IL)-17 immune signaling pathway, while AGER is associated with the neutrophil extracellular traps (NETs) signaling immune pathway. No positive co-localization results of the target genes were observed between two other SGLT2 inhibitors (canagliflozin and empagliflozin) and the occurrence of IgAN, nor between the three SGLT2 inhibitors and the occurrence of MN.
UNASSIGNED: Our study provided evidence supporting a causal relationship between specific SGLT2 inhibitors and IgAN. Furthermore, we found that dapagliflozin may act on IgAN through the genes LCN2 and AGER.

IgA nephropathy progresses to kidney failure, making early detection important. However, definitive diagnosis depends on invasive kidney biopsy. This study aimed to develop non-invasive prediction models for IgA nephropathy using machine learning. We collected retrospective data on demographic characteristics, blood tests, and urine tests of the patients who underwent kidney biopsy. The dataset was divided into derivation and validation cohorts, with temporal validation. We employed five machine learning models-eXtreme Gradient Boosting (XGBoost), LightGBM, Random Forest, Artificial Neural Networks, and 1 Dimentional-Convolutional Neural Network (1D-CNN)-and logistic regression, evaluating performance via the area under the receiver operating characteristic curve (AUROC) and explored variable importance through SHapley Additive exPlanations method. The study included 1268 participants, with 353 (28%) diagnosed with IgA nephropathy. In the derivation cohort, LightGBM achieved the highest AUROC of 0.913 (95% CI 0.906-0.919), significantly higher than logistic regression, Artificial Neural Network, and 1D-CNN, not significantly different from XGBoost and Random Forest. In the validation cohort, XGBoost demonstrated the highest AUROC of 0.894 (95% CI 0.850-0.935), maintaining its robust performance. Key predictors identified were age, serum albumin, IgA/C3, and urine red blood cells, aligning with existing clinical insights. Machine learning can be a valuable non-invasive tool for IgA nephropathy.

Tonsillectomy with steroid pulse therapy (SPT) has been established as an effective treatment for immunoglobulin A nephropathy (IgAN) in Japan. However, the underlying mechanisms supporting tonsillectomy remain unclear. This study assessed palatine tonsils from 77 patients with IgAN, including 14 and 63 who received SPT before and after tonsillectomy, respectively. Tonsils from 21 patients with chronic tonsillitis were analyzed as controls. Specific tonsillar lesions were confirmed in patients with IgAN, correlating with active or chronic renal glomerular lesions and SPT. T-nodule and involution of lymphoepithelial symbiosis scores in tonsils correlated with the incidence of active crescents and segmental sclerosis in the glomeruli, respectively. The study revealed an essential role of the tonsil-glomerular axis in early active and late chronic phases. Moreover, the SPT-preceding group demonstrated no changes in the T-nodule score, which correlated with active crescent formation, but exhibited a considerable shrinkage of lymphatic follicles that produced aberrant IgA1. The study underscores the involvement of innate and cellular immunity in IgAN and advocates for tonsillectomy as a necessary treatment alongside SPT for IgAN, based on a stepwise process.

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