Pathogenesis Of IgA Nephropathy Research Articles

POS-546 EFFICACY AND SAFETY OF IPTACOPAN IN IgA NEPHROPATHY: RESULTS OF A RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED PHASE 2 STUDY AT 6 MONTHS

No approved targeted therapies currently exist for IgA nephropathy (IgAN). Targeting the alternative complement pathway (AP) is an attractive therapeutic strategy given its role in the pathogenesis of IgAN. Iptacopan (LNP023) is a first-in-class, oral, potent and highly selective inhibitor of factor B of AP. This randomized, double-blind, dose-ranging, parallel-group adaptive design Phase 2 study (NCT03373461) enrolled patients with biopsy-confirmed IgAN (within the previous 3 years), urine protein-to-creatinine ratio (UPCR) ≥0.8 g/g or urine protein ≥0.75 g/24 h, and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. Part 1 of the study enrolled patients for a 3-month treatment period; Part 2 of the study enrolled patients for a 6-month treatment period; both Parts comprised a 3-month treatment-free follow-up. Patients were randomized to one of the four iptacopan arms (10, 50, 100 [in Part 2 only], and 200 mg bid) or placebo. In this analysis, we report efficacy and biomarker data assessed at 6 months and treatment-emergent adverse events (AEs) assessed for the entire study duration. In addition to the pre-specified efficacy analysis of Part 2 at 6 months, Post hoc analyses combining data from Parts 1 and 2 were also performed. 46 and 66 patients were randomized in Parts 1 and 2, respectively. In Part 2, 58 patients completed 6 months of treatment. Demographic and baseline characteristics were generally well-balanced across all arms. The primary analysis yielded a statistically significant dose-response effect (1-sided p=0.038) of iptacopan versus placebo at 3 months, with maximal reduction in UPCR achieved with iptacopan 200 mg bid (23%; 80% CI: 8–34% using MCP-mod; Primary results were presented at 58thERA-EDTA Congress 2021 as late-breaking clinical trial ). UPCR continued to decrease between 3 and 6 months in the higher dosed iptacopan arms in Part 2, albeit with a wider 80% CI reflecting the smaller sample size. To allow better comparison with the primary analysis at 3 months, a Post hoc analysis of pooled data from Parts 1 and 2 was performed. The results indicated UPCR reduction from baseline up to 6 months in iptacopan 200 mg bid arm by up to 40% (80% CI: 16–53% using MCP-mod model) and at least 28% (80% CI: 3–46% using MMRM model) versus placebo (Figure 1). Sustained inhibition of AP biomarkers including plasma Bb, serum Wieslab, and urinary C5b-9 through 6 months was also observed with all doses of iptacopan above 10 mg bid (Figure 2). Iptacopan had a well-tolerated safety profile, with no deaths, no serious adverse events (SAEs) suspected to be treatment-related, and no serious infections caused by encapsulated bacteria. Iptacopan was well tolerated and led to continuous reduction in proteinuria and strong inhibition of AP activity through 6 months in patients with IgAN. These data are consistent with previous findings from the interim analysis at 3 months and support further evaluation of iptacopan in the ongoing Phase 3 APPLAUSE-IgAN trial (NCT04578834).

POS-098 HYDROXYCHLOROQUINE PREVENTS THE DISEASE PROGRESSION IN THE MURINE IGA NEPHROPATHY MODEL VIA INHIBITING TLR9/TLR7 SIGNALS AND RELATED CYTOKINES

Galactose-deficient IgA1 (Gd-IgA1) plays a crucial role in the pathogenesis of IgA nephropathy (IgAN). There has been increasing evidence suggested overactivation of Toll-like receptor (TLR) signals, especially TLR9 and TLR7, is involved in the production of Gd-IgA1 and affects disease progression of IgAN. Recently, several clinical trials suggested hydroxychloroquine (HCQ) which is known to suppress TLR9 and TLR7 signals might be effective to reduce proteinuria in patients with IgAN. However, because of the complicated pharmacological effects of HCQ, the exact mechanism in treating IgAN has not been fully elucidated.

