IgA nephropathy and mucosal immunity

The precise pathogenesis of immunoglobulin A nephropathy (IgAN) is still not clearly established but emerging evidence confirms a pivotal role for mucosal immunity. This review focuses on the key role of mucosa-associated lymphoid tissue (MALT) in promoting the onset of the disease, underlying the relationship among microbiota, genetic factors, food antigen, infections, and mucosal immune response. Finally, we evaluate potential therapies targeting microbes and mucosa hyperresponsiveness in IgAN patients.

IgA nephropathy (IgAN) is a common form of primary glomerulonephritis and represents an important cause of chronic kidney disease globally, with observational studies indicating that most patients are at risk of developing kidney failure within their lifetime. Several research advances have provided insights into the underlying disease pathogenesis, framed by a multi-hit model whereby an increase in circulating IgA1 that lacks galactose from its hinge region — probably derived from the mucosal immune system — is followed by binding of specific IgG and IgA antibodies, generating immune complexes that deposit within the glomeruli, which triggers inflammation, complement activation and kidney damage. Although treatment options are currently limited, new therapies are rapidly emerging that target different pathways, cells and mediators involved in the disease pathogenesis, including B cell priming in the gut mucosa, the cytokines APRIL and BAFF, plasma cells, complement activation and endothelin pathway activation. As more treatments become available, there is a realistic possibility of transforming the long-term outlook for many individuals with IgAN. IgA nephropathy (IgAN) is thought to result from multiple hits that culminate in immune complex deposition in the kidney. Here, the authors describe the latest insights into the pathogenesis of IgAN and how they have revealed novel therapeutic targets and approaches to this disease. IgA nephropathy (IgAN) is an important cause of progressive kidney disease and kidney failure globally, with most patients being at risk of developing kidney failure within their lifetime. Advances in the understanding of the pathogenesis of IgAN have highlighted an (auto)immune basis for the disease, with increased circulating levels of galactose-deficient IgA1 (Gd-IgA1) being associated with the presence of IgA and IgG antibodies specific to these IgA1 O-glycoforms. The circulating Gd-IgA1 that forms immune complexes and is deposited within the glomeruli in IgAN is probably mucosal in origin. The presence of elevated levels of Gd-IgA1 alone is insufficient to trigger IgAN; genetic and epigenetic factors contribute to the susceptibility of developing IgAN and the risk of progressive disease. Several therapies that target mucosal B cell priming, B cell production of Gd-IgA1, complement activity and the endothelin system are in development for the treatment of IgAN. IgA nephropathy (IgAN) is an important cause of progressive kidney disease and kidney failure globally, with most patients being at risk of developing kidney failure within their lifetime. Advances in the understanding of the pathogenesis of IgAN have highlighted an (auto)immune basis for the disease, with increased circulating levels of galactose-deficient IgA1 (Gd-IgA1) being associated with the presence of IgA and IgG antibodies specific to these IgA1 O-glycoforms. The circulating Gd-IgA1 that forms immune complexes and is deposited within the glomeruli in IgAN is probably mucosal in origin. The presence of elevated levels of Gd-IgA1 alone is insufficient to trigger IgAN; genetic and epigenetic factors contribute to the susceptibility of developing IgAN and the risk of progressive disease. Several therapies that target mucosal B cell priming, B cell production of Gd-IgA1, complement activity and the endothelin system are in development for the treatment of IgAN.

Infections have been considered to play a critical role in the pathogenesis of IgA nephropathy (IgAN) because synpharyngitic hematuria is a common feature in IgAN. However, how infections participate in this process is still debated. More recent studies have also revealed that the alteration of the gut microbiome exerts a profound effect on host immune responses, contributing to the etiology or progression of autoimmunity. Considering IgA as the first line of defense against bacterial and viral antigens, this review evaluates the relationships among intestinal infections, gut microbiome, and IgA for a better understanding of the pathogenesis of IgAN. Moreover, as a prototype of IgA immunity, we provide detailed clarification of IgAN pathogenesis to shed light on other diseases in which IgA plays a role. Finally, we discuss potential therapies focusing on microbes and mucosal immune responses in IgAN.

… abnormalities of the IgA mucosal immune system could be a … function of the IgA mucosal immune system are disordered in … Physiology of mucosal IgA production The mucosal immune …

ABSTRACT IgA nephropathy (IgAN) is related to the balance of gut microbiota. However, it is unclear whether changes in the gut microbiota can cause IgAN or attenuate its progression. This study employed IgAN and human microbiota-associated (HMA)-IgAN models to investigate the impact of IgAN on gut microbiota alteration and the mechanisms by which gut microbiota might trigger IgAN. Furthermore, this study examined the effects of chitooligosaccharides (COS) and COS formulation (COSF) with microbiota-targeting function on enhancing intestinal barrier and renal functions. These results revealed that IgAN led to a reduction in α-diversity and structural alterations in the gut microbiota, characterized by an increase in Shigella sonnei, Streptococcus danieliae, Desulfovibrio fairfieldensis, and a decrease in Bifidobacterium pseudolongum and Clostridium leptum. There was also an imbalance in intestinal B-cell immunity and a decrease in the level of tight junction proteins (ZO-1 and Occludin). Intestinal barrier and mucosal immune-related microbiota (Clostridium leptum, unclassified Lachnospiraceae NK4Al36 group, unclassified Clostridia vadinBB60 group, unclassified Oscillospiraceae, and unclassified Roseburia) were enriched through targeted modulation with COS/COSF, enhancing intestinal ZO-1 expression and reducing APRIL/BAFF overexpression, thereby reducing renal damage in IgAN. In conclusion, this study clarified the kidney-gut crosstalk between gut microbiota and IgAN, providing scientific evidence for developing microbiota-targeted food interventions to improve IgAN outcomes. HIGHLIGHTS IgAN disrupted specific microbial community, affecting barrier and immunity. The specific microbial community can affect ZO-1, Occludin, and B-cell immunity, contributing to IgAN disease. Renal injury in IgAN was repaired by targeting the intestinal barrier and mucosal immune-related microbiota. Targeted modulation of gut microbiota alleviated intestinal B cell immune imbalance by inhibiting APRIL/BAFF overproduction. GRAPHICAL ABSTRACT

The hallmark of IgA nephropathy (IgAN) is macroscopic hematuria coinciding with, or immediately following, a mucosal infection, usually of the upper respiratory airways. The role of mucosal pathogens has been proven in different experimental models. Mucosal (or innate) immunity acts through the recognition of pathogen-associated molecular patterns by macrophages, dendritic cells, leukocytes and other cells, and favors opsonization and phagocytosis. Then, mature dendritic cells interact with lymphocytes leading to activation of specific T cell and antibody synthesis. A dysregulation of innate immunity in IgAN is likely to result in failure of mucosal antigen elimination and/or altered IgA synthesis as well as inflammation. Complement system activation is a relevant arm of the innate immunity armamentarium and is associated with IgAN activity and progression. Other powerful mediators of mucosal immunity, Toll-like receptors (TLRs), were reported to modulate the severity of IgAN in ddy mice spontaneously developing IgA deposits, while some new data in peripheral lymphomonocytes of patients with IgAN show TLR hyperexpression particularly during phases of clinical activity. The involvement of innate immunity in IgAN represents a new, exciting field of research.

IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide, with diverse clinical manifestations characterized by recurrent gross hematuria or microscopic hematuria, and pathological changes featuring poorly O-galactosylated IgA1 deposition in the glomerular mesangium. Pathogenesis has always been the focus of IgAN studies. After 50 years of research, most scholars agree that IgAN is a group of clinicopathological syndromes with certain common immunopathological characteristics, and multiple mechanisms are involved in its pathogenesis, including immunology, genetics, and environmental or nutritional factors. However, the precise pathogenetic mechanisms have not been fully determined. One hypothesis about the pathogenesis of IgAN suggests that immunological factors are engaged in all aspects of IgAN development and play a critical role. A variety of immune cells (e.g., dendritic cells, NK cells, macrophages, T-lymphocyte subsets, and B-lymphocytes, etc.) and molecules (e.g., IgA receptors, Toll-like receptors, complements, etc.) in innate and adaptive immunity are involved in the pathogenesis of IgAN. Moreover, the abnormality of mucosal immune regulation is the core of IgAN immunopathogenesis. The roles of tonsil immunity or intestinal mucosal immunity, which have received more attention in recent years, are supported by mounting evidence. In this review, we will explore the latest research insights on the role of immune modulation in the pathogenesis of IgAN. With a better understanding of immunopathogenesis of IgAN, emerging therapies will soon become realized.

IgA nephropathy, presently recognized as the foremost primary glomerular disorder, emerges as a principal contributor to renal failure globally, with its pathogenesis yet to be fully elucidated. Extensive research has highlighted the critical role of gut microbiome in the onset and progression of IgA nephropathy, underscoring its importance in accurately delineating the disease’s etiology. For example, gut microbiome dysbacteriosis can lead to the production of nephritogenic IgA1 antibodies, which form immune complexes that deposit in the kidneys, causing inflammation and damage. The gut microbiome, a source of numerous bioactive compounds, interacts with the host and plays a regulatory role in gut-immune axis modulation, earning it the moniker of the “second brain.” Recent investigations have particularly emphasized a significant correlation between IgA nephropathy and gut microbiome dysbacteriosis. This article offers a detailed overview of the pathogenic mechanisms of IgA nephropathy, specifically focusing on elucidating how alterations in the gut microbiome are associated with anomalies in the intestinal mucosal system in IgA nephropathy. Additionally, it describes the possible influence of gut microbiome on recurrent IgA nephropathy following kidney transplantation. Furthermore, it compiles potential therapeutic interventions, offering both theoretical and practical foundations for the management of IgA nephropathy. Lastly, the challenges currently faced in the therapeutic approaches to IgA nephropathy are discussed.

… It is commonly stated that mucosal immunity plays a role in the pathogenesis of IgA nephropathy (… A dysregulated mucosal immune system with defective immune tolerance to commonly …

IgA nephropathy (IgAN) is the most common pattern of primary glomerular disease reported worldwide. Up to 40% of those with IgAN progress to end‐stage kidney disease within 20 years of diagnosis, with no currently available disease‐specific treatment. This is likely to change rapidly, with evolving insights into the mechanisms driving this disease. IgAN is an immune‐complex–mediated disease, and its pathophysiology has been framed by the ‘four‐hit hypothesis’, which necessitates four events to occur for clinically significant disease to develop. However, this hypothesis does not explain the wide variability observed in its presentation or clinical progression. Recently, there has been great interest in exploring the role of the mucosal immune system in IgAN, especially given the well‐established link between mucosal infections and disease flares. Knowledge of antigen–mucosal interactions is now being successfully leveraged for therapeutic purposes; the gut‐directed drug Nefecon (targeted release formulation‐budesonide) is on track to become the first medication to be approved specifically for the treatment of IgAN. In this review, we examine established immunological paradigms in IgAN, explore how antigen–mucosal immune responses drive disease, and discuss how this knowledge is being used to develop new treatments.

The mucosal immune system, via a dynamic immune network, serves as the first line of defense against exogenous antigens. Mucosal immune system dysregulation is closely associated with the pathogenesis of immunoglobulin A nephropathy (IgAN), as illustrated by IgAN having the clinical feature of gross hematuria, often concurrent with mucosal infections. Notably, previous studies have demonstrated the efficacy of tonsillectomy and found that a targeted-release formulation of budesonide reduced proteinuria in patients with IgAN. However, it remains unclear how exogenous antigens interact with the mucosal immune system to induce or exacerbate IgAN. Thus, in this review, we focus on the dysregulation of mucosal immune response in the pathogenesis of IgAN.

The connection between a dysregulated gut-associated lymphoid tissue and IgA nephropathy (IgAN) was supposed decades ago after the observation of increased association of IgAN with celiac disease. Pivotal studies have shown a role for alimentary antigens, particularly gliadin in developing IgAN in BALB/c mice, and a reduction in IgA antigliadin antibodies and proteinuria was reported after gluten free-diet in patients with IgAN. Recently a genome-wide association study showed that most loci associated with IgAN also are associated with immune-mediated inflammatory bowel diseases, maintenance of the intestinal barrier, and response to gut pathogens. Transgenic mice that overexpress the B-cell activating factor develop hyper-IgA with IgAN modulated by alimentary components and intestinal microbiota. Mice expressing human IgA1 and a soluble form of the IgA receptor (sCD89) develop IgAN, which is regulated by dietary gluten. Recent observations have confirmed gut-associated lymphoid tissue hyper-reactivity in IgAN patients with IgA against alimentary components. Interesting results were provided by the NEFIGAN randomized controlled trial, which adopted an enteric controlled-release formulation of the corticosteroid budesonide targeted to Peyer's patches. After 9 months of treatment, a reduction in proteinuria was observed with stabilized renal function and limited adverse events. The gut-renal connection is an area of promising new treatment approaches for patients with IgAN.

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide with most patients progressing to kidney failure. Although its pathophysiology remains incompletely understood, deposition of IgA-containing immune complexes in the glomerular mesangium induces mesangial cell proliferation and overproduction of extracellular matrix components and cytokines and chemokines, that lead to glomerular injury. The properties of nephritogenic IgA1 include abnormal glycosylation of its polymeric forms and its capacity to bind IgG autoantibodies to form immune complexes. Nephritogenic IgA1 is thought to be secreted by B cells originating from or residing in mucosa-associated lymphoid tissues (MALT), such as gut-associated lymphoid tissues (GALT) and nasopharynx-associated lymphoid tissues (NALT). However, little is known how the immune abnormalities in MALT elevate the circulatory levels of nephritogenic IgA. This review summarizes fundamental insights into IgA production and its regulation in MALT in general, provides an overview of the immune abnormalities in the MALT of patients with IgAN relevant to the production of abnormally glycosylated IgA, and summarizes relevant emerging treatments tested in clinical trials.

