In IgA nephropathy (IgAN), pathogenic IgA1 deposits in the glomerular mesangium through specific interactions with mesangial cell surface receptors. However, the precise molecular mechanisms underlying this deposition remain incompletely understood. In this study, we observed a significant upregulation of transferrin receptor 2 (TFR2) expression in mesangial cells derived from the kidney tissue of IgAN patients, with TFR2 expression levels positively correlating with disease severity. Mechanistically, TFR2 was found to bind stably to IgA1, as demonstrated by molecular docking, immunofluorescence, and co-immunoprecipitation experiments. Moreover, TFR2 upregulation induced mitochondrial iron overload and promoted mesangial cell proliferation. Through high-throughput drug screening and molecular dynamics simulations, we identified CBL0137 as a small-molecule TFR2 inhibitor, which effectively suppressed TFR2-mediated IgA1 deposition and mesangial cell proliferation in an IgAN mouse model. These findings were further confirmed in human mesangial cells in vitro. Taken together, our results suggest that IgA1 promotes mesangial cell proliferation by upregulating TFR2 expression and inducing mitochondrial iron overload, contributing to IgA1 deposition in IgAN. This study provides novel insights into the molecular mechanisms of IgA1 deposition in mesangial cells and identifies TFR2 as a potential therapeutic target for IgAN.

Emerging evidence suggests a potential role of endothelial activation and oxidative stress in the pathogenesis of diabetic kidney disease (DKD). Endothelial activation and stress index (EASIX) is a reliable alternative biomarker of endothelial dysfunction. We aimed to investigate the relationship between the EASIX and both all-cause and cardiovascular mortality in individuals with DKD. Data were extracted from the National Health and Nutrition Examination Survey database. Multivariable Cox proportional hazards models were applied to assess the relationship between EASIX and mortality. Kaplan-Meier survival curves, Subgroup analyses, receiver operating characteristic curves, and sensitivity analyses were conducted. Additionally, restricted cubic spline analysis was employed to elucidate the nonlinear relationships between EASIX and hazard ratio in DKD patients. A total of 1700 participants were included in this study. Over a median follow-up of 87.6 months, 571 all-cause deaths were recorded. The highest EASIX group showed higher hazard ratios for all-cause and cardiovascular mortality in both crude and multivariable-adjusted models. In the fully adjusted model, the hazard ratios for the highest EASIX group were 1.59 (95

Aberrant mucosal IgA production is central to IgA nephropathy (IgAN), yet the regulatory mechanisms remain poorly understood. TRIM21 has been identified as a key gene in IgAN, but its functional contribution to disease pathogenesis is unclear. In this study, we investigated whether TRIM21 regulates mucosal IgA synthesis and disease progression. TRIM21 expression was significantly reduced in peripheral blood mononuclear cells from IgAN patients and correlated inversely with serum IgA levels. In Trim21-/- mice subjected to oral mucosal immunization, TRIM21 deficiency exacerbated disease phenotypes, including increased urinary protein-to-creatinine ratio and serum creatinine, impaired intestinal barrier integrity, and expansion of IgA+ B cells in gut-associated lymphoid tissues. Mechanistically, TRIM21 may directly bind IκBα and promote its ubiquitination, thereby restraining NF-κB activation and downstream AID expression. Loss of TRIM21 relieved this suppression, leading to enhanced IgA class switching. Collectively, these findings demonstrate that TRIM21 negatively regulates intestinal IgA biosynthesis by ubiquitinating IκBα and inhibiting the NF-κB-AID axis, identifying the TRIM21-IκBα-NF-κB pathway as a potential therapeutic target in IgAN.

IgA nephropathy (IgAN) is currently the most common primary glomerular disease worldwide, and early diagnosis and intervention contribute significantly to improving outcomes and reducing the incidence of renal failure. The pathogenesis of IgAN remains incompletely understood. In recent years, the rapid development of single-cell RNA-sequencing (scRNA-seq) technology has provided the high-resolution and rich data necessary to elucidate disease characteristics and enabled the analysis of complex interactions between individual cells and cell types. The application of scRNA-seq in IgAN successfully revealed the landscape of immunological features, including peripheral blood B-cell and Th-cell activation, cytotoxic T-cell depletion, and renal infiltrating cell subtypes, as well as the crucial role of mesangial cells and endothelial cells in the early stage of kidney injury, and also revealed the extensive intercellular interactions between renal cells. Here, we discuss the research progress of scRNA-seq technology in IgAN. These scRNA-seq profiles help us to understand the complex molecular mechanisms of IgAN and develop biomarkers and specific therapeutic strategies.