POS-108 A PHASE 1/2, MULTICENTER TRIAL TO INVESTIGATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS AND PHARMACODYNAMICS OF BION-1301 IN HEALTHY VOLUNTEERS AND ADULTS WITH IgA NEPHROPATHY

IgA nephropathy (IgAN) is the most common primary glomerulonephritis globally, with up to 45% of IgAN patients at risk of progressing to ESKD. There are currently no approved treatments specifically for IgA nephropathy. The initiating step in IgAN pathogenesis is the excess production of galactose-deficient IgA1 (Gd-IgA1) resulting in formation of pathogenic immune complexes that cause kidney inflammation and damage. A Proliferation-Inducing Ligand (APRIL), a TNF-superfamily cytokine, is elevated in IgAN patients and correlated with higher levels of Gd-IgA1 and proteinuria, and lower eGFR.

POS-109 INTERIM RESULTS OF PHASE 1 AND 2 TRIALS TO INVESTIGATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, PHARMACODYNAMICS, AND CLINICAL ACTIVITY OF BION-1301 IN PATIENTS WITH IgA NEPHROPATHY

IgA nephropathy (IgAN) is an autoimmune disease with no approved treatments. A critical step in IgAN pathogenesis is the production of galactose-deficient IgA1 (Gd-IgA1) leading to the generation of anti-Gd-IgA1 autoantibodies and the formation of immune complexes that result in kidney inflammation and damage. A Proliferation-Inducing Ligand (APRIL), a soluble factor that regulates B cell differentiation, proliferation and survival of plasma cells, and IgA class-switching is elevated in patients with IgAN. IgAN patients with high plasma APRIL levels are reported as having higher levels of Gd-IgA1 and proteinuria and lower estimated glomerular filtration rates compared to those with lower plasma APRIL levels. BION-1301 is a novel humanized blocking antibody targeting APRIL that has been evaluated in a Phase 1 study of healthy volunteers (HV). In that study, BION-1301 was well-tolerated with no serious adverse events (SAEs), a pharmacokinetic (PK) half life >30 days and demonstrated dose-dependent pharmacodynamic (PD) effects characterized by durable reductions in serum levels of free April (fAPRIL), IgA and Gd-IgA1, IgM, and to a lesser extent IgG. Here we present interim results from Part 3 of the Phase 1 and the Phase 2 Open-Label Extension (OLE) trials that characterize the safety, PK and PD profile, and preliminary efficacy of BION-1301 in patients with IgAN. The Phase 1 study (NCT03945318) comprises 3 parts. Parts 1 and 2 assessed single- and multiple ascending doses of BION-1301 in HV from 10mg to 1350mg and 50mg to 450mg once every 2 weeks for one month, respectively. Part 3 is an ongoing, open-label, two cohort design in approximately 20 IgAN patients with BION-1301 at 450mg once every 2 weeks for a total of 12 weeks. Key eligibility criteria for Part 3 include: (1) biopsy-verified diagnosis of IgAN within the past 10 years,(2) urine protein ≥0.5 g/24h or baseline UPCR ≥0.5 g/g, and (3) stable/optimized dose of ACE-I/ARB (or intolerant). Patients completing Part 3 are eligible to enroll in the Phase 2 OLE study (NCT04684745) to receive BION-1301 for an additional 2 years. To evaluate PK and PD effects of BION-1301, serum levels of BION-1301, fAPRIL, antidrug antibodies (ADA), neutralizing antibodies (NAbs), and Gd-IgA1 were quantitated using ELISA-based immunoassays. Serum levels of IgA, IgG, and IgM were measured by immunoturbidimetry. UPCR was assessed from 24-hour urine collections. BION-1301 has been well tolerated in IgAN patients receiving a 450mg IV dose every two weeks for 12+ weeks with no SAEs or treatment related AE’s. Consistent with PD responses reported in HVs, durable reductions in serum levels of fAPRIL and immunoglobulins were observed in IgAN patients. Clinically meaningful reductions in proteinuria were seen as early as 12 weeks and were associated with the reduction in Gd-IgA1 levels. Additional data from patients receiving long-term treatment will be updated. This abstract was also submitted for the 58thERA-EDTA Congress. BION-1301 offers disease modifying potential by directly targeting the underlying multi-hit immune pathogenesis of IgAN, which is not addressed with the current standard of care treatment. Promising early biomarker and clinical activity responses support the continued development of BION-1301 in IgAN.