Immunoglobulin A nephropathy (IgAN) is the commonest primary glomerular disease worldwide and responsible for a significant proportion of the global end-stage kidney disease (ESKD) burden. While IgAN was described over 50 years ago, and despite steady progress in our understanding of this clinically heterogeneous disease, there remain significant gaps in our appreciation of the fundamental disease pathways operating in IgAN. This is reflected by the paucity of disease-specific treatments currently available for patients with IgAN. Encouragingly, this is changing with more clinical trials of novel therapies being conducted in 2021 than ever before, reflecting a growing awareness of the interactions between the mucosal immune system, innate and adaptive immune responses and tissue remodelling and regeneration. In this edition, authors cover each of these areas and offer insights into how this new understanding may be leveraged to deliver new therapies for patients living with IgAN. Firstly, Oliver Pabst and Claudia Seikrit provide an overview of the IgA immune system, describing the normal physiological role of IgA with a focus on the mucosal associated lymphoid tissues [1]. The challenges and successes of studying IgAN and evaluating novel therapies using animal models are then discussed by Renato Monteiro and Yusuke Suzuki [2]. An increasingly important focus of research in IgAN is the mucosal immune system–kidney axis, and this is addressed firstly by Kei Haniuda, Jennifer Gommerman and Heather Reich who summarises the available evidence for a contribution of the mucosal microbiome in IgAN [3] and Loreto Gesualdo, Vicenzo Di Leo and Rosanna Coppo who provides an overview of the evidence supporting mucosal immune system dysregulation in IgAN [4]. Fundamental to the generation of kidney injury is the mesangial accumulation of IgA immune complexes and Jan Novak and Hitoshi Suzuki review the contribution of changes in the pattern of IgA1 O-glycosylation to immune complex formation and triggering of glomerular inflammation [5]. Following IgA and/or IgA-containing immune complex deposition in the glomerular mesangium, it is important to understand the local responses that generate tissue injury as these may direct novel therapeutic approaches. The role of complement activation is covered by Nicholas Medjeral-Thomas, H. Terence Cook and Matthew C. Pickering [6], and the downstream molecular mechanisms for inflammation and scarring reviewed by Paolo Schena [7]. Two key unanswered questions in IgAN are whether IgAN is a single disease and whether it is the same disease in different parts of the world. Hong Zhang and Jonathan Barratt discuss the available literature, comparing observations across populations, and in particular how reported differences in disease behaviour might necessitate differential therapeutic approaches in different patient populations [8]. Treatment of IgAN has been largely empiric in the past, focusing predominantly on the so-called supportive therapy, i.e. generic measures to retard progression of glomerular disease, and non-specific immunosuppression. In the contribution by Thomas Rauen, Sydney Tang and Jürgen Floege, they critically discuss this in the light of recent trial data and in particular the KDIGO treatment guidelines that will be published in October 2021 [9]. Another poorly understood aspect of IgAN is its relationship with IgA vasculitis (IgAV; previously termed HenochSchönlein purpura), a disease largely confined to children but occasionally also observed in adults. IgAV can be clinically heterogeneous and may be manifest as a multisystem vasculitis or alternatively be completely limited to the skin, and when involving the kidneys is histopathologically indistinguishable from IgAN. In their review, Evangeline This article is a contribution to the Special issue on: The IgA system, IgA nephropathy and IgA vasculitis Guest Editors: Jürgen Floege & Jonathan Barratt

… serum immunoglobulin A (IgA) in the mouse suggesting that the mucosal immune system is a … While primarily approached as a toxicological problem, this model provides mucosal …

… The crosstalk between the mucosa and bone marrow during a mucosal infection, mediated … receptors Mucosal surfaces have an important role in innate immunity and mucosal immunity …

… Modulation of mucosal immunity may offer new therapeutic options. (2) Generation of IgG antibodies against poorly galactosylated IgA1. This could lay the foundation for …

The study aimed to conduct a bibliometric analysis of mucosal immunity in IgA nephropathy (IgAN) and indicate its current status, hot sopts, and direction of future studies.

Background Therapeutic approaches that target the gut microbiota (GM) may be helpful in the potential prevention and treatment of IgA nephropathy (IgAN). Meanwhile, relevant studies demonstrated a correlation between GM and IgAN, however, these confounding evidence cannot prove a causal relationship between GM and IgAN. Methods Based on the data from the GM genome-wide association study (GWAS) of MiBioGen and the IgAN GWAS data from the FinnGen research. A bi-directional Mendelian randomization (MR) study was performed to explore the causal relationship between GM and IgAN. We used inverse variance weighted (IVW) method as the primary method to determine the causal relationship between exposure and outcome in our MR study. Besides, we used additional analysis (MR-Egger, weighted median) and sensitivity analysis (Cochrane’s Q test, MR-Egger and MR-PRESSO) to select significant results, followed by Bayesian model averaging (MR-BMA) to test the results of MR study. Finally, a reverse MR analysis was conducted to estimate the probability of reverse causality. Results At the locus-wide significance level, the results of IVW method and additional analysis showed that Genus Enterorhabdus was a protective factor for IgAN [OR: 0.456, 95% CI: 0.238-0.875, p=0.023], while Genus butyricicoccus was a risk factor for IgAN [OR: 3.471, 95% CI: 1.671-7.209, p=0.0008]. In the sensitivity analysis, no significant pleiotropy or heterogeneity of the results was found. Conclusion Our study revealed the causal relationship between GM and IgAN, and expanded the variety of bacterial taxa causally related to IgAN. These bacterial taxa could become novel biomarkers to facilitate the development of targeted therapies for IgAN, developing our understanding of the “gut-kidney axis”.

… a pivotal role of intestinal microbiota in the development of … into the intestinal lumen, which favors the development of nephritis. In … and intestinal microbiota triggers the IgA response and …

Background: Although recent research suggests that alterations in gut microbiota and metabolites play a critical role in the pathophysiology of immunoglobulin A nephropathy (IgAN), the causal relationship between specific intestinal flora and metabolites and the risk of IgAN remains unclear. Method: This study employed Mendelian randomization (MR) to investigate the causal association between gut microbiota and IgAN. To explore potential associations between gut microbiota and various outcomes, four MR methods were applied: inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode. If the results of the four methods are inconclusive, we prefer the IVW as the primary outcome. Additionally, MR-Egger, MR-PRESSO-Global, and Cochrane’s Q tests were used to detect heterogeneity and pleiotropy. The stability of MR findings was assessed using the leave-one-out approach, and the strength of the causal relationship between exposure and outcome was tested using Bonferroni correction. Additional clinical samples were utilized to validate the results of Mendelian randomization, and the outcomes were visualized through an ROC curve, confusion matrix, and correlation analysis. Result: This study examined a total of 15 metabolites and 211 microorganisms. Among them, eight bacteria and one metabolite were found to be associated with the risk of IgAN (p < 0.05). The Bonferroni-corrected test reveals that only Class. Actinobacteria (OR: 1.20, 95% CI: 1.07–1.36, p = 0.0029) have a significant causal relationship with IgAN. According to Cochrane’s Q test, there is no substantial heterogeneity across different single-nucleotide polymorphisms (p > 0.05). Furthermore, MR-Egger and MR-PRESSO-Global tests (p > 0.05) showed no evidence of pleiotropy. No reverse causal association was found between the risk of IgAN and microbiota or metabolites (p > 0.05). Clinical specimens demonstrated the effectiveness and accuracy of Actinobacteria in distinguishing IgAN patients from those with other glomerular diseases (AUC = 0.9, 95% CI: 0.78–1.00). Additionally, our correlation analysis revealed a potential association between Actinobacteria abundance and increased albuminuria (r = 0.85) and poorer prognosis in IgAN patients (p = 0.01). Conclusion: Through MR analysis, we established a causal link between Actinobacteria and the incidence of IgAN. Moreover, clinical validation using fecal samples indicated that Actinobacteria might be associated with the onset and poorer prognosis of IgAN. This finding could provide valuable biomarkers for early, noninvasive detection of the disease and potential therapeutic targets in IgAN.

Background Growing evidence has shown that the gut-renal connection and gut microbiota dysbiosis play a critical role in immunoglobulin A nephropathy (IgAN). However, the fecal microbiome profile in Chinese patients with IgAN remains unknown. A cross-sectional study was designed for the first time to investigate the fecal microbiota compositions in patients with primary IgAN in China and to evaluate the relationship between the fecal microbiome and IgAN clinical presentation. Methods Fecal samples were collected from 17 IgAN patients and 18 age-, sex-, and body mass index-matched healthy controls, and bacterial DNA was extracted for 16S ribosomal RNA gene sequencing targeting the V3-V4 region. Results Fecal samples from the IgAN patients and healthy controls showed differences in gut microbiota community richness and compositions. Compared to the healthy controls, IgAN patients at the phylum level had an increased abundance of Fusobacteria , but a decreased abundance of Synergistetes . The significantly increased genera in the IgAN group were Escherichia-Shigella, Hungatella, and Eggerthella, all of which possess pathogenic potential. Furthermore, the genus Escherichia-Shigella was negatively associated with the estimated glomerular filtration rate (eGFR) but was positively associated with the urinary albumin-to-creatinine ratio (uACR). However, the genus rectale_group was present in the IgAN group with a low abundance and was negatively associated with the uACR. Functional analysis disclosed that infection-related pathways were enriched in the IgAN group. Conclusions We demonstrate that gut microbiota dysbiosis occurs in patients with IgAN, and that changes in gut bacterial populations are closely related to IgAN clinical features, suggesting that certain specific gut microbiota may be a potential therapeutic target for IgAN.

Abstract Immunoglobulin A nephropathy (IgAN) is characterized by the deposition of glycosylation-deficient IgA1 in the glomeruli and has been linked to the gut-kidney axis. This study aimed to determine if baseline differences in gut microbiota could predict therapeutic responses in IgAN patients. We analyzed fecal microbiomes of 55 biopsy-confirmed IgAN patients and followed them for over 6 months. Patients were classified as responders (n = 39) or nonresponders (n = 16) based on remission status. Fecal microbiomes were profiled using 16S rRNA sequencing, revealing significant microbiota differences. Nonresponders had increased Proteobacteria and Firmicutes, with notable enrichment of opportunistic bacteria like Escherichia-Shigella and Pseudomonas. A predictive classifier based on 24 amplicon sequence variants, with Escherichia-Shigella and Pseudomonas as key contributors, showed high accuracy in identifying nonresponders (AUC 0.9103, p < 0.0001). These findings highlight the role of microbial dysbiosis in IgAN progression and treatment response, suggesting that gut microbiota analysis could guide personalized therapy for IgAN. Future studies with larger cohorts are needed to validate these results and explore microbiome-based treatments. GRAPHICAL ABSTRACT

Abstract Objective The aim of this study was to investigate the characteristics and related functional pathways of the gut microbiota in patients with IgA nephropathy (IgAN) through metagenomic sequencing technology. Methods We enrolled individuals with primary IgAN, including patients with normal and abnormal renal function. Additionally, we recruited healthy volunteers as the healthy control group. Stool samples were collected, and species and functional annotation were performed through fecal metagenome sequencing. We employed linear discriminant analysis effect size (LEfSe) analysis to identify significantly different bacterial microbiota and functional pathways. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was used to annotate microbiota functions, and redundancy analysis (RDA) was performed to analyze the factors affecting the composition and distribution of the gut microbiota. Results LEfSe analysis revealed differences in the gut microbiota between IgAN patients and healthy controls. The characteristic microorganisms in the IgAN group were classified as Escherichia coli, with a significantly greater abundance than that in the healthy control group (p < 0.05). The characteristic microorganisms in the IgAN group with abnormal renal function were identified as Enterococcaceae, Moraxella, Moraxella, and Acinetobacter. KEGG functional analysis demonstrated that the functional pathways of the microbiota that differed between IgAN patients and healthy controls were related primarily to bile acid metabolism. Conclusions The status of the gut microbiota is closely associated not only with the onset of IgAN but also with the renal function of IgAN patients. The characteristic gut microbiota may serve as a promising diagnostic biomarker and therapeutic target for IgAN.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with a particularly high prevalence in Asia, and is a leading cause of end-stage renal disease (ESRD). The disease typically presents initially with hematuria and proteinuria, accompanied by progressive decline in renal function. The hallmark pathological feature of IgAN is mesangial IgA1 deposition, and aberrant production of galactose-deficient IgA1 (Gd-IgA1) is considered the key pathogenic driver. Studies have shown that Gd-IgA1 forms immune complexes (ICs) with autoantibodies, which deposit in the glomeruli, elicit inflammatory cascades, and lead to renal tissue injury. Emerging evidence indicates that gut microbiota dysbiosis is closely linked to the pathophysiology of IgAN. Such dysbiosis may promote disease progression by modulating immune responses and disrupting intestinal barrier integrity. Under healthy conditions, the gut microbiota supports host homeostasis through immune regulation and barrier maintenance, whereas dysbiosis may trigger systemic immune activation and contribute to the development of IgAN. This review delineates the relationship between gut microbiota and IgAN, explores the mechanisms of the gut–kidney axis and its relevance to IgAN pathogenesis, and highlights the therapeutic potential of intestinal interventions, including probiotics and fecal microbiota transplantation, for the treatment of IgAN. By synthesizing current evidence, this review aims to provide a theoretical foundation for future research and clinical translation in this field.