Most IgA nephropathy (IgAN) patients will progress to end-stage renal disease within 10-15 years of diagnosis. Telitacicept is a B lymphocyte stimulator/A proliferation-inducing ligand dual-target fusion protein that has recently been used in autoimmune diseases. A phase II clinical trial with a small sample size indicated the efficacy of Telitacicept treatment with 160 mg or 240 mg once a week in reducing proteinuria in patients with IgAN. This study assessed the efficacy and safety of low-dose Telitacicept in IgAN patients. Biopsy-proven IgAN patients with 24-hour proteinuria > 0.5 g/day or UPCR > 500 mg/g who received low-dose Telitacicept (80 mg qw) were recruited in this study. This study included 15 IgAN patients who received Telitacicept treatment, forming the ‘Telitacicept group’. Additionally, 15 patients selected to match historical controls received immunosuppressive (IS) therapy (IS agents with or without corticosteroid therapy) and were classified as the ‘IS group’. These patients were matched 1:1 with the Telitacicept group based on age, sex, eGFR, and UPCR levels to enhance the comparability between groups (as detailed in Table 1). Telitacicept was partially used with the supplement of hydroxychloroquine or IS agents (but without corticosteroids) in different doses. Among the Telitacicept group, 6 patients showed severe renal impairment, with eGFR < 35 mL/min/1.73 m2, which was the exclusion criteria in the Telitacicept phase II clinical trial. The primary outcomes were the changes in UPCR and eGFR over time. This study analyzed changes from baseline in UPCR and eGFR through 4 months using a mixed-effects model for repeated measurements. The median duration of follow-up was 126 and 130 days for the Telitacicept and IS groups, respectively. As for reducing proteinuria, reductions in UPCR in the Telitacicept group were observed in month 2 (P = 0.036) and persisted until month 4 (P = 0.010). In the fourth month, the Telitacicept group showed a change in UPCR from a baseline of −44.65% compared with 5.63% in the IS group, despite no statistical difference between Telitacicept and IS group over the current observation (P = 0.180). Additionally, Telitacicept was superior to reducing proteinuria among patients with severe renal impairment (P = 0.022), with a change in UPCR from baseline at 4 months of −30.38%, compared with 111.17% in the conventional IS group (P < 0.001). At 4 months, the eGFR change from baseline was 0.57 mL/min/1.73 m2 in all participants who received Telitacicept treatment, compared to −1.57 mL/min/1.73 m2 in IS groups. Compared with the IS group, Telitacicept exhibited a kidney protection effect according to the values of eGFR change from baseline over 4 months of observation (P = 0.037), while the percentage change of eGFR from baseline showed no difference between groups during observation. Telitacicept was generally well-tolerated during the research period, with the most common adverse event in the Telitacicept group assessed as related by the study investigator was blood IgG decrease (4/15 [26.7%]). This study indicates that low-dose Telitacicept alone or assisted with IS therapy can significantly and safely reduce proteinuria and protect eGFR in patients with IgAN. Additionally, Telitacicept showed superior kidney protection efficacy compared with IS agents during the 4-month follow-up.

OBJECTIVES:IgA nephropathy (IgAN) is the most common primary glomerular disease in China, but its pathogenesis remains unclear. This study aims to explore the regulatory role of the mammalian target of rapamycin (mTOR) signaling pathway in autophagy and mesangial proliferation during renal injury in IgA. METHODS:The activity of mTOR and autophagy was evaluated in kidney samples from IgAN patients and in an IgAN mouse model induced by oral bovine serum albumin and carbon tetrachloride (CCl4) injection. mTOR inhibitors (rapamycin) and activators [bpV(phen)] were administered to the IgAN mouse model to observe the effects of mTOR on autophagy and renal lesions. In human mesangial cells treated with polymeric IgA1 (p-IgA1) and mTOR modulators, the expression and distribution of cell cycle proteins were assessed, along with the effects of mTOR on mesangial cell proliferation and autophagy. RESULTS:Increased mTOR activity and decreased autophagy were observed in kidney tissues from IgAN patients and the mouse model, as evidenced by elevated phosphorylated mTOR (p-mTOR) levels and reduced LC3 expression. In the IgAN mouse model, rapamycin inhibited mTOR, restored autophagy, reduced mesangial IgA deposition, alleviated mesangial cell proliferation, and decreased proteinuria (all P<0.05). In contrast, bpV(phen) activated mTOR, further suppressed autophagy, exacerbated kidney damage, and increased proteinuria (all P<0.05). In vitro, p-IgA1 induced mesangial cell proliferation and inhibited autophagy, effects that were reversed by rapamycin and aggravated by bpV(phen) (all P<0.05). mTOR regulated mesangial cell proliferation by altering cell cycle distribution, with rapamycin inducing G1 phase arrest and bpV(phen) promoting cell cycle progression. Additionally, cyclinD1 expression in renal cortex was up-regulated in the IgAN mouse model, further increased by bpV(phen), and reduced by rapamycin (all P<0.05). CONCLUSIONS:Inhibition of the mTOR signaling pathway enhances renal autophagy, reduces mesangial cell proliferation, and improves renal injury in IgAN.