New insights into pathogenesis of IgA nephropathy.

IgA nephropathy (IgAN) is the usual form of glomerulonephritis worldwide; however, the pathogenesis remains complex and uncertain. The interactions of gene, immune and environment lead to the variability of IgAN clinical presentations. Except for gene, it is still a question that what kind of the external factors that may cause IgAN. We summarized exposome, microbiome and infectome may be involved in the pathogenesis of IgAN through literature. Based on the above discoveries, we proposed a hypothesis of the course of IgAN that gene determines the internal cause, while skin and mucosa inflammations are the conditions of inducing immune disorders, the low point of immune disorders and change of immune status caused by internal and external environment lead to the disease onset. Therefore, a more detailed clinical phemomics of IgAN was required to be collected for further study.

Downregulation of PPARα mediates FABP1 expression, contributing to IgA nephropathy by stimulating ferroptosis in human mesangial cells.

Immunoglobulin A nephropathy (IgAN) is the commonest primary glomerulonephritis, and a major cause of end-stage renal disease; however, its pathogenesis requires elucidation. Here, a hub gene, FABP1, and signaling pathway, PPARα, were selected as key in IgAN pathogenesis by combined weighted gene correlation network analysis of clinical traits and identification of differentially expressed genes from three datasets. FABP1 and PPARα levels were lower in IgAN than control kidney, and linearly positively correlated with one another, while FABP1 levels were negatively correlated with urinary albumin-to-creatinine ratio, and GPX4 levels were significantly decreased in IgAN. In human mesangial cells (HMCs), PPARα and FABP1 levels were significantly decreased after Gd-IgA1 stimulation and mitochondria appeared structurally damaged, while reactive oxygen species (ROS) and malondialdehyde (MDA) were significantly increased, and glutathione and GPX4 decreased, relative to controls. GPX4 levels were decreased, and those of ACSL4 increased on siPPARα and siFABP1 siRNA treatment. In PPARα lentivirus-transfected HMCs stimulated by Gd-IgA1, ROS, MDA, and ACSL4 were decreased; glutathione and GPX4, and immunofluorescence colocalization of PPARα and GPX4, increased; and damaged mitochondria reduced. Hence, PPARα pathway downregulation can reduce FABP1 expression, affecting GPX4 and ACSL4 levels, causing HMC ferroptosis, and contributing to IgAN pathogenesis.

Molecular insights into the early stage of glomerular injury in IgA nephropathy using single-cell RNA sequencing

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and defined by the presence of IgA-containing immune complexes in the mesangium that induce an inflammation leading to glomerulonephritis. Since we poorly understand early mechanisms of glomerular injury in IgAN we performed single-cell RNA sequencing (scRNA-seq) analysis of glomerulus-associated cells using SMARTseq2-technology at the early stage of IgAN in grouped ddY-mice. Cell-specific molecular signatures unraveled a key role of endothelial cells in the early pathogenesis of IgAN, especially in the recruitment and infiltration of immune cells. Mesangial and podocyte cells demonstrated less molecular changes. Several intra-glomerular paracrine pathways were detected, such as mesangial cell-derived Slit3 potentially activating Robo-receptors in podocyte/endothelial cells. Surprisingly, proximal tubular cells were strongly affected at the early stage and potential glomerulo-tubular cell-cell crosstalk pathways were identified. Importantly, many of the cellular transcriptomic signatures identified in this well-established mouse model were also detected in published bulk transcriptomic data in human IgAN. Moreover, we validated the functionality of key cell-cell crosstalk pathways using cell culture models, such as the effect of the Slit-Robo signalling axis. Thus, our study provides important novel molecular insights into the pathogenesis of early IgAN-associated glomerulopathy.