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide, and inflammatory bowel disease (IBD) comprises a group of chronic, relapsing inflammatory bowel disorders. Although IgAN and IBD differ in clinical manifestations, both involve interactions among genetic susceptibility, epigenetic abnormalities, and gut microbiota dysbiosis, ultimately pointing to mucosal immune dysregulation and chronic inflammation. They share similar alterations in gut microecology, characterized by a reduction in short-chain fatty acid-producing protective commensals and an increase in pathogenic symbionts. This leads to intestinal barrier disruption and aberrant microbial metabolites, promoting the production of galactose-deficient IgA1 (Gd-IgA1), activating intestinal mucosal immune cells, and driving both local and systemic inflammation. Notably, glucocorticoids (GC) and immunomodulators are common therapeutic agents for both diseases, and effective treatment is accompanied by restoration of the gut microbiota and improvement of immune imbalance. The four currently marketed budesonide enteric-coated capsules employ pH-dependent targeted-release technology and act on different sites ranging from the terminal ileum to the colon to modulate B-cell activation and attenuate local inflammation. IgAN and IBD may be closely related mucosal immune disorders, with immune inflammation associated with gut microbiota dysbiosis may represent a key link between them. Furthermore, upper respiratory tract infection may participate in the development of IgAN through mucosal immunity. The efficacy of tonsillectomy as a therapeutic intervention suggests the existence of crosstalk between the respiratory tract and the kidneys.

Gut microbiota exert core regulatory effects on systemic metabolic homeostasis and immune balance under physiological and pathological conditions. Marked gut dysbiosis occurs during the progression of chronic kidney disease (CKD), characterized by abnormal enrichment of opportunistic pathogens and depletion of beneficial commensal bacteria. This pathological alteration leads to excessive accumulation of uremic toxins including indoxyl sulfate, p-cresyl sulfate and trimethylamine N-oxide (TMAO), as well as sharp reductions in the synthesis of intestinal protective metabolites such as short-chain fatty acids (SCFAs) and indole-3-aldehyde. The imbalance between harmful and protective metabolites persistently triggers renal inflammatory activation and interstitial fibrosis via activating multiple signaling pathways, including the renin-angiotensin system, oxidative stress, Toll-like receptor 4, aryl hydrocarbon receptor, IκB/NF-κB, Keap1/Nrf2, NLRP3 inflammasome and ferroptosis. This review systematically summarizes the pathological correlations between gut microbiota disturbance and various renal disorders, namely diabetic kidney disease, membranous nephropathy, lupus nephritis, IgA nephropathy, hypertension-associated nephropathy and dialysis-related renal injury, and clarifies the universal mechanisms and disease-specific characteristics underlying gut-kidney axis-mediated progression of different subtypes of kidney diseases. Natural products represented by natural polysaccharides, traditional Chinese medicine formulas and plant polyphenols are capable of remodeling gut microbiota composition, repairing intestinal mucosal barrier function, balancing microbial metabolic profiles and regulating gut-kidney axis homeostasis, thereby exerting renal and multi-organ protective effects in patients with CKD and dialysis-dependent individuals. Targeted modulation of intestinal microecology and intervention against gut-kidney axis dysfunction using natural products provide novel strategies for early prevention and control of CKD, disease progression retardation and prognosis improvement in dialysis patients, and also lay a theoretical foundation for the development and clinical translational application of novel therapeutic targets for kidney diseases.

This study investigated the sex-specific differences in the correlation between intestinal microbiota and end-stage renal disease. Here, we compared the differences in the gut microbiota of male and female healthy controls (HC) and patients with end-stage renal disease (ESRD) caused by immunoglobulin A (IgA) nephropathy (ESRD-IgAN) or type-2 diabetes mellitus (ESRD-T2DM) using high-throughput sequencing of the 16S rRNA gene. We also analyzed the correlation between gut microbiota and clinical immune indicators. We assigned 8, 10, 5, 7, 11, and 20 volunteers to female HC, ESRD-IgAN, and ESRD-T2DM, and male HC, ESRD-IgAN, and ESRD-T2DM, respectively. The results showed sex-specific differences in both physiological and biochemical indices and intestinal microbiota composition, as well as the correlation between them. The correlations between physiological and biochemical indices in men were significantly lower than those in women, especially for indices related to immunity, blood glucose, and cardiac color sonography. Urine output, lymphocyte ratio, serum albumin, blood calcium, dialysis status, serum urea nitrogen, urine protein, and diabetes significantly correlated with male fecal microbiota composition, whereas only creatinine and 2-h post-prandial blood glucose significantly correlated with female fecal microbiota composition. The top 50 dominant operational taxonomic units showed a stronger correlation with physiological and biochemical indices in samples obtained from females than from males. These differences highlight sex-specific differences in the effectiveness of ESRD prevention and treatments via regulating intestinal microbiota.

Background Recent data indicate the importance of gut-kidney axis in the pathogenesis of Immunoglobulin A nephropathy (IgAN). Growing evidence suggests the alterations of diversity and composition of gut microbiome among patients with IgAN, however, the details are not yet fully understood. Methods Eligible studies comparing the gut microbiome between patients with IgAN and non-IgAN individuals were systematically searched from PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, and ClinicalTrials.gov. The primary outcomes were alpha- and beta-diversity, and the differences in gut microbiota composition between patients with IgAN and non-IgAN persons. Qualitative analysis and meta-analysis were performed according to available data. Results Eleven cross-sectional studies, including 409 patients with IgAN and 243 healthy controls, were enrolled. No significant differences in the diversity and enrichment of gut bacteria were found between IgAN and healthy individuals, whereas the beta-diversity consistently showed significant microbial dissimilarities among the two groups. Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia were the dominant phyla, however, no significant differences were found between IgAN patients and healthy controls at the phylum level. The genera, Streptococcus and Paraprevotella showed a higher proportion in patients with IgAN compared to healthy individuals, whereas Fusicatenibacter showed a lower abundance according to meta-analysis. Qualitative analyses suggested that Escherichia-Shigella might be increased in IgAN patients; the genera, Clostridium, Prevotella 9,and Roseburia, members of Ruminococcaceae and Lachnospiraceae families, were likely to have decreased abundances in patients with IgAN compared to healthy individuals. Conclusion Gut microbiota dysbiosis was demonstrated in IgAN, which might be involved in the pathogenesis of IgAN. Further studies are needed to confirm the findings of this study, due to the substantial heterogeneity. Systematic Review Registration https://www.crd.york.ac.uk/prospero/, identifier PROSPERO (CRD42022304034).

Introduction Immunoglobulin A nephropathy (IgAN) and membranous nephropathy (MN) are among the most common forms of primary glomerular diseases, with a rising global incidence. Despite their clinical importance, the underlying pathogenesis of these diseases and the development of reliable non-invasive diagnostic tools remain inadequately understood. Accumulating evidence suggests that gut microbiota and its associated metabolites may play a crucial role in the development of kidney diseases via the gut-kidney axis. However, comprehensive studies integrating both microbiome and metabolomic data in IgAN and MN are still limited. Methods In this study, we performed integrated metagenomic sequencing and untargeted metabolomic profiling to investigate alterations in gut microbial composition and systemic metabolic changes associated with IgAN and MN. Fecal samples were collected from 24 patients with IgAN, 20 patients with MN, and 17 healthy controls. Microbial diversity and composition were assessed using metagenomic analysis, while metabolic profiles were evaluated through untargeted LC -MS-based metabolomics. Multivariate statistical analyses and biomarker modeling were employed to identify discriminative features and evaluate diagnostic performance. Microbiota-metabolite correlation networks were constructed to explore potential mechanistic links. Results Metagenomic analysis showed that both the IgAN and MN groups had significantly reduced α-diversity. Although β-diversity analysis did not reveal significant differences between the three groups, the IgAN and MN groups exhibited higher sample dispersion than the control group. Notably, both IgAN and MN patients showed a decrease in the abundance of certain specific microbial taxa. A total of 34 and 28 differentially abundant microbial species were identified in IgAN and MN, respectively, compared to healthy controls, with 16 taxa consistently downregulated in both disease groups. Notably, Streptococcus oralis was significantly enriched in the MN group, while [Clostridium] innocuum was markedly depleted. Metabolomic profiling identified 307 and 209 differentially abundant metabolites in IgAN and MN, respectively. Dipeptides (e.g., prolylleucine) were consistently upregulated, while the levels of certain short-chain fatty acids (SCFA) were reduced. Multivariate biomarker models demonstrated excellent diagnostic performance, achieving area under the curve (AUC) of 0.919 (IgAN vs. control), 0.897 (MN vs. control) and 0.912 (IgAN vs. MN), surpassing individual metabolite markers. Discussion Our findings highlight significant alterations in gut microbial composition and systemic metabolite profiles in both IgAN and MN patients compared to healthy individuals. The consistent reduction in microbial diversity and SCFA-producing taxa, along with characteristic changes in metabolic signatures, supports the involvement of the gut-kidney axis in disease pathogenesis. The diagnostic models developed in this study provide promising non-invasive biomarkers for distinguishing IgAN and MN with high accuracy. These results contribute novel insights into the microbe-metabolite interplay in glomerular diseases and offer potential targets for future diagnostic and therapeutic strategies.

Immunoglobulin A nephropathy (IgAN) is the most prevalent glomerulonephritis in the world, and it is one of the leading causes of end-stage kidney disease. It is now believed that the pathogenesis of IgAN is the mesangial deposition of immune complex containing galactose-deficient IgA1, resulting in glomerular injury. Current treatments for IgAN include supportive care and immunosuppressive therapy. A growing number of studies found that the gut microbiota in IgAN was dysregulated. Gut microbiota may be involved in the development and progression of IgAN through three main aspects: destruction of intestinal barrier, changes in metabolites and abnormal mucosal immunity. Interestingly, therapies by modulating the gut microbiota, such as fecal microbiota transplantation, antibiotic treatment, probiotic treatment, Chinese herbal medicine Zhen Wu Tang treatment, gluten-free diet, and hydroxychloroquine treatment, can improve IgAN. In this review, the alteration of gut microbiota in IgAN, potential pathogenic roles of gut microbiota on IgAN and potential approaches to treat IgAN by modulating the gut microbiota are summarized.

The pathogenesis of immunoglobulin A nephropathy (IgAN) and membranous nephropathy (MN) is characterized by immune dysregulation, which is related to gut dysbiosis. The aim of the study was to compare the gut microbiota of patients with IgAN and MN vs. healthy controls. We used 16S rDNA amplicon sequencing to investigate the bacterial communities of 44 patients with kidney biopsy-proven IgAN, 40 patients with kidney biopsy-proven MN, and 30 matched healthy controls (HC). The abundance of Escherichia-Shigella and Defluviitaleaceae_incertae_sedis were significantly higher in IgAN than in HC, whereas lower abundances were observed for Roseburia, Lachnospiraceae_unclassified, Clostridium_sensu_stricto_1, and Fusobacterium. Furthermore, the abundance of Escherichia-Shigella, Peptostreptococcaceae_incertae_sedis, Streptococcus, and Enterobacteriaceae_unclassified increased, while that of Lachnospira, Lachnospiraceae_unclassified, Clostridium_sensu_stricto_1, and Veillonella decreased in MN. The abundance of Megasphaera and Bilophila was higher, whereas that of Megamonas, Veillonella, Klebsiella, and Streptococcus was lower in patients with IgAN than in those with MN. Analysis of the correlations showed that in the IgAN group, Prevotella was positively correlated, while Klebsiella, Citrobacter, and Fusobacterium were negatively correlated with the level of serum albumin. Positive correlation also existed between Bilophila and Crescents in the Oxford classification of IgAN. In the MN group, negative correlation was observed between Escherichia-Shigella and proteinuria, Bacteroides and Klebsiella showed positive correlation with the MN stage. Patients with IgAN and MN exhibited gut microbial signatures distinct from healthy controls. Our study suggests the potential of gut microbiota as specific biomarker and contributor in the pathogenesis of IgAN and MN.

ABSTRACT Immunoglobulin A nephropathy (IgAN) is a primary glomerular disease characterized by the deposition of IgA. The pathogenesis of it is related to the dysbiosis of gut microbiota. Dysbiosis of gut microbiota influences mucosal immune response and systemic immune system, leading to glycosylation‐deficient IgA1 (Gd‐IgA1) increasing, which promotes the development of IgAN. Diet plays an important role in regulating gut microbiota and treating IgAN. In this review, we summarize the interplay between gut microbiota and IgAN, and their underlying mechanisms. We also describe the effects of dietary intake on IgAN, as well as the composition of gut microbiota. The progress on IgAN treatment mainly focuses on inhibiting or regulating the immune system. Moreover, therapeutic strategies related to gut microbiota such as dietary intervention, supplement of probiotics and prebiotics, as well as fecal microbiota transplantation (FMT) have shown the possibility of improving IgAN prognosis. Thus, exploration of the gut‐kidney axis, the long‐term effects of diet and microbiome is necessary to develop more effective treatment strategies.