INTRODUCTION:Due to the confounding heterogeneity, the therapeutic strategy for proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) remains to be defined. CASE REPRESENTATION:We report a 38-year-old man with recurrent swelling of the eyelids and lower limbs, undergoing rituximab combined with steroid and tacrolimus treatment, who achieved an improved renal outcome. Underlying solid malignant tumours were excluded from the diagnosis. DISCUSSION:We treated patients with rituximab along with steroids and tacrolimus. Improvements in proteinuria and renal function were observed. We also reviewed the current literature to assess the efficacy of rituximab in the treatment of PGNMID. CONCLUSION:However, a larger pool of patients and a longer follow-up period are required to establish the role of rituximab and steroids in the treatment of PGNMID.

Increasing evidence suggests that the mononuclear/macrophage system is vital in amplifying the inflammatory cascade in IgA Nephropathy (IgAN). However, the pathogenic mechanism of macrophages in IgAN and targeted treatment strategies still need to be explored. This study found that botanical triterpene celastrol (CLT) effectively alleviated renal lesions, M1-like macrophage infiltration, inflammatory factors production, and improved renal function in IgAN mice. We found that the renal macrophages of IgAN patients had high expression of ECM1, a crucial molecule involved in macrophage inflammatory polarization, positively correlated with the IgAN clinical severity. In murine macrophage Raw 264.7 cells, CLT inhibited macrophage M1-like polarization and the output of TNF-α and IL-6 by downregulating the ECM1/STAT5 pathway. Mechanistically, molecular docking, CESTA, and immunoprecipitation verified that CLT directly bound to ECM1 and increased the ubiquitination of ECM1. Collectively, these results illustrated that CLT inhibited proinflammatory macrophage in IgAN by directly targeting ECM1 to promote ubiquitination degradation of ECM1. Therefore, this study may provide a theoretical basis for exploring the pathogenesis of IgAN and identifying new perspectives for targeted therapy of IgAN.

Department of Nephrology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China.

Department of Nephrology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China.

Purpose:Accumulating clinical evidence showed that Tripterygium hypoglaucum (Lév.) Hutch (THH) is effective against IgA nephropathy (IgAN), but the mechanism is still unclear. This study is to evaluate the renal protective effect and molecular mechanism of THH against IgAN via network pharmacology, molecular docking strategy and experimental validation. Methods:Several databases were used for obtaining the active ingredients of THH, the corresponding targets, as well as the IgAN-related genes. The critical active ingredients, functional pathways, and potential for the combination of the hub genes and their corresponding active components were determined through bioinformatics analysis and molecular docking. The IgAN mouse model was treated with celastrol (1 mg/kg/d) for 21 days, and the aggregated IgA1-induced human mesangial cell (HMC) was treated with various concentrations of celastrol (25, 50 or 75 nM) for 48 h. The immunohistochemistry and Western blot techniques were applied to evaluate the protein expression of the predicted target. The cell counting kit 8 (CCK8) was used to detect HMC proliferation. Results:A total of 17 active ingredients from THH were screened, covering 165 IgAN-related targets. The PPI network identified ten hub targets, including PTEN. The binding affinity between the celastrol and PTEN was the highest (-8.69 kJ/mol). The immunohistochemistry showed that celastrol promoted the expression of PTEN in the glomerulus of IgAN mice. Furthermore, the Western blot techniques showed that celastrol significantly elevated the expression of PTEN and inhibited PCNA and Cyclin D1 in vitro and in vivo. The CCK8 assay determined that celastrol decreased HMC proliferation in a concentration-dependent manner. Conclusion:This study suggests that activating PTEN by celastrol may play a pivotal role in THH alleviating IgAN renal injury.

Department of Nephrology, The Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China.