Immune Characteristics of IgA Nephropathy With Minimal Change Disease

Background: IgA nephropathy (IgAN) has a high degree of heterogeneity in clinical and pathological features. Among all subsets of IgAN, the pathogenesis of IgAN with minimal change disease (MCD-IgAN) remained controversial. Methods: We analyzed the clinical and pathological characteristics of MCD-IgAN patients in a retrospective cohort. Patients diagnosed with IgAN, excluding MCD-IgAN, were randomly selected as controls. Levels of plasma galactose-deficient IgA1 (GdIgA1), IgG autoantibodies against GdIgA1, GdIgA1 deposition in the glomerulus, and inflammatory reactivity of circulating poly-IgA1 complexes to cultured mesangial cells were evaluated. Results: Patients with MCD-IgAN had significantly higher levels of proteinuria and estimated glomerular filtration rate (eGFR), lower levels of albumin and urine blood cells, and milder histological lesions by a light microscope compared to IgAN patients, which bears a resemblance to MCD. Lower levels of GdIgA1 (3.41 ± 1.68 vs. 4.92 ± 2.30 μg/ml, p = 0.009) and IgG antiglycan autoantibodies (23.25 ± 22.59 vs. 76.58 ± 71.22 IU/ml, p < 0.001) were found in MCD-IgAN patients than those in IgAN controls. Meanwhile, weaker fluorescence intensities of both IgA and GdIgA1 were observed in the glomerulus of MCD-IgAN patients compared to those in IgAN patients. Furthermore, poly-IgA1 complexes from MCD-IgAN patients induced weaker inflammatory effects on cultured mesangial cells than those from IgAN patients in vitro. Conclusion: The results demonstrated that MCD-IgAN cases represent a dual glomerulopathy, namely, mild IgAN with superimposed MCD, which furthermore provides substantial evidence for the corticosteroids therapy in MCD-IgAN patients as the guidelines recommended.

Relationship between IgA Nephropathy and Porphyromonas gingivalis; Red Complex of Periodontopathic Bacterial Species.

IgA nephropathy (IgAN) has been considered to have a relationship with infection in the tonsil, because IgAN patients often manifest macro hematuria just after tonsillitis. In terms of oral-area infection, the red complex of periodontal bacteria (Porphyromonas gingivalis (P. gingivalis), Treponema denticol (T. denticola) and Tannerella forsythia (T. forsythia)) is important, but the relationship between these bacteria and IgAN remains unknown. In this study, the prevalence of the red complex of periodontal bacteria in tonsil was compared between IgAN and tonsillitis patients. The pathogenicity of IgAN induced by P. gingivalis was confirmed by the mice model treated with this bacterium. The prevalence of P. gingivalis and T. forsythia in IgAN patients was significantly higher than that in tonsillitis patients (p < 0.001 and p < 0.05, respectively). A total of 92% of tonsillitis patients were free from red complex bacteria, while only 48% of IgAN patients had any of these bacteria. Nasal administration of P. gingivalis in mice caused mesangial proliferation (p < 0.05 at days 28a nd 42; p < 0.01 at days 14 and 56) and IgA deposition (p < 0.001 at day 42 and 56 after administration). Scanning-electron-microscopic observation revealed that a high-density Electron-Dense Deposit was widely distributed in the mesangial region in the mice kidneys treated with P. gingivalis. These findings suggest that P. gingivalis is involved in the pathogenesis of IgAN.

Transmembrane signaling molecules play a key role in the pathogenesis of IgA nephropathy: a weighted gene co-expression network analysis study