Introduction: Numerous research works have shown that serum Gal-deficient (Gd) IgA1 levels are increased in IgA nephropathy (IgAN) patients and these levels are a dangerous risk factor for IgAN. A relationship between the gut microbiota and IgAN has been reported. Whether the gut microbiota participates in the pathogenesis of IgAN was still controversial. Methods: We evaluated changes in the gut flora and the levels of Gd-IgA1 in IgAN patients and healthy controls (HCs). We investigated the Gd-IgA1 levels in both blood and urine specimens. C57BL/6 mice were given a broad-spectrum antibiotic cocktail to deplete the endogenous gut flora. We established a model of IgAN in pseudosterile mice and investigated the expression of the markers of intestinal permeability, inflammation, and local immune responses. Results: Studies have shown that the levels of certain gut flora differ between IgAN patients and HCs. Moreover, elevated Gd-IgA1 levels were found in both the serum and urine. Interestingly, Coprococcus, Dorea, Bifidobacterium, Blautia, and Lactococcus, selected from 10 candidate biomarkers to predict risk in IgAN patients according to random forest analysis, were inversely associated with urinary Gd-IgA1 levels. Notably, the urine level of Gd-IgA1 could best distinguish IgAN patients from HCs. Additionally, the degree of kidney damage in pseudosterile mice with IgAN was more severe than that in mice with IgAN. Furthermore, the markers of intestinal permeability were significantly elevated in pseudosterile IgAN mice. Moreover, the inflammation responses (TLR4, MyD88, and NF-κB in intestinal and renal tissues; TNF-α and IL-6 in serum) and local immune responses (BAFF and APRIL in intestinal tissue) were upregulated in pseudosterile IgAN mice. Conclusions: The urine Gd-IgA1 level may be as a biomarker for the early screening of potential IgAN, and gut microbiota dysbiosis was demonstrated in IgAN, which might involve the dysfunction of the mucosal barrier, inflammation, and local immune responses.

Objective To explore the common differential flora of IgAN, Kawasaki disease and IgA vasculitis by screening and analyzing the differential intestinal flora between the three disease groups of IgAN, Kawasaki disease and IgA vasculitis and their healthy controls. Methods Papers on 16srRNA sequencing-related intestinal flora of IgAN, Kawasaki disease and IgA vasculitis were searched in databases, the literature was systematically collated and analysed, the original data was download from the relevant databases, and then the operational taxonomic unit and species classification analysis were performed. Besides, Alpha diversity analysis and Beta diversity analysis were performed to screen for IgAN, Kawasaki disease and I1gA vasculitis groups and finally compare the common intestinal differential flora among the three groups. Results Among the common differential flora screened, Lachnospiracea_incertae_sedis was lower in both the IgAN and Kawasaki disease groups than in the respective healthy controls; Coprococcus was low in the IgAN group but high in the IgA vasculitis group. Fusicatenibacter was lower in both the Kawasaki disease and IgA vasculitis groups than in their respective healthy controls, and Intestinibacter was low in the Kawasaki disease group, but its expression was high in the IgA vasculitis group. Conclusion The dysbiosis of the intestinal flora in the three groups of patients with IgAN, Kawasaki disease and IgA vasculitis, its effect on the immunity of the organism and its role in the development of each disease group remain unclear, and the presence of their common differential flora may further provide new ideas for the association of the pathogenesis of the three diseases.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis and one of the leading causes of renal failure worldwide. The pathophysiology of IgAN involves nephrotoxic IgA1-immune complexes. These complexes are formed by galactose-deficient (Gd) IgA1 with autoantibodies against the hinge region of Gd-IgA1 as well as soluble CD89, an immune complex amplifier with an affinity for mesangial cells. These multiple molecular interactions result in the induction of the mesangial IgA receptor, CD71, injuring the kidney and causing disease. This review features recent immunological and microbiome studies that bring new microbiota-dependent mechanisms developing the disease based on data from IgAN patients and a humanized mouse model of IgAN. Dysbiosis of the microbiota in IgAN patients is also discussed in detail. Highlights of this review underscore that nephrotoxic IgA1 in the humanized mice originates from mucosal surfaces. Fecal microbiota transplantation (FMT) experiments in mice using stools from patients reveal a possible microbiota dysbiosis in IgAN with the capacity to induce progression of the disease whereas FMT from healthy hosts has beneficial effects in mice. The continual growth of knowledge in IgAN patients and models can lead to the development of new therapeutic strategies targeting the microbiota to treat this disease.

Introduction The alteration of the gut microbiome in the gut-kidney axis has been associated with a pro-inflammatory state and chronic kidney disease (CKD). A small-scaled Italian study has shown an association between the gut microbiome and Immunoglobulin A Nephropathy (IgAN). However, there is no data on gut microbiota in IgAN in the Asian population. This study compares the gut microbial abundance and diversity between healthy volunteers and Malaysian IgAN cohort. Methods A comparative cross-sectional study was conducted involving biopsy-proven IgAN patients in clinical remission with matched controls in a Malaysian tertiary centre. Demographic data, routine blood and urine results were recorded. Stool samples were collected and their DNA was extracted by 16S rRNA gene sequencing to profile their gut microbiota. Results Thirty-six IgAN patients (13 male; 23 female) with the mean age of 45.5 ± 13.4 years and median estimated glomerular filtration rate (eGFR) of 79.0 (62.1–92.2) mls/min/1.73m 2 with median remission of 7 years were analysed and compared with 12 healthy controls (4 male; 8 female) with the mean age of 46.5 ± 13.5 years and eGFR of 86.5 (74.2–93.7) mls/min/1.73m 2 . Other demographic and laboratory parameters such as gender, ethnicity, body mass index (BMI), haemoglobin, serum urea and serum albumin were comparable between the two groups. There were no significant differences seen in the Operational Taxonomic Unit (OTU) and alpha diversity (Shannon index) between IgAN and healthy controls. Alpha diversity increased with increasing CKD stage ( p  = 0.025). Firmicutes/Bacteroidetes (F/B) ratio was low in both IgAN and healthy cohort. Fusobacteria phylum was significantly increased ( p  = 0.005) whereas Euryarchaoeota phylum was reduced ( p  = 0.016) in the IgAN group as compared to the control cohort. Conclusion Although we found no differences in OTU and alpha diversity between IgAN in remission and control cohort, there were some differences between the two groups at phylum level.

… with mucosal infection again points to the mucosal IgA immune … polymeric IgA-secreting plasma cells are reduced at mucosal … To explain the mucosal phenotype of mesangial IgA in the …

… Since immunoglobulin A nephropathy (IgAN) was first described in the seminal papers by … systemic and mucosal IgA systems provide some insight into these possibilities. If the mucosa-…

… IgA biosynthesis, interaction with receptors, and clearance can be disrupted in certain pathologies, like IgA nephropathy… Characteristics of serum IgA and mucosal IgA are summarized …

Immunoglobulin A (IgA) is the most abundant isotype of antibodies, provides a first line of defense at mucosal surfaces against pathogens, and thereby contributes to mucosal homeostasis. IgA is generally considered as a non-inflammatory antibody because of its main function, neutralizing pathogenic virus or bacteria. Meanwhile, IgA can induce IgA-mediated diseases, such as IgA nephropathy (IgAN) and IgA vasculitis. IgAN is characterized by the deposition of IgA and complement C3, often with IgG and/or IgM, in the glomerular mesangial region, followed by mesangial cell proliferation and excessive synthesis of extracellular matrix in glomeruli. Almost half a century has passed since the first report of patients with IgAN; it remains debatable about the mechanism how IgA antibodies selectively bind to mesangial region—a hallmark of IgAN—and cause glomerular injuries in IgAN. Previous lectin- and mass-spectrometry-based analysis have revealed that IgAN patients showed elevated serum level of undergalactosylated IgA1 in O-linked glycans of its hinge region, called galactose-deficient IgA1 (Gd-IgA1). Thereafter, numerous studies have confirmed that the glomerular IgA from IgAN patients are enriched with Gd-IgA1; thus, the first hit of the current pathogenesis of IgAN has been considered to increase circulating levels of Gd-IgA1. Recent studies, however, demonstrated that this aberrant glycosylation alone is not sufficient to disease onset and progression, suggesting that several additional factors are required for the selective deposition of IgA in the mesangial region and induce nephritis. Herein, we discuss the current understanding of the characteristics of pathogenic IgA and its mechanism of inducing inflammation in IgAN.

… Drugs can be targeted to the effects enhanced by aberrantly glycosylated IgA1 on mesangial cells. Recent data suggest that aberrant IgA1 glycosylation may modulate clinical …

… the pathogenesis of IgA nephropathy. Abnormal expression of miR-148b may explain the aberrant glycosylation of IgA1, providing a potential pharmacologic target for IgA nephropathy. …

… glycosylated IgA1 secreted by immortalized B cells derived from patients with sporadic forms of IgA nephropathy (… of diagnosis, monitoring, and therapy for patients with IgA nephropathy. …

Galactose-deficient IgA1 (Gd-IgA1) plays a crucial role in the development of IgA nephropathy (IgAN). However, the pathogenic mechanisms driving Gd-IgA1 production have not been fully elucidated. Innate-immune activation via Toll-like receptor 9 (TLR9) is known to be involved in Gd-IgA1 production. A proliferation-inducing ligand (APRIL) and IL-6 are also known to enhance Gd-IgA1 synthesis in IgAN. Here, we investigated how TLR9 activation in IgA-secreting cells results in overproduction of nephritogenic IgA in the IgAN-prone ddY mouse model and in human IgA1-secreting cells. Injection of CpG-ODN (TLR9 ligand) increased production of aberrantly glycosylated IgA and IgG-IgA immune complexes (IC) in ddY mice that, in turn, exacerbated kidney injury. CpG-ODN-stimulated mice had elevated serum levels of APRIL that correlated with those of aberrantly glycosylated IgA and IgG-IgA IC. In vitro, TLR9 activation enhanced production of the nephritogenic IgA as well as APRIL and IL-6 in splenocytes of ddY mice and in human IgA1-secreting cells. However, siRNA knock-down of APRIL completely suppressed overproduction of Gd-IgA1 induced by IL-6. Neutralization of IL-6 reduced CpG-ODN-induced overproduction of Gd-IgA1. Furthermore, APRIL and IL-6 pathways each independently mediated TLR9-induced overproduction of Gd-IgA1. In summary, TLR9 activation enhanced synthesis of aberrantly glycosylated IgA that, in a mouse model of IgAN, further enhanced kidney injury. These findings indicate that APRIL and IL-6 synergistically, as well as independently, enhance synthesis of Gd-IgA1.

… basis for the aberrant IgA glycosylation, we established EBV-… blood cells of patients with IgA nephropathy. The secreted IgA1 … lupus nephritis and healthy individuals did not produce IgA …

AbstractAberrant glycosylated IgA1 molecules, mainly galactose-deficient IgA1 (Gd-IgA1), are important causal factors in IgA nephropathy; however, the underlying mechanism for the production of aberrantly glycosylated IgA1 is unknown. A recent genome-wide association study identified a novel IgAN susceptibility gene, TNFSF13, which encoded a proliferation-inducing ligand (APRIL) that promotes lymphocyte proliferation and IgA class switching. We aimed to explore the mechanism of APRIL's involvement in IgAN.We enrolled 166 patients with IgAN and 77 healthy controls and detected the plasma APRIL levels by the ELISA method, identified the mRNA expression of APRIL and its receptors by relative quantitative PCR, and confirmed by in vitro experiment.We identified increased plasma APRIL levels in IgAN, which was further proved by upregulated mRNA expression in B-lymphocytes from 27 IgAN patients. Analysis of the clinical characteristics of patients with IgAN showed that higher plasma APRIL level was associated with more severe clinical presentations (high proteinuria and low eGFR). The plasma APRIL level was positively correlated with Gd-IgA1 levels. Furthermore, exogenous APRIL could induce more production of Gd-IgA1 in cultured lymphocytes from patients with IgAN, compared with that from healthy controls. And, the relative higher expression of receptors of APRIL, that is, BCMA and TACI, in B-lymphocytes from IgAN patients were observed.Our findings implied that in patients with IgAN, increased APRIL is accompanied elevated expression of its receptors in B-lymphocytes, which induces overproduction of Gd-IgA1, ultimately contributing to the pathogenesis of IgAN.

… aberrantly glycosylated IgA1 play a pivotal role in the pathogenesis of IgA nephropathy (IgAN). … Recent studies of the origin of these aberrant molecules, their glycosylation profiles, and …

… IgA nephropathy (IgAN) is a complex trait determined by genetic and … this aberrant glycosylation is the result of an acquired or inherited defect, or whether the presence of aberrant IgA1 …

Dysbiosis represents changes in composition and structure of the gut microbiome community (microbiome), which may dictate the physiological phenotype (health or disease). Recent technological advances and efforts in metagenomic and metabolomic analyses have led to a dramatical growth in our understanding of microbiome, but still, the mechanisms underlying gut microbiome–host interactions in healthy or diseased state remain elusive and their elucidation is in infancy. Disruption of the normal gut microbiota may lead to intestinal dysbiosis, intestinal barrier dysfunction, and bacterial translocation. Excessive uremic toxins are produced as a result of gut microbiota alteration, including indoxyl sulphate, p-cresyl sulphate, and trimethylamine-N-oxide, all implicated in the variant processes of kidney diseases development. This review focuses on the pathogenic association between gut microbiota and kidney diseases (the gut–kidney axis), covering CKD, IgA nephropathy, nephrolithiasis, hypertension, acute kidney injury, hemodialysis and peritoneal dialysis in clinic. Targeted interventions including probiotic, prebiotic and symbiotic measures are discussed for their potential of re-establishing symbiosis, and more effective strategies for the treatment of kidney diseases patients are suggested. The novel insights into the dysbiosis of the gut microbiota in kidney diseases are helpful to develop novel therapeutic strategies for preventing or attenuating kidney diseases and complications.

IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. Its incidence and prevalence vary widely, with estimates of annual incidence ranging from 0.06 to 10.5 per 100,000 per year in adults and children. IgAN represents an important cause of progressive kidney disease, leading to kidney failure in a large proportion of patients, and is associated with a wide spectrum of clinical symptoms, which negatively impact quality of life. Although the consequences of IgAN manifest in the kidney, multiple lines of evidence support a major role for the gut in the pathogenesis of IgAN, including genome-wide association studies that identify risk loci for IgAN that encode genes related to mucosal immunity, maintenance of the intestinal epithelial barrier, and inflammatory bowel disease. Further insights into the underlying disease pathogenesis have led to the development of a multihit model comprising 4 sequential “hits”: (i) increased levels of galactose-deficient IgA1 in the systemic circulation, (ii) followed by binding of specific autoantibodies directed against galactose-deficient IgA1, which (iii) form pathogenic IgA-containing immune complexes that (iv) deposit within the glomerular mesangium of the kidney, triggering inflammation, damage, and progressive decline in kidney function. The purpose of this article is to provide an overview of IgAN, examining its epidemiology and clinical features, and the mechanisms underlying its pathophysiology.

IgA Nephropathy (IgAN) is the commonest primary glomerular disease around the world and represents a significant cause of end-stage renal disease. IgAN is characterized by mesangial deposition of IgA-immune complexes and mesangial expansion. The pathophysiological process includes an abnormally glycosylated IgA1, which is an antigenic target. Autoantibodies specifically recognize galactose-deficient IgA1 forming immune complexes that are amplified in size by the soluble IgA Fc receptor CD89 leading to deposition in the mesangium through interaction with non-classical IgA receptors. The local production of cytokines promotes local inflammation and complement system activation, besides the stimulation of mesangial proliferation. The spectrum of clinical manifestations is quite variable from asymptomatic microscopic hematuria to rapidly progressive glomerulonephritis. Despite all the advances, the pathophysiology of the disease is still not fully elucidated. The mucosal immune system is quoted to be a factor in triggering IgAN and a “gut-kidney axis” is proposed in its development. Furthermore, many recent studies have demonstrated that food intake interferes directly with disease prognosis. In this review, we will discuss how mucosal immunity, microbiota, and nutritional status could be interfering directly with the activation of intrinsic pathways of the mesangial cells, directly resulting in changes in their function, inflammation and development of IgAN.

Jonathan Barratt, Brad H. Rovin, Daniel Cattran, Jürgen Floege, Richard Lafayette, Vladimir Tesar, Hernán Trimarchi and Hong Zhang; on behalf of the NefIgArd Study Steering Committee Department of Cardiovascular Sciences, University of Leicester and Leicester General Hospital, Leicester, UK; Division of Nephrology, Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Toronto General Hospital Research Institute, Toronto, Ontario, Canada; University Hospital, Rheinisch Westfälische Technische Hochschule, Aachen, Germany; Stanford Glomerular Disease Center, Stanford University Medical Center, Stanford, California, USA; General University Hospital, First Faculty of Medicine, Charles University, Prague, Czech Republic; Department of Nephrology, Nephrology Service and Kidney Transplant Unit, Hospital Británico de Buenos Aires, Buenos Aires, Argentina; and Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China

Purpose of review Growing evidence show the importance of gut/kidney axis in renal diseases. Advances in gut microbiome sequencing, associated metabolites, detection of gut permeability and inflammation provide new therapeutic strategies targeting gut for kidney diseases and particularly for Immunoglobulin A (IgA) nephropathy (IgAN). Recent findings The diversity and composition of gut flora have been recently deeply explored in kidney diseases. Modulation and depletion of microbiota in animal models allowed the understanding of molecular mechanisms involved in the crosstalk between gut, immune system and kidney. New clinical trials in order to positively modulate microbiota result in improvement of gastrointestinal disorders and inflammation in patients suffering with kidney diseases. Summary The investigation of gut alterations in kidney diseases open new therapeutic strategies. In IgAN, targeted treatments for intestinal inflammation and modifications of gut microbiota seem promising.

Background IgA nephropathy(IgAN)) is the common pathological type of glomerular diseases. The role of gut microbiota in mediating “gut-IgA nephropathy” has not received sufficient attention in the previous studies. The purpose of this study was to investigate the changes of fecal short-chain fatty acids(SCFAs), a metabolite of the intestinal microbiota, in patients with IgAN and its correlation with intestinal flora and clinical indicators, and to further investigate the role of the gut-renal axis in IgAN. Methods There were 29 patients with IgAN and 29 normal control subjects recruited from January 2018 to May 2018. The fresh feces were collected. The fecal SCFAs were measured by gas chromatography/mass spectrometry and gut microbiota was analysed by16S rDNA sequences, followed by estimation of α- and β-diversity. Correlation analysis was performed using the spearman’s correlation test between SCFAs and gut microbiota. Results The levels of acetic acid, propionic acid, butyric acid, isobutyric acid and caproic acid in the IgAN patients were significantly reduced compared with control group( P  < 0.05). Butyric acid(r=-0.336, P  = 0.010) and isobutyric acid(r=-0.298, P  = 0.022) were negatively correlated with urea acid; butyric acid(r=-0.316, P  = 0.016) was negatively correlated with urea nitrogen; caproic acid(r=-0.415, P  = 0.025) showed negative correlation with 24-h urine protein level.Exemplified by the results of α-diversity and β-diversity, the intestinal flora of IgAN patients was significantly different from that of the control group. Acetic acid was positively associated with c_Clostridia (r = 0.357, P  = 0.008), o_Clostridiales (r = 0.357, P  = 0.008) and g_Eubacterium_coprostanoligenes_group (r = 0.283, P  = 0.036). Butyric acid was positively associated with g_Alistipes (r = 0.278, P  = 0.040). The relative abundance of those were significantly decreased in IgAN group compared to control group. Conclusions The levels of fecal SCFAs in the IgAN patients were reduced, and correlated with clinical parameters and gut microbiota, which may be involved in the pathogenesis of IgAN, and this finding may provide a new therapeutic approach.

ABSTRACT Background Immunoglobulin A nephropathy (IgAN) is a major cause of primary glomerulonephritis characterized by mesangial deposits of galactose-deficient IgA1 (Gd-IgA1). Toll-like receptors (TLRs), particularly TLR4, are involved in the pathogenesis of IgAN. The role of gut microbiota on IgAN patients was recently investigated. However, whether gut microbial modifications of Gd-IgA1 through TLR4 play a role in IgAN remains unclear. Methods We recruited subjects into four groups, including 48 patients with untreated IgAN, 22 treated IgAN patients (IgANIT), 22 primary membranous nephropathy and 31 healthy controls (HCs). Fecal samples were collected to analyze changes in gut microbiome. Gd-IgA1 levels, expression of TLR4, B-cell stimulators and intestinal barrier function were evaluated in all subjects. C57BL/6 mice were treated with a broad-spectrum antibiotic cocktail to deplete the gut microbiota and then gavaged with fecal microbiota transplanted from clinical subjects of every group. Gd-IgA1 and TLR4 pathway were detected in peripheral blood mononuclear cells (PBMCs) from IgAN and HCs co-incubated with lipopolysaccharide (LPS) and TLR4 inhibitor. Results Compared with the other three groups, different compositions and decreased diversity demonstrated gut dysbiosis in the untreated IgAN group, especially the enrichment of Escherichia-Shigella. Elevated Gd-IgA1 levels were found in untreated IgAN patients and correlated with gut dysbiosis, TLR4, B-cell stimulators, indexes of intestinal barrier damage and proinflammatory cytokines. In vivo, mice colonized with gut microbiota from IgAN and IgANIT patients mimicked the IgAN phenotype with the activation of TLR4/MyD88/nuclear factor-κB pathway and B-cell stimulators in the intestine, and had with enhanced proinflammatory cytokines. In vitro, LPS activated TLR4/MyD88/NF-κB pathway, B-cell stimulators and proinflammatory cytokines in PBMCs of IgAN patients. This process may induce the overproduction of Gd-IgA1, which was inhibited by TLR4 inhibitors. Conclusions Our results illustrated that the gut–kidney axis is involved in the pathogenesis of IgAN. Gut dysbiosis could stimulate the overproduction of Gd-IgA1 via TLR4 signaling pathway production and B-cell stimulators.

The interplay between multiple organs, known as inter-organ crosstalk, represents a complex and essential research domain in understanding the mechanisms and therapies for kidney diseases. The kidneys not only interact pathologically with many other organs but also communicate with other systems through various signaling pathways. It is of paramount importance to comprehend these mechanisms for the development of more efficient therapeutic strategies. Despite extensive research in IgA nephropathy (IgAN), the most common kidney disease, the elaboration mechanism of IgAN remains challenging. Numerous studies suggest that alterations in the intestinal microbiome and its metabolites are pivotal in the progression of IgAN, opening new avenues for understanding its mechanisms. Interestingly, certain presumed probiotics, such as Akkermansia muciniphila, have been implicated in the onset of IgAN, making the exploration of gut microbiota in the context of IgAN pathogenesis even more intriguing. In this review, we summarize the status of gut microbiology studies of IgAN and explore the possible mechanisms and intervention prospects. Future research and treatment directions may increasingly emphasize systemic, multi-organ combined interventions to decelerate the advancement of kidney disease and enhance the overall prognosis of patients.

Inflammatory bowel disease (IBD) can extend beyond the gastrointestinal tract, affecting extraintestinal organs and significantly increasing morbidity and mortality. Despite early studies revealing kidney involvement in nearly a quarter of patients with IBD, renal manifestations have been notably overlooked. Among these manifestations, nephrolithiasis, obstructive uropathy, and fistula formation between the bowel and urinary tract are the most reported occurrences. Additionally, renal parenchymal involvement in IBD, including glomerulonephritis (GN), tubulointerstitial nephritis, and amyloidosis, has been documented. GN is particularly noteworthy, as a significant proportion of patients progress to end-stage kidney disease (ESKD). Although GN has long been recognized as a potential extraintestinal manifestation (EIM) of IBD, it has often been dismissed as an anecdotal association. Recently, several studies highlighted the clinical correlation between GN and IBD, suggesting a pathogenic interplay involving gut inflammation, dysbiosis, and intrinsic glomerular processes. Thus, our objective is to elucidate the basis of IBD-related nephropathies, with a specific focus on IgA nephropathy (IgAN) and the gut–kidney axis.

Immunoglobulin A nephropathy(IgAN) is the most common primary glomerulonephritis worldwide. The working model for the pathogenesis of IgAN involves a multistep process starting from the production of galactose-deficient and polymeric immunoglobulin A-1 (gd-IgA1) that enters systemic circulation from gut-associated lymphoid tissue (GALT). Galactose-deficient IgA are targeted by endogenous IgG, leading to the formation of circulating immune complexes that deposit in the mesangium and resulting in glomerular inflammation. Disease onset and relapses are often associated with gut infections, supporting the hypothesis that the gut plays an important pathogenic role. In the presence of microbial pathogens or food antigens, activated dendritic cells in the gut mucosa induce T cell dependent and independent B cell differentiation into IgA secreting plasma cells. In IgAN patients, this promotes the systemic release of mucosal gd-IgA1. Not all bacterial strains have the same capacity to elicit IgA production, and little is known about the antigen specificity of the pathogenic gd-IgA1. However, efficacy of treatments targeting gut inflammation support a pathogenic link between the bowel immune system and IgAN. Herein, we review the evidence supporting the role of gut inflammation in IgAN pathogenesis.

Background IgA nephropathy (IgAN) is the leading type of primary glomerulonephritis, significantly contributing to chronic kidney disease (CKD) and renal failure. The pathogenesis of IgAN is the multi-hit hypothesis regarding overproduction and accumulation of galactose-deficient (Gd-IgA1). Recent findings have revealed gut microbiota dysbiosis and immune responses are essential in the development of IgAN, attracting increasing attention. This study aimed to map mucosal immune cells in IgAN influenced by gut microbiota, investigating the role of innate immune cells in kidney damage. Methods Fecal samples were acquired from both patients and controls for subsequent animal experiments. Mice received a broad-spectrum antibiotic cocktail to eliminate their intestinal microflora, followed by a gavage with fecal microbiota from clinical individuals. Murine intestinal and kidney tissues were collected for flow cytometry. Intestine and kidney histopathology, immunofluorescence, and inflammatory cytokine expression were assessed in the murine models. The mucosal epithelium’s structure and function, along with the innate immune cell response, were analyzed. Results Mice exhibited the IgAN phenotype following colonization with gut microbiota from IgAN patients. These mice (IgAN-FMT mice) showed renal dysfunction and increased pathology of tissue injury in both intestine and kidneys. IgAN-FMT mice showed heightened pro-inflammatory cytokine (IL-6 and TNF-α) activity, greater antibody (IgA and complement C3) deposition and decreased expression of mucosal barrier protein (ZO-1, Occludin) compared to the control group. Furthermore, CD11c+dendritic cells were more abundant in the murine intestine and kidneys compared to the control group. Conclusion The gut-kidney axis, including microbiota homeostasis and innate immune cell response, contributes to the pathogenesis of IgAN. Gut dysbiosis and hyperactivated immune cells like CD11c+dendritic cells can affect the mucosal barrier and exacerbate the renal damage, being novel insights into immunotherapeutic strategies for IgAN.