AbstractBackground Severe renal impairment is a common complication of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and is associated with poor prognosis and shorter survival. It is urgent to find effective treatments to improve the prognosis of AAV patients. This study was designed to assess the efficacy and safety of protein A immunoadsorption (PAIA) and therapeutic plasma exchange (TPE) for AAV with severe renal involvement.Methods A total of 48 AAV patients with renal involvement admitted to the Second Xiangya Hospital from January 2018 to February 2021 were selected. Clinical data, myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA), remission at 6 months, and outcomes were evaluated. The primary outcomes of interest were death and renal survival as defined by the occurrence of end-stage renal disease (ESRD).Results PAIA was effective in the removal of MPO-ANCA and IgG, and showed superior over TPE in the clearance of MPO-ANCA within 1 month after treatment. After a median follow-up of 14.5 months, PAIA therapy showed an advantage in reducing mortality over TPE. There was no difference in the development of ESRD between the two groups. Multivariate Cox regression analysis indicated that higher serum creatinine (SCr) and lower haemoglobin level were independent risks of ESRD. Age > 60, lower serum albumin (ALB), and failure to achieve remission at 6 months were independent risks of death.Conclusions PAIA treatment reduces MPO-ANCA and IgG as well as mortality in AAV patients, and may be beneficial for severe AAV in clinical practice. Higher SCr, lower serum ALB or haemoglobin levels, age > 60, and failure to achieve remission at 6 months independently predict the ESRD or death of AAV patients with severe renal involvement.KEY MESSAGESCompared with therapeutic plasma exchange, protein A immunoadsorption treatment eliminates myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) and IgG better and reduces mortality in ANCA-associated vasculitis (AAV) patients with severe renal involvement.Higher serum creatinine, lower serum albumin or haemoglobin levels, age > 60, and failure to achieve remission at 6 months independently predict the end-stage renal disease (ESRD) or death of AAV patients with severe renal involvement.

Background The efficacy and indications of tonsillectomy in IgA nephropathy (IgAN) remain uncertain. Methods We performed a retrospective cohort study of 452 patients with primary IgAN, including 226 patients who received tonsillectomy and 226 controls selected by propensity score matching who had never undergone tonsillectomy. Study outcomes were clinical remission defined as negative hematuria and proteinuria on three consecutive visits over a 6-month period, the endpoint defined as end-stage renal disease or an irreversible 100% increase in serum creatinine from the baseline value. In addition, we further analyzed the critical level of proteinuria in the efficacy of tonsillectomy and the correlation between MEST-C score and tonsillectomy. Results Up to December 2019, the follow-up period lasted 46 ± 23 months (12–106 months). Kaplan–Meier and multivariate Cox regression analysis revealed that tonsillectomy was beneficial for clinical remission and renal survival. Whether proteinuria was ≤ 1 g/24h or >1 g/24h, the clinical remission and renal survival rates were greater in patients treated with tonsillectomy than without. When the pathological damage was mild or relatively severe, tonsillectomy may be beneficial to clinical remission or renal survival. Conclusions Tonsillectomy had a favorable effect on clinical remission and delayed renal deterioration in IgAN. In addition to patients with early stage IgAN, it may also be beneficial to IgAN patients with higher levels of proteinuria and relatively severe pathological damage.

Background.The efficacy and indications of tonsillectomy in IgA nephropathy (IgAN) remain uncertain.Methods.We performed a retrospective cohort study of 452 patients with primary IgAN, including 226 patients who received tonsillectomy and 226 controls selected by propensity score matching who had never undergone tonsillectomy.Study outcomes were clinical remission defined as negative hematuria and proteinuria on three consecutive visits over a 6-month period, the endpoint defined as end-stage renal disease or an irreversible 100% increase in serum creatinine from the baseline value.Besides, we further analyzed the critical level of proteinuria in the efficacy of tonsillectomy and the correlation between MEST-C score and tonsillectomy.Results.Up to December 2019, the follow-up period lasted 46±23 months (12-106 months).Kaplan-Meier and multivariate Cox regression analysis revealed that tonsillectomy was beneficial for clinical remission and renal survival.Whether proteinuria was ≤1g/24h or >1g/24h, the clinical remission and renal survival rates were greater in patients treated with tonsillectomy than without.When the pathological damage was mild or relatively severe, tonsillectomy may be beneficial to clinical remission or renal survival. Conclusions.Tonsillectomy had a favorable effect on clinical remission and delayed renal deterioration in IgAN.In addition to patients with early stage IgAN, it may also be beneficial to IgAN patients with higher levels of proteinuria and relatively severe pathological damage.