BackgroundImmunoglobulin A nephropathy (IgAN) is one of the most common primary glomerulonephritis and a serious health concern worldwide; though still the underlying molecular mechanisms of IgAN are yet to be known and there is no efficient treatment for this disease. The main goal of this study was to explore the IgAN underlying pathogenic pathways, plus identifying the disease correlated modules and genes using the weighted gene co-expression network analysis (WGCNA) algorithm.ResultsGSE104948 dataset (the expression data from glomerular tissue of IgAN patients) was analyzed and the identified differentially expressed genes (DEGs) were introduced to the WGCNA algorithm for building co-expression modules. Genes were classified into six co-expression modules. Genes of the disease’s most correlated module were mainly enriched in the immune system, cell–cell communication and transmembrane cell signaling pathways. The PPI network was constructed by genes in all the modules and after hub-gene identification and validation steps, 11 genes, mostly transmembrane proteins (CD44, TLR1, TLR2, GNG11, CSF1R, TYROBP, ITGB2, PECAM1), as well as DNMT1, CYBB and PSMB9 were identified as potentially key players in the pathogenesis of IgAN. In the constructed regulatory network, hsa-miR-129-2-3p, hsa-miR-34a-5p and hsa-miR-27a-3p, as well as STAT3 were spotted as top molecules orchestrating the regulation of the hub genes.ConclusionsThe excavated hub genes from the hearts of co-expressed modules and the PPI network were mostly transmembrane signaling molecules. These genes and their upstream regulators could deepen our understanding of IgAN and be considered as potential targets for hindering its progression.

TRIM40 inhibits IgA1-induced proliferation of glomerular mesangial cells by inactivating NLRP3 inflammasome through ubiquitination

IgA nephropathy, as the most common type of glomerulonephritis, causes chronic renal disease and progresses into kidney failure. Aberrant IgA deposition in the glomerular mesangium induces NLRP3 inflammasome activation for massive local inflammation, and is recognized as the primary pathogenesis in IgA nephropathy. Tripartite motif (TRIM)-containing proteins are E3 ubiquitin ligases that possess crucial regulatory functions in innate immunity, but their functional roles in IgA nephropathy are still unclear. Here, we aimed to identify TRIM-containing proteins that regulate IgA nephropathy and their underlying mechanisms. An in vitro IgA1-induction model was established in glomerular mesangial cells (GMCs) and showed that IgA1 could promote GMC proliferation by activating NLRP3 inflammasome. TRIM40, which was downregulated by IgA1 and interacted with NLRP3, was recognized as a promising candidate. In addition, TRIM40 could suppress IgA1-induced GMC proliferation by inhibiting the activation of NLRP3 inflammasome. Based on coimmunoprecipitation and ubiquitination assays, we confirmed that TRIM40 could mediate the ubiquitination of NLRP3, which explained its regulatory effects on NLRP3 inflammasome and GMC proliferation. More importantly, a dominant-negative mutant of TRIM40 lacking the RING domain (ΔRING) did not affect NLRP3 ubiquitination, and had no effects on IgA1-induced GMC proliferation or NLRP3 inflammasome activation. This study revealed the biological functions of TRIM40 in IgA nephropathy, facilitating its application as therapeutic target for IgA nephropathy and other NLRP3 inflammasome-relevant diseases.

KM55 in the Evaluation of IgA-Containing Glomerular Diseases

Introduction: Mucosal-derived galactose-deficient IgA is central to the pathogenesis of primary IgA nephropathy (IgAN). Recent reports suggest similar pathogenesis in Henoch-Schonlein purpura (HSP) and secondary IgAN. Its role in other IgA-containing glomerular diseases is still under investigation. It can be detected in glomeruli with the recently described antibody KM55. We aimed to evaluate the role of KM55 by immunostaining a wide spectrum of IgA-containing glomerular diseases. Methods: After standardization and colocalization in a case of IgAN, a spectrum of 60 cases including IgAN, HSP, chronic liver disease (CLD)-related IgAN, other secondary IgAN, IgA-dominant/codominant membranoproliferative glomerulonephritis (MPGN), and lupus nephritis were subjected to immunofluorescence with KM55. KM55 was used to resolve diagnostic dilemma in cases of IgA deposition with confounding histology. Results: The group of primary IgAN (17 cases), HSP (4 cases), and secondary IgAN (19 cases) including CLD showed 2–3+ granular staining with KM55, suggesting mucosal-derived IgA. In contrast, cases of IgA-dominant/codominant MPGN (8 cases) and lupus nephritis (12 cases) were negative for KM55, suggesting systemic derivation of IgA. In cases of IgA deposition with confounding histology such as membranoproliferative or diffuse endocapillary proliferative pattern, KM55 helped to resolve the diagnosis. Discussion/Conclusion: This cross-sectional study concludes that KM55 is useful in the evaluation of IgA-containing glomerular diseases from a pathogenetic perspective and is a practical tool in resolving differential diagnosis in cases with overlapping histopathological features.

Soluble CD89 is a critical factor for mesangial proliferation in childhood IgA nephropathy

Childhood IgA nephropathy (IgAN) includes a wide spectrum of clinical presentations, from isolated hematuria to acute nephritis with rapid loss of kidney function. In adults, IgAN is an autoimmune disease and its pathogenesis involves galactose deficient (Gd) IgA1, IgG anti-Gd-IgA1 autoantibodies and the soluble IgA Fc receptor (CD89). However, implication of such factors, notably soluble CD89, in childhood IgAN pathogenesis remains unclear. Here, we studied these biomarkers in a cohort of 67 patients with childhood IgAN and 42 pediatric controls. While Gd-IgA1 was only moderately increased in patient plasma, levels of circulating IgA complexes (soluble CD89-IgA and IgG-IgA) and free soluble CD89 were markedly increased in childhood IgAN. Soluble CD89-IgA1 complexes and free soluble CD89 correlated with proteinuria, as well as histological markers of disease activity: mesangial, endocapillary hypercellularity and cellular crescents. Soluble CD89 was found in patient's urine but not in urine from pediatric controls. Mesangial deposits of soluble CD89 were detected in biopsies from patients with childhood IgAN. Serum chromatographic fractions containing covalently linked soluble CD89-IgA1 complexes or free soluble CD89 from patients induced mesangial cell proliferation invitro in a soluble CD89-dependent manner. Recombinant soluble CD89 induced mesangial cell proliferation invitro which was inhibited by free soluble recombinant CD71 (also a mesangial IgA receptor) or mTOR blockers. Interestingly, injection of recombinant soluble CD89 induced marked glomerular proliferation and proteinuria in mice expressing human IgA1. Thus, free and IgA1-complexed soluble CD89 are key players in mesangial proliferation. Hence, our findings suggest that soluble CD89 plays an essential role in childhood IgAN pathogenesis making it a potential biomarker and therapeutic target.

O- and N-Glycosylation of Serum Immunoglobulin A is Associated with IgA Nephropathy and Glomerular Function.

IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and is a leading cause of renal failure. The disease mechanisms are not completely understood, but a higher abundance of galactose-deficient IgA is recognized to play a crucial role in IgAN pathogenesis. Although both types of human IgA (IgA1 and IgA2) have several N-glycans as post-translational modification, only IgA1 features extensive hinge-region O-glycosylation. IgA1 galactose deficiency on the O-glycans is commonly detected by a lectin-based method. To date, limited detail is known about IgA O- and N-glycosylation in IgAN. To gain insights into the complex O- and N-glycosylation of serum IgA1 and IgA2 in IgAN, we used liquid chromatography-mass spectrometry (LC-MS) for the analysis of tryptic glycopeptides of serum IgA from 83 patients with IgAN and 244 age- and sex-matched healthy controls. Multiple structural features of N-glycosylation of IgA1 and IgA2 were associated with IgAN and glomerular function in our cross-sectional study. These features included differences in galactosylation, sialylation, bisection, fucosylation, and N-glycan complexity. Moreover, IgA1 O-glycan sialylation was associated with both the disease and glomerular function. Finally, glycopeptides were a better predictor of IgAN and glomerular function than galactose-deficient IgA1 levels measured by lectin-based ELISA. Our high-resolution data suggest that IgA O- and N-glycopeptides are promising targets for future investigations on the pathophysiology of IgAN and as potential noninvasive biomarkers for disease prediction and deteriorating kidney function.

MIR17HG genetic variations affect the susceptibility of IgA nephropathy in Chinese Han people.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease worldwide. It accounts for approximately 30~40% of glomerular diseases in China. However, the exact pathogenesis of IgAN is not well established. This study aimed to explore the association between MIR17HG polymorphisms and IgAN susceptibility. Six single nucleotide polymorphisms (SNPs) of MIR17HG were genotyped in 417 patients with IgAN and 424 healthy controls. The association analysis was conducted by logistic regression adjusted for age and gender in multiple genetic models and different subgroups. Our results revealed that rs72640334 and rs1428 increased the susceptibility to IgAN in total populations (p<0.05). The stratification analysis by age indicated that rs72640334 enhanced the risk of IgAN people older than 35years, while rs7318578 played a protective role in the development of IgAN patients aged >35years (p<0.05). In addition, MIR17HG-rs72640334 could facilitate the occurrence of IgAN in females (p<0.05). In Lee's grade III-Vsubgroup, rs72640334 and rs7336610 have an increasing effect on IgAN risk, while rs7318578 has a decreasing effect on IgAN susceptibility (p<0.05). Our findings suggested that MIR17HG genetic polymorphisms were correlated with IgAN susceptibility. It provided new evidence for the potential molecular mechanism of IgAN and may serve as a new biomarker for the treatment and early diagnosis of IgAN.

The increased miRNA-150-5p expression of the tonsil tissue in patients with IgA nephropathy may be related to the pathogenesis of disease

BackgroundThe microRNA (miRNA) expression of the tonsil tissues in patients with immunoglobulin A (IgA) nephropathy (IgAN) has not been reported in the literature. MethodsIn this study, the expression of nine miRNAs was measured in the tonsil tissues of patients with IgAN, including miRNA-21-5p, miRNA-29a-3p, miRNA-34a-5p, miRNA-146a-5p, miRNA-146b-5p, miRNA-148b-3p, miRNA-150-5p, miRNA-155-5p, and miRNA-181a-5p. Forty patients with proved primary IgA nephropathy were enrolled in our study, 20 IgAN patients with gross hematuria, which induced by tonsillitis (GH-IgAN group) and 20 IgAN patients without gross hematuria in the history (non-GH-IgAN group). Another 20 patients recruited as the control group (CT group) were chronic tonsillitis without kidney disease. ResultsCompared to the CT group, the expression level of miRNA-150-5p in the tonsils was significantly upregulated in the GH-IgAN group, but not in the non-GH-IgAN group (P = 0.031 and P = 0.122, respectively). A correlation analysis was performed between the expression of miRNAs in the tonsils and the clinical data of IgAN patients. The results showed that in the GH-IgAN group, the miRNA-150 expression was positively correlated with systolic blood pressure (β = 2.36, 95% CI 1.11–3.61, P = 0.0016), diastolic blood pressure (β = 1.02, 95% CI 0.22–1.82, P = 0.0224), uric acid (β = 7.43, 95% CI 1.81–13.04, P = 0.0184), leukocyte count (β = 0.22, 95% CI 0.09–0.35, P = 0039), neutrophil count (β = 0.19, 95% CI 0.06–0.32, P = 0.0096), cholesterol (β = 0.09, 95% CI 0.02–0.16, P = 0.0207) and triglyceride level (β = 0.16, 95% CI 0.10–0.22, P < 0.000). Besides, it was negatively correlated with the estimated glomerular filtration rate (eGFR) (β = -2.06, 95% CI: -3.90 – -0.21, P = 0.0421) in the GH-IgAN group; however, no significant correlation was found in the non-GH-IgAN group. ConclusionThe present findings suggest that miRNA-150-5p may be important in the pathogenesis of IgAN, especially in mucosal immunity against the disease.

IgA glycosylation and immune complex formation in IgAN.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. This disease, discovered in 1968, is characterized by IgA-IgG glomerular immunodeposits with a mesangial pattern. It is thought that these immunodeposits originate from the immune complexes formed in the circulation. It is hypothesized that the pathogenesis of IgAN is driven by aberrant glycoforms of IgA1 (galactose-deficient IgA1, Gd-IgA1). Gd-IgA1, in genetically susceptible individuals, represents the initiating factor for the formation of circulating immune complexes due to its recognition by IgG autoantibodies and the subsequent formation of pathogenic IgA1-IgG immune complexes. Complement activation through alternative and/or lectin pathways is likely playing an important role in the pathogenic properties of these complexes and may further upregulate local inflammatory responses and glomerular injury.

An Update on Targeted Treatment of IgA Nephropathy: An Autoimmune Perspective.