IgA nephropathy (IgAN) is a primary glomerular disease closely linked to mucosal immune dysregulation, involving a complex interplay between intestinal immune homeostasis and renal injury. The “gut-kidney axis” has recently emerged as a central conceptual framework for understanding IgAN pathogenesis, connecting intestinal mucosal immunity with kidney pathology. This perspective article scrutinizes the mechanistic role of this axis, focusing on key processes such as the production of galactose-deficient IgA1, intestinal barrier dysfunction, and gut microbiota dysbiosis. Building on this foundation, we propose “precision targeting of the gut-kidney axis” as a novel therapeutic paradigm for mucosal immunomodulation in IgAN, and discuss integrated strategies ranging from microbial and barrier modulation to specific immune interventions. By emphasizing multi-target, cross-organ approaches, this paradigm offers a promising alternative to conventional therapies and provides a translational roadmap for developing mechanism-based treatments in IgAN.

… IgA nephropathy (IgAN) and intestinal flora and mucosal immune response disorder based on the theory of "intestinal-kidney axis"… of IgAN by regulating intestinal flora, mucosal immune …

The recent new developments in technology with culture-independent techniques including genome sequencing methodologies shed light on the identification of microbiota bacterial species and their role in health and disease. Microbiome is actually reported as an important predictive tool for evaluating characteristic shifts in case of disease. Our present review states the development of different renal diseases and pathologies linked to the intestinal dysbiosis, which impacts on host homeostasis. The gastrointestinal–kidney dialogue provides intriguing features in the pathogenesis of several renal diseases. Without any doubt, investigation of this interconnection consists one of the most cutting-edge areas of research with potential implications on our health.

… relevant in patients with chronic kidney disease (CKD). Interactions are … kidney disease is associated with increased intestinal (colonic) permeability (often referred to as ‘leaky gut…

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide. It is well known that upper respiratory tract infections, particularly acute tonsillitis, often worsen IgAN. Recent many clinical studies clearly show that tonsillectomy with steroid pulse therapy is the effective treatments for IgAN patients. Recently, the immunological evidence of association between tonsil and IgAN has been reported.

IgA nephropathy (IgAN), the common primary glomerulonephritis, is a tonsillar focal infection characterized by the qualitative abnormality of IgA in circulation and IgA deposition in the renal mesangium. Mesangial deposition of IgA, which is composed predominantly of poorly galactosylated polymeric IgA1 (pIgA1), seems to be the initiating event in the pathogenesis of IgAN. The origin of poorly galactosylated IgA, however, remains unclear. Recent studies suggest that the mesangial polymeric IgA1 deposition could be derived from mucosally primed plasma cells. B cells may undergo IgA class switching to acquire the expression of IgA via T-cell-dependent or T-cell-independent pathways in mucosa-associated lymphoid tissue and then differentiate to IgA plasma cells or home in on systemic sites. Dendritic cells, including plasmacytoid dendritic cells and another type of antigen-retaining cell, follicular dendritic cells, have an irreplaceable role in IgA class-switch mechanisms by producing IgA-inducing signals. Furthermore, an increased number of pIgA1-secreting plasma cells in the bone marrow and tonsil, as well as increased IgA class switching, have been found in IgAN, providing a link between the mucosal immunity and IgAN. The favorable effect of tonsillectomy on patients with IgAN showed that tonsillar focal infection may be closely related to pIgA1 deposition in glomerular mesangium of patients with IgAN and at least a part of pIgA1 may originate from affected tonsils. Therefore, the indication for tonsillectomy should be considered in patients with IgA nephropathy, especially at a mild or early stage, to prevent future renal deterioration. In this paper, we focus on IgA class switching and the role of tonsils with focal infection in IgAN.

The tonsils, specifically the palatine tonsils, serve as a first line of defense against pathogenic microorganisms that enter the nasal or oral cavity. They release antigen-specific immune cells and antibodies that circulate not only in the upper respiratory tract but also throughout the rest of the body. Numerous clinical studies, including randomized prospective trials, have shown that tonsillectomy is highly effective in treating immunoglobulin A nephropathy (IgAN), palmoplantar pustulosis (PPP), and psoriasis. However, the precise pathogenic association of the tonsils with these diseases remains incompletely understood. The author previously proposed the concept of tonsil-induced autoimmune/inflammatory syndrome (TIAS) as a common underlying mechanism for these diseases. TIAS suggests that an excessive immune response initiated by the tonsils, often triggered by common bacteria such as α- and β-hemolytic streptococcus and Haemophilus parainfluenzae, which are indigenously present in the oral cavity, can become dysregulated. This immune response also involves unmethylated DNA sequences (CpG-ODN) that are shared among various bacteria. In reaction to these bacteria or CpG-ODN, tonsillar T-cell populations, including type 17 helper T (Th17), Th22, Th1, and cytotoxic T cells, become proliferative. Simultaneously, tonsillar B-cell populations responding to these triggers produce antibodies against epidermal keratins and heat shock proteins, or aberrant IgA1. These tonsillar T-cell populations and the antibodies then enter the systemic circulation, migrating to the kidneys or skin. Upon reaching the organs, they contribute to tissue damage, aided by various cytokine actions. IgAN, PPP, and psoriasis, which are representative disorders of TIAS, all share this common pathogenic mechanism. In this article, the author discusses the pathogenesis of TIAS based on recent research findings.

Although impaired immune regulation along the mucosa-bone marrow axis has been postulated to play an important role, the pathogenesis of IgA nephropathy (IgAN) is unknown; thus, no disease-specific therapy for this disease exists. The therapeutic efficacy of tonsillectomy or tonsillectomy in combination with steroid pulse therapy for IgAN has been discussed. Although randomized control trials for these therapies are ongoing in Japan, the scientific rationale for these therapies remains obscure. It is now widely accepted that abnormally glycosylated IgA1 and its related immune complex (IC) are probably key molecules for the pathogenesis, and are thus considered possible noninvasive biomarkers for this disease. Emerging evidence indicates that B cells in mucosal infections, particularly in tonsillitis, may produce the nephritogenic IgA. In this paper, we briefly summarize characteristics of the nephritogenic IgA/IgA IC, responsible B cells, and underlying mechanisms. This clinical and experimental information may provide important clues for a therapeutic rationale.

… IgA nephropathy (IgAN) is recognized as the most common immune complex related to the cause of glomerulonephritis worldwide.We know that many IgAN patients show episodic …

Abstract Background Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by mesangial polymeric IgA1 deposition. IgAN is believed to develop owing to aberrant mucosal immunoreaction against commensals in the tonsils. However, the exact interrelation between pathogenic IgA and mucosal microbiota in IgAN patients is unclear. Methods Biopsy-proven IgAN or recurrent tonsillitis (RT) patients who had undergone tonsillectomy were enrolled. We used 16S ribosomal RNA gene amplicon sequencing with a flow cytometry-based bacterial cell sorting technique) and immunoglobulin repertoire sequencing of the IgA heavy chain to characterize IgA-coated bacteria of the tonsillar microbiota (IgA-SEQ) and their corresponding IgA repertoire. Furthermore, we fractionated patient serum using gel-filtration chromatography and performed flow cytometry-based analysis of IgA binding to bacteria cultured from incised tonsils. Results Tonsillar proliferation-inducing ligand and B-cell activating factor levels were significantly higher in IgAN than in RT patients. IgA-SEQ for tonsillar microbiota revealed the preferential binding ability of IgA to Bacteroidetes in IgAN tonsils compared with those from RT patients. Expression of immunoglobulin heavy (IGH) constant alpha 1 with IGH variable 3–30 was significantly higher in IgAN than that in RT, and positively correlated with the IgA-coated enrichment score of Bacteroidetes. Serum polymeric IgA, comprising high levels of GdIgA1, exhibited considerable binding to Bacteroidetes strains cultured from the tonsils of IgAN patients. Conclusions These findings provide evidence that aberrant mucosal immune responses to tonsillar anaerobic microbiota, primarily consisting of members of the phylum Bacteroidetes, are involved in IgAN pathophysiology.

The benefits of tonsillectomy in IgA nephropathy (IgAN) are still debated. Tonsillectomy may remove pathogen sources and reduce the mucosal associated lymphoid tissue (MALT), limiting degalactosylated IgA1 (deGal-IgA1) production, which is considered to be the initiating pathogenetic event leading to IgA glomerular deposition. In the European network VALIGA, 62/1147 IgAN patients underwent tonsillectomy (TxIgAN). In a cross-sectional study 15 of these patients were tested and compared to 45 non-tonsillectomized IgAN (no-TxIgAN) and healthy controls (HC) regarding levels of deGal-IgA1, and markers of innate immunity and oxidative stress, including toll-like receptors (TLR)2, 3, 4 and 9 mRNAs, proteasome (PS) and immunoproteasome (iPS) mRNAs in peripheral blood mononuclear cells (PBMC), and advanced oxidation protein products (AOPP). Levels of deGal-IgA1 were lower in TxIgAN than in no-TxIgAN (p = 0.015), but higher than in HC (p = 0.003). TLR mRNAs were more expressed in TxIgAN than in HC (TLR4, p = 0.021; TLR9, p = 0.027), and higher in TxIgAN than in no-TxIgAN (p ≤ 0.001 for TLR2, 4, 9). A switch from PS to iPS was detected in PBMC of TxIgAN in comparison to HC and it was higher than in no-TxIgAN [large multifunctional peptidase (LMP)2/β1, p = 0.039; LPM7/β5, p < 0.0001]. The levels of AOPP were significantly higher in TxIgAN than HC (p < 0.001) and no-TxIgAN (p = 0.033). In conclusion, the activation of innate immunity via TLRs and ubiquitin–proteasome pathways and the pro-oxidative milieu were not affected by tonsillectomy, even though the levels of aberrantly galactosylated IgA1 were lower in patients with IgAN who had tonsillectomy. The residual hyperactivation of innate immunity in tonsillectomized patients may result from extra-tonsillar MALT.

… in tonsillitis from different gene expression between patients with IgA nephropathy and … Therefore, we suspect that the time of an immune low point or the change of immune status …

… that immune complexes formed by H. pylori and this antibody in the palatine tonsils are a … Long-term results of tonsillectomy as a treatment for IgA nephropathy. Acta Otolaryngol 555: …

BACKGROUND The pathogenesis of IgA nephropathy is mediated by B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). Telitacicept is a fusion protein that targets and neutralizes both BAFF and APRIL and, as such, might be effective in IgA nephropathy. METHODS We now report a prespecified interim analysis of a phase 3, multicenter, double-blind, randomized, placebo-controlled trial, which enrolled adults with biopsy-proven IgA nephropathy and persistent proteinuria (protein level, ≥1.0 g per day), despite appropriate supportive care. Patients were randomly assigned in a 1:1 ratio to receive subcutaneous once-weekly telitacicept (240 mg) or matching placebo. The primary end point was the geometric mean ratio of the 24-hour urinary protein-to-creatinine ratio at 39 weeks relative to baseline. Safety was also evaluated. RESULTS A total of 318 patients were assigned to receive telitacicept or placebo (159 in each group). At week 39, the percentage change in the 24-hour urinary protein-to-creatinine ratio was -58.9% with telitacicept and -8.8% with placebo, which corresponded to a relative difference (based on the ratio of geometric mean reductions between the two groups) of -55.0% (95% confidence interval [CI], -61.3 to -47.6; P<0.001) in favor of active medication. The percentage change in the estimated glomerular filtration rate relative to baseline was -1.0% (95% CI, -3.2 to 1.2) with telitacicept and -7.7% (95% CI, -9.9 to -5.4) with placebo. Adverse events were more common with telitacicept than with placebo (in 89.3% vs. 78.6% of patients), although serious adverse events were less common (in 2.5% vs. 8.2%). No unexpected safety findings were reported with telitacicept. CONCLUSIONS In patients with IgA nephropathy at high risk for progression, 39 weeks of treatment with telitacicept led to a greater reduction in the 24-hour urinary protein-to-creatinine ratio than placebo. (Funded by RemeGen; TELIGAN ClinicalTrials.gov number, NCT05799287.).