Immunoglobulin (Ig) A nephropathy (IgAN) is the commonest form of primary glomerulonephritis worldwide and is, considered a significant cause of end-stage renal disease in young adults. The precise pathogenesis of IgAN is unclear. The clinical and pathological features vary significantly between individuals and races, which makes treating IgAN difficult. Currently, the therapeutic strategies in IgAN are still optimal blood pressure control and proteinuria remission to improve the renal function in most cases. Immunosuppressive drugs such as corticosteroids can be considered in patients with persistent proteinuria and a high risk of renal function decline; however, they include a high toxicity profile. Therefore, the safety and selectivity of medications are critical concerns in the treatment of IgAN. Various pharmacological therapeutic targets have emerged based on the evolving understanding of the autoimmune pathogenesis of IgAN, which involves the immune response, mucosal immunity, renal inflammation, complement activation, and autophagy; treatments based on these mechanisms have been explored in preclinical and clinical studies. This review summarizes the progress concerning targeted therapeutic strategies and the relevant autoimmune pathogenesis in IgAN.

Aberrantly Glycosylated IgA1 in IgA Nephropathy: What We Know and What We Don't Know.

IgA nephropathy (IgAN), the most common primary glomerular disease worldwide, is characterized by glomerular deposition of IgA1-containing immune complexes. The IgA1 hinge region (HR) has up to six clustered O-glycans consisting of Ser/Thr-linked N-acetylgalactosamine usually with β1,3-linked galactose and variable sialylation. Circulating levels of IgA1 with abnormally O-glycosylated HR, termed galactose-deficient IgA1 (Gd-IgA1), are increased in patients with IgAN. Current evidence suggests that IgAN is induced by multiple sequential pathogenic steps, and production of aberrantly glycosylated IgA1 is considered the initial step. Thus, the mechanisms of biosynthesis of aberrantly glycosylated IgA1 and the involvement of aberrant glycoforms of IgA1 in disease development have been studied. Furthermore, Gd-IgA1 represents an attractive biomarker for IgAN, and its clinical significance is still being evaluated. To elucidate the pathogenesis of IgAN, it is important to deconvolute the biosynthetic origins of Gd-IgA1 and characterize the pathogenic IgA1 HR O-glycoform(s), including the glycan structures and their sites of attachment. These efforts will likely lead to development of new biomarkers. Here, we review the IgA1 HR O-glycosylation in general and the role of aberrantly glycosylated IgA1 in the pathogenesis of IgAN in particular.

Urinary exosomal circular RNAs of sex chromosome origin are associated with gender-related risk differences of clinicopathological features in patients with IgA nephropathy.

There are arguments for individualized treatments and the necessity of non-invasive biomarkers for patients with IgA nephropathy (IgAN) according to gender, but the rationale remains unclear. We aimed to investigate the relationship between urine exosomal circular RNA (circRNA) levels, related genes, clinical features, and renal pathological features in IgA nephropathy patients of different genders. Clinicopathological data from patients of different genders from a multicenter cohort were retrospectively analyzed. We used the Oxford classification to examine the severity of pathological damage in these patients. We compared clinical features and renal pathologies between IgAN patients of different genders. Using findings of urine exosomal circRNAs from male IgAN patients, we analyzed the relationship between this factor, the regulated genes located on the sex chromosomes, and renal pathologies. A total of 502 IgAN patients were included. The proportion of male patients with crescent formation was higher than that of females (p = 0.019). Multivariate logistic regression analysis showed that proteinuria was an independent markerfor crescent formation in male and female patients with IgAN, while smoking and higher low-density lipoprotein cholesterol (LDL-C) levels were independent risk factors for crescent formation in males alone. Urine exosomal circRNA chrY:15478147-15481229- located on the Y chromosome in male patients was negatively correlated with the expressions of UTY in specific regions of the Y chromosome. Compared with female patients, males with IgAN had more severe renal dysfunction and a higher probability of glomerular crescent formation. Urine exosomal circRNA chrY:15478147-15481229- might participate in the pathogenesis of IgAN in male patients by altering UTY expressions.