Introduction Povetacicept is an inhibitor of B-cell activating factor (BAFF) and A proliferation–inducing ligand (APRIL), 2 cytokines central to the pathogenesis of autoimmune glomerulonephritis. Both BAFF and APRIL promote B-cell and plasma cell survival and function. APRIL primarily supports plasma cell survival and function, whereas BAFF regulates early pathogenic B-cell development, activates pathogenic T cells and innate immune cells, and contributes to mesangial cell proliferation and podocyte injury. Methods Our phase 1 and 2, open-label study evaluated povetacicept in adult participants with IgA nephropathy (IgAN) or primary membranous nephropathy (pMN), all with estimated glomerular filtration rate (eGFR) of ≥ 30 ml/min per 1.73 m2. The primary objective was safety. Secondary objectives included change from baseline in urine protein-to-creatinine ratio (UPCR), eGFR, galactose-deficient IgA1 (Gd-IgA1) (IgAN), antiphospholipase A2 receptor autoantibody (aPLA2R; pMN), and clinical remission (with hematuria resolution for IgAN). Results Povetacicept was administered subcutaneously every 4 weeks (Q4W) to 54 participants with IgAN (21 received 80 mg, 33 received 240 mg) and 10 with pMN (all received 80 mg). In this interim analysis, participants with IgAN on 80 mg had a 64% mean 24-hour UPCR decrease (95% confidence interval: –76 to –48) from baseline (1.3 g/g to 0.5 g/g; 65% with UPCR < 0.5 g/g) with stable eGFR at week 48. Early decline in Gd-IgA1 at week 12 (57%), continued at week 48 (77%). Approximately 90% achieved hematuria resolution and 53% achieved clinical remission. Efficacy outcomes were similar with 240 mg povetacicept. Participants with pMN had an 82% mean 24-hour UPCR decrease (95% confidence interval: –92 to –60) from baseline (3.8 g/g to 0.7 g/g) with stable eGFR. Early decline in aPLA2R at week 12 (73%), continued at week 48 (83%) with 100% in immunologic remission (40% achieved complete remission; 100% achieved partial remission). Povetacicept was generally safe and well-tolerated for IgAN and pMN. Conclusion Povetacicept had substantial, sustained UPCR reductions with stable eGFR, significant Gd-IgA1 reductions, hematuria resolution, clinical remission, with favorable safety in IgAN. Similar results were observed in pMN. By inhibiting both BAFF and APRIL, povetacicept targets the underlying cause of disease and has potential to provide a significant therapeutic advancement for autoimmune glomerular diseases.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis and a leading cause of end-stage renal disease (ESRD) for young adults. The key pathogenesis of IgAN involves overproduction of galactose-deficient IgA1 (Gd-IgA1) and anti-Gd-IgA1 antibodies, resulting in formation of circulating immune complexes that deposit in the glomerular mesangium. Consequently, emerging therapeutic strategies for IgAN aim to target and reduce aberrant Gd-IgA1 and its associated immune complexes. This disease-modifying approach confers benefits across multiple stages of IgAN progression, particular in the early phase to halt irreversible renal damage. B-cell activating factor (BAFF) and proliferation-inducing ligand (APRIL) are critical cytokines that promote the differentiation, development, and activation of B cells and plasma cells. Telitacicept, a novel recombinant fusion protein that dual-targets BAFF and APRIL, exhibits considerable therapeutic potential by inhibiting the production of Gd-IgA1 and its autoantibodies. Stage A results of the phase 3 clinical trial demonstrated that patients in the telitacicept group achieved a 55% reduction in 24-hour urinary protein-to-creatinine ratio (UPCR) and stable eGFR at week 39 versus the placebo group, with favorable tolerability and safety. This review summarizes current progresses in targeting Gd-IgA1-producing cells for the treatment of IgAN, with a focus on therapeutic strategies including BAFF/APRIL inhibitors. Furthermore, it delineates the major challenges and future research directions aimed at optimizing these interventions.

B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) drive the galactose-deficient IgA1 (Gd-IgA1) production that underlies IgA nephropathy (IgAN). Several BAFF/APRIL-pathway inhibitors have entered randomized testing, but none has been compared head-to-head. We systematically searched MEDLINE, Scopus, the Cochrane Central Register, Web of Science, and Embase to July 2026 for randomized, placebo-controlled trials of BAFF/APRIL-pathway inhibitors in adults with biopsy-proven IgAN. Random-effects pairwise meta-analysis used the standardized mean change for proteinuria and estimated glomerular filtration rate (eGFR), change-score standardization for biomarkers, and risk ratios (RR) for safety, and a frequentist star network meta-analysis with placebo as reference ranked agents by P-score. Seven trials (1,590 adults) evaluating telitacicept, atacicept, and sibeprenlimab were included. Versus placebo, BAFF/APRIL-pathway inhibition reduced proteinuria (SMCR −0.73, 95% CI −0.88 to −0.58, p < 0.001, I2 = 0%) and a small difference in eGFR favouring active treatment (+0.21, 95% CI 0.04 to 0.38, p = 0.016, I2 = 0%). Serum Gd-IgA1 and total IgA fell substantially but with high heterogeneity (I2 > 95%). Serious adverse events (RR 0.52, 95% CI 0.30 to 0.90) and treatment discontinuations (RR 0.31, 95% CI 0.11 to 0.88) were fewer with active treatment, overall adverse events did not differ (RR 1.03, 95% CI 0.92 to 1.16), and injection-site reactions were more frequent (RR 5.98, 95% CI 2.39 to 14.96). In the network, the exploratory P-score for proteinuria reduction was highest for sibeprenlimab (0.94), with no significant between-agent difference, and atacicept showed the only significant reduction in serious adverse events (RR 0.24, 95% CI 0.08 to 0.70). In adults with IgAN, BAFF/APRIL-pathway inhibitors consistently and substantially reduced proteinuria versus placebo, with a small short-term eGFR difference and no evident short-term safety signal, although longer follow-up is required to define uncommon, infectious, and immunological risks. Whether this antiproteinuric effect, seen over approximately 6 to 12 months, translates into durable preservation of kidney function remains uncertain. The between-agent and biomarker estimates are exploratory, and longer trials reporting kidney-failure endpoints are needed to confirm a disease-modifying effect. Not applicable.

Immunoglobulin A nephropathy (IgAN) often has a poor outcome, with many patients reaching kidney failure within their lifetime. Therefore, the primary goal for the treatment of IgAN should be to reduce nephron loss from the moment of diagnosis. To achieve this, IgAN must be recognized and treated as both a chronic kidney disease and an immunological disease. Agents that have received US Food and Drug Administration and European Medicines Agency approval for the treatment of IgAN include modified-release/targeted-release formulation budesonide (Nefecon) and sparsentan, a selective dual endothelin-A and angiotensin II receptor type 1 antagonist. Other agents, including selective endothelin receptor antagonists, selective or combined APRIL and BAFF antagonists, and a vast array of complement inhibitors are being investigated for the treatment of IgAN. Furthermore, treatment combinations are also being studied, including sodium–glucose cotransporter-2 inhibitors with endothelin receptor antagonists. Due to the complexity of IgAN, combination treatment, rather than a single-agent approach, may provide maximum benefit. With the number of treatments for IgAN likely to increase, combinations allowing safe and effective treatment to halt progression to kidney failure seem within grasp. While trials evaluating combinations are ongoing, more are needed to pave the way for a comprehensive IgAN treatment strategy. Furthermore, an approach to IgAN treatment in which agents are combined early to achieve rapid induction of remission and prevent unnecessary and irreversible nephron loss is required. Following remission, treatments may be adjusted and stripped back as necessary in the maintenance phase with close monitoring. This review discusses the current status of IgAN treatment and explores future strategies to improve outcomes for patients with IgAN.

IgA nephropathy (IgAN) is the most common primary glomerular disease in the world, and up to 40% of patients with IgAN develop end-stage renal disease (ESRD). At present, an increasing amount of evidence indicates that the pathogenesis of IgAN is related to autoimmunity. In recent years, several studies have shown that B cell activating factors (BAFF), also known as B lymphocyte stimulators (BLyS), and proliferation-inducing ligand APRIL are extremely important for the activation of autoimmune signalling pathways, which have become key targets for the treatment of IgAN. As a dual-target biological agent, telitacicept can inhibit both BLyS and APRIL cytokines, improve the function of renal immune complexes, and reduce haematuria and proteinuria, which play important roles in IgAN pathogenesis and long-term prognosis. This article reviews the role of telitacicept in IgA nephropathy and discusses its potential for use in the treatment of IgAN and other autoimmune diseases where pathogenesis is driven by B cells.

Rapidly progressive IgA nephropathy (IgAN) and IgA vasculitis nephritis (IgAVN) are characterized by marked glomerular inflammation, extensive extracapillary proliferation, and rapid renal function decline. Despite increasing insights into their shared pathogenic mechanisms, optimal treatment strategies remain uncertain. Here, we report two patients with rapidly progressive crescentic disease, one with primary IgAN and one with IgAVN, who received sequential complement inhibition combined with BAFF/APRIL blockade. Both patients showed substantial reductions in proteinuria and stabilization of kidney function during follow-up. These cases suggest that multi-pathway targeted therapy may represent a promising approach for selected patients with aggressive IgAN or IgAVN.

… that BAFF and APRIL are important regulators of mucosal IgA … Serum and urinary levels of BAFF and APRIL are elevated in … and clinical data on the BAFF and APRIL axis in IgAN, …

ABSTRACT Introduction IgA nephropathy is the most common primary glomerulonephritis worldwide. Immune complexes, composed of galactose-deficient IgA1 and Gd-IgA1 autoantibodies, are deposited in the mesangial area of the glomeruli where they induce complement-mediated inflammation. This may result in the reduced kidney function, which can progress to end-stage kidney disease. Treatment options are very limited. Treatments which directly affect the formation of pathogenic Gd-IgA1 antibodies and anti-Gd-IgA1 antibody-containing immune complexes are needed. Areas covered This article reviews potential therapies, namely monoclonal antibodies, that may affect the main axis of pathogenesis of IgA nephropathy with a discussion of their potential impact on the outcome of IgAN. PubMed was used to perform the literature search, which included papers on “treatment of IgA nephropathy“combined with “biological therapy“, or ‘monoclonal antibodies, atacicept, sibeprenlimab, rituximab, felzartamab, narsoplimab, iptacopan’ published up to 2023. Expert opinion The new treatment options are aimed at the immunopathogenesis of IgAN, including depletion or modulation of Gd-IgA1 producing B cells, plasma cells, alternate or lectin pathway of complement. Monoclonal antibodies may target both B cells and T cells and also the factors needed for their activation and survival, e.g. BAFF or APRIL.

B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are critical factors in the differentiation and longevity maintenance of the B-cells pool thereby mediating humoral immunity. BAFF and APRIL are involved in initiating B-cells to become self-reactive and elevated levels of these cytokines are detected in the sera of patients with systemic autoimmune diseases. The aim of the study was to estimate role of APRIL and BAFF in IgA-nephropathy (IgAN) patients and to determine the appropriate IgAN treatment based on the assessment of BAFF and APRIL dynamics in IgAN patients’ sera after 6 months of different treatments. The 52 IgAN patients aged 32,0 (27,0; 36,0) y.o., male/female ratio as 34/18 despite using of renin-angiotensin-aldosterone system inhibitors (RAASIs) for 6 months with PU 1,8 (1,0; 1,9) g/day and estimated glomerular filtration rate (eGFR) 78 (61; 103) ml/min were divided into 3 treatment groups: 1 group (n = 20) – 200 mg hydroxychloroquine (HCQ) twice a day, 2 group (n = 20) – received glucocorticoids (GC) regimen Pozzi protocol, 3 group (n = 12) – received (RAASIs) in maximal tolerated dose. The control group included age- and sex-matched healthy donors (n = 10). The number of B-cells in peripheral blood was identified by flow cytometry method. The concentrations of total IgM, IgG, IgA, IgE, APRIL and BAFF were determined by ELISA method using commercial kits. Statistical analysis was done using Statistica 10.0. Despite the absence of statistically significant differences in the number of B-lymphocytes the increased levels of total IgM, IgA and IgE (p = 0,001) as well as APRIL (5336 (3574; 5965) pg/ml vs 4543 (4518 ÷ 4755) pg/ml (p = 0,05) and BAFF 378 (191; 541) vs 336 (257; 424) pg/ml (p = 0,07) were established in sera of IgAN patients as compared to control group, respectively. The initial APRIL level was correlated with the degree of tubular atrophy with interstitial fibrosis (R = 0,40, p = 0,05) and serum IgG level (R = 0,35, p = 0,05) in IgAN patients. After 6 months of treatment proteinuria was significantly reduced in HCQ (p = 0,03) and GC (p = 0,02) groups while kidney function was stable in all patients. The dynamic of immunological parameters is presented in the Table 1. It was established that HCQ treatment in IgAN patients decreased the production of IgM (p = 0,01) and IgG (p = 0,02) as well as serum concentration of the APRIL factor (p = 0,05) what correlated with the tendency to eGFR increase (R = –0,46, p = 0,06) as well as with clinical effect of therapy improvement of (R = –0,45, p = 0,04). There were no statistical changes in the level of the BAFF factor in patients with HCQ. After GC treatment a decrease in the synthesis of serum IgA (p = 0,01) as well as trend to decline of B-cells number (p = 0,07) were determined, while in patients treated with RAASIs a significant increase in IgE production (p = 0,05) and tendency in elevation in BAFF levels (p = 0,06) were observed. Immunological changes may be the determining factors in the choice of treatment in IgAN patients.

Abstract Increased activity of B lymphocytes underpins many autoimmune conditions. A key component of the humoral immune response involves the A PRoliferation-Inducing Ligand (APRIL) and B-cell-activating factor (BAFF) system. These proteins are responsible for the activation, maturation, and survival of B lymphocytes, playing a pivotal role in autoimmunity. Therefore, targeting the BAFF/APRIL system proves promising for the treatment of various autoimmune diseases. Meticulous research into pathomechanisms of lupus nephritis (LN) has enabled the introduction of biological treatments targeting the BAFF-mediated pathway, significantly improving prognosis. In certain types of glomerulonephritis (GN), increased levels of the BAFF/APRIL system might be associated with higher proteinuria, elevated serum creatinine, but also with specific histopathological features. This indicates that biological therapies currently available could be repurposed for conditions where increased activation of B lymphocytes plays a critical role in the disease's pathophysiology. Understanding the mechanisms underlying autoimmune diseases will facilitate the adaptation of novel drugs for orphan diseases. That is why the use of chimeric antigen receptor T (CAR-T) cells as agents against B-cells receptor (BCR), represents a highly targeted and potentially optimal treatment approach. This study summarizes current knowledge about the role of the BAFF/APRIL system in lymphocyte activation mechanisms, particularly in GN. It also discusses existing biological treatments and explores future directions for drug development based on the CAR-T cell technology.

In IgA nephropathy (IgAN), elevated levels of the circulating autoantigen, galactose-deficient IgA1, are critical to disease pathogenesis. Abnormal B-cell glycosylation pathways produce the autoantigen that, upon recognition by autoantibodies, forms immune complexes. Genetic as well as in vitro, in vivo, and human immunologic studies identified APRIL (a proliferation-inducing ligand) and BAFF (B-cell activating factor) as key cytokines controlling B-cell development and differentiation of antibody-secreting cells. Targeting APRIL with or without BAFF is emerging as a viable strategy for the treatment of IgAN and nascent data from global clinical trials are showing very promising results.

… In this study, we systematically evaluated the efficacy and safety of APRIL-targeted and dual BAFF/APRIL blockade in adults with primary IgA nephropathy, based on a prespecified …

… , the exact roles 101 of APRIL and BAFF in IgA nephropathy have not been fully elucidated … potential of targeting APRIL or both APRIL and BAFF. 103 Because APRIL and BAFF act at …

… factor (BAFF) and A proliferation-inducing ligand (APRil). therefore, dual inhibition of BAFF/APRil … , which represents a soluble receptor for BAFF and APRil, and which has demonstrated …

Aberrantly glycosylated IgA1 molecules are important in the pathogenesis of IgA nephropathy. A proliferation-inducing ligand (APRIL) and B-cell activating factor (BAFF) are cytokines involved in immunoglobulin class switching and production of galactose deficient IgA1(Gd IgA1). We aimed to study the association of serum levels of APRIL and BAFF with the clinical severity and pathological grading of IgA nephropathy (IgAN) and to assess the strength of the association by studying the clinicopathological correlation. The research study was conducted as a single-center longitudinal observational study. The study subjects were recruited based on the pathological diagnosis of primary IgA nephropathy. The plasma levels of APRIL, BAFF and Gd IgA1 were estimated using enzyme-linked immunosorbent assay (ELISA). All the study subjects were followed up for one year to study the renal outcome. In our study group of thirty-eight patients, the median estimated glomerular filtration rate(eGFR) was 33.9(15.9,79.4) ml/minute/1.73m2. The median levels of the cytokines APRIL and BAFF were 170.81(82.45, 550.61) ng/L and 6.66(3.39,16.33) ng/ml respectively. The baseline characteristics of the study group is given in table 1. APRIL levels had significant positive correlation with Gd IgA1 levels (correlation coefficient 0.556, p=0.003) in patients with IgAN. We also observed that patients with elevated APRIL levels had elevated BAFF levels also (correlation coefficient 0.657, p <0.001). Patients who had crescents, mesangial hypercellularity and endocapillary proliferation in biopsy had elevated APRIL and BAFF levels whereas patients with segmental sclerosis and tubular atrophy had low levels of APRIL(Table 2). However, the levels of APRIL and BAFF did not show any significant correlation with eGFR and proteinuria at time of presentation. At the end of one year, 12(31.5%) patients reached end stage renal disease (ESRD) and these patients had lower levels of APRIL, BAFF, and Gd IgA1. It was also seen that eighty-three percent of those who reached ESRD had chronic changes in biopsy like tubular atrophy and interstitial fibrosis(p=0.05). Hence the severity of tubulointerstitial fibrosis in histology correlated well with progression to end stage renal disease as seen in most glomerular diseases. But we did not find any association between APRIL, BAFF, and Gd IgA1 levels and the decline in eGFR over one year. We conclude that levels of APRIL and BAFF are associated with elevated levels of Gd IgA1 in patients with IgAN and had a significant association with proliferative lesions in renal biopsy. But these cytokines levels did not have any association with the eGFR at time of presentation nor decline in eGFR over one year.

… bowel disease may present with extraintestinal manifestations. Crohn’s disease complicated with IgA nephropathy or IgA … was diagnosed with IgA vasculitis and IgA nephropathy at the …

… PH also decreases small intestinal motility promoting bacterial overgrowth[31,32], while in the same time increases intestinal permeability[33]. In this regard, increased circulating …

… not only induces IgA synthesis in the intestinal sub mucosa but also increases IgA transcytosis into the gut lumen, causing a major increase in polymeric mouse IgA levels in the serum. …

BACKGROUND Intestinal-barrier damage plays an important pathogenic role in immunoglobulin A nephropathy (IgAN). In this study, we explored the characteristics of the intestinal barrier in rats with IgAN. MATERIALS AND METHODS We randomly divided 17 Sprague Dawley (SD) male rats into a normal control group (NC; n = 9) and an IgAN model group (n = 8). Feces in the distal ileum were taken for intestinal-microbiota 16sDNA sequencing. We also took a segment of terminal ileum to analyze intestinal morphology and to detect mRNA and protein expression of the tight-junction proteins zonula occludens-1 (ZO-1) and occludin (OCLN), as well as of mucin 2 (MUC2). We then measured levels of serum diamine oxidase (DAO) and D-lactic acid (D-LA), the biomarkers of intestinal permeability. RESULTS Compared with the NC group, mRNA expression levels of ZO-1 (t = 4.216, P = 0.0007), OCLN (t = 2.413, P = 0.029) and MUC2 (t = 0.859, P < 0.0001) were significantly decreased in the IgAN model group. Protein expression of ZO-1 (t = 7.349, P < 0.0001) and OCLN (t = 6.367, P < 0.0001) was also decreased in the IgAN model group. Conversely, serum DAO (t = 3.758, P = 0.0024) and D-LA (t = 2.246, P = 0.0427) levels increased in this group. At the genus level, the relative abundance of Ruminococcus2 (P = 0.0086) was increased in the IgAN model group. CONCLUSIONS Decreased expression of ZO-1, OCLN and MUC2, plus intestinal-microbiota dysbiosis, are associated with intestinal-barrier damage in IgAN rats.

AIM To investigate the effects of rhein on intestinal epithelial tight junction proteins in rats with IgA nephropathy (IgAN). METHODS Twenty-eight female Sprague-Dawley rats were randomly divided into four groups (7 per group): Control, IgAN, Rhein-treated, and Rhein-prevented. Bovine serum albumin, lipopolysaccharide and CCl4 were used to establish the rat model of IgA nephropathy. The Rhein-treated group was given rhein from week 7 until the rats were sacrificed. The Rhein-prevented group was given rhein from week 1. Animals were sacrificed at the end of week 10. We observed the changes in the intestinal epithelial tight junctions using transmission electron microscopy, and expression of intestinal epithelial tight junction proteins zona occludens protein (ZO)-1 and occludin by immunofluorescence using laser confocal microscopy. Changes in mRNA and protein expression of ZO-1 and occludin were measured by reverse transcriptase polymerase chain reaction and Western blotting. The ratio of urinary lactulose/mannitol was measured by high performance liquid chromatography (HPLC) for assessing the intestinal permeability. RESULTS In the control group, the tight junctions lied between epithelial cells on the top of the outer side of the cell membrane, and appeared in dense dotted crystal structures, the neighboring cells were binded tightly with no significant gap, and the tight junction protein ZO-1 and occludin were evenly distributed in the intestinal epithelial cells at the top of the junction. Compared with the control group, in the IgAN group, the structure of the tight junction became obscured and the dotted crystal structures had disappeared; the fluorescence of ZO-1 and occludin was uneven and weaker (5.37 ± 1.27 vs 10.03 ± 1.96, P < 0.01; 4.23 ± 0.85 vs 12.35 ± 4.17, P < 0.01); the mRNA expression of ZO-1 and occludin decreased (0.42 ± 0.19 vs 0.92 ± 0.24, P < 0.01; 0.40 ± 0.15 vs 0.97 ± 0.25, P < 0.01); protein expression of ZO-1 and occludin was decreased (0.85 ± 0.12 vs 1.98 ± 0.43, P < 0.01; 0.72 ± 0.15 vs 1.38 ± 0.31, P < 0.01); and the ratio of urinary lactulose/mannitol increased (3.55 ± 0.68 vs 2.72 ± 0.21, P < 0.01). In the Rhein-prevented and Rhein-treated groups, compared with the IgAN group, the intestinal epithelial tight junctions were repaired; fluorescence of ZO-1 and occludin was stronger (11.16 ± 3.52 and 8.81 ± 2.30 vs 5.37 ± 1.27, P < 0.01; 10.97 ± 3.40 and 9.46 ± 2.40 vs 4.23 ± 0.85, P < 0.01); mRNA of ZO-1 and occludin increased (0.81 ± 0.17 and 0.64 ± 0.16 vs 0.42 ± 0.19, P < 0.01; 0.82 ± 0.22 and 0.76 ± 0.31 vs 0.40 ± 0.15, P < 0.01); protein expression of ZO-1 and occludin was increased (2.07 ± 0.41 and 1.57 ± 0.23 vs 0.85 ± 0.12, P < 0.01; 1.34 ± 0.21 and 1.15 ± 0.17 vs 0.72 ± 0.15, P < 0.01); and the ratio of urinary lactulose/mannitol decreased (2.83 ± 0.43 and 2.87 ± 0.18 vs 3.55 ± 0.68, P < 0.01). CONCLUSION Rhein can enhance the expression of ZO-1 and occludin, repair damaged tight junctions, and protect the intestinal barrier.

… permeability and plasma IgA concentrates in nephropathy, and between … intestinal permeation of 51CrEDTA and IgA immune complex plasma concentrations in patients with IgA …

… gluten and had no evidence of abnormal mucosal permeability. The finding that the patient with the … to the hypothesis that increased intestinal permeability allows chronic excess antigen …

… levels of IgA against gliadin, soy and ovalbumin [4]. Increased intestinal permeability of patients … Although we used a different methodology in our study, increased intestinal permeability …

AIM To evaluate methods measuring the intestinal per-meability in chronic kidney disease (CKD) and clarify whether there is an increased intestinal permeability in CKD. METHODS We reviewed the literature in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol and performed a systematic literature search through MEDline and EMBASE. All controlled trials and cohort studies using non-invasive methods to assess intestinal permeability in CKD patients were included. Excluded were: Conference abstracts and studies including patients younger than 18 years or animals. From the included studies we summarized the used methods and their advantages and disadvantages. For the comparison of their results we divided the included studies in two categories based on their included patient population, either assessing the intestinal permeability in mild to moderate CKD patients or in end stage renal disease (ESRD) patients. Results were graphically displayed in two plots, one comparing the intestinal permeability in mild to moderate CKD patients to healthy controls and one comparing the intestinal permeability in ESRD patients to healthy controls. RESULTS From the 480 identified reports, 15 met our inclusion criteria. Methods that were used to assess the intestinal permeability varied from markers measured in plasma to methods based on calculating the urinary excretion of an orally administered test substance. None of the applied methods has been validated in CKD patients and the influence of decreased renal function on the different methods remains unclear to a certain extent. Methods that seem the least likely to be influenced by decreased renal function are the quantitative PCR (qPCR) for bacterial DNA in blood and D-lactate. Considering the results published by the included studies; the studies including patients with mild to moderate CKD conducted conflicting results. Some studies did report an increase in intestinal permeability whilst other did not find a significant increased permeability. However, despite the variety in used methods among the different studies, all studies measuring the intestinal permeability in ESRD point out a significant increased intestinal permeability. Results should nevertheless be interpreted with caution due to the possible influence of a decreased glomerular filtration rate on test results. CONCLUSION The intestinal permeability in CKD: (1) could be measured by qPCR for bacterial DNA in blood and D-lactate; and (2) seems to be increased in ESRD.

Abstract Introduction: Presence of subclinical intestinal inflammation has repeatedly been shown in IgA nephropathy (IgAN) and the degree of histological inflammation has correlated with abnormal urinary findings. There is lack of noninvasive biomarkers evaluating the presence of subclinical intestinal damage in IgAN. We conducted this study hypothesizing that selected biomarkers regarded as indirect markers of intestinal damage could be elevated in IgAN. Methods: Eighty-five primary IgAN patients (median age 55 years, 54% men) participated in this single-center study in Tampere, Finland. None had end-stage kidney disease or previously diagnosed enteropathies. Celiac disease was excluded with serum transglutaminase 2 antibody (TG2Ab) and endomysial antibody tests and inflammatory bowel disease with fecal calprotectin. Intestinal damage was evaluated from sera with analyses of intestinal fatty-acid binding protein (I-FABP), soluble cluster of differentiation molecule 14 (sCD14), and lipopolysaccharide binding protein. Fourteen people suffering from dyspepsia and 15 healthy people served as controls. Results: I-FABP levels among IgAN patients were higher than in the healthy controls (median 830 pg/mL vs. 289 pg/mL, p < 0.001). Also, sCD14 was increased in IgAN patients compared to dyspepsia controls. Although TG2Ab levels were within the normal range among IgAN patients, they were higher than in the healthy controls (median 1.3 U/mL vs. 0.6 U/mL, p < 0.001). Conclusions: Elevated serum levels of I-FABP were present in primary IgAN patients without known enteropathies. Serum I-FABP may indicate the presence of subclinical intestinal damage. These findings encourage further investigation into the role of the intestine in the pathophysiology of IgAN.

Background Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerular disease in adults worldwide. Several studies have reported that galactose-deficient IgA1 (Gd-IgA1) is involved in the pathogenesis of IgAN. Methods Thirty-five patients with IgAN diagnosed with renal biopsy for the first time served as the experimental group, who were hospitalized in our department. Twenty normal healthy cases in the physical examination center of our hospital served as the control group. Then the levels of Gd-IgA1 in serum and urine, and intestinal mucosal barrier injury indexes [diamine oxidase (DAO), serum soluble intercellular adhesion molecule-1 (sICAM-1), D-lactate (D-LAC), and lipopolysaccharide (LPS)] and inflammatory factors [interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α)] in the serum samples were detected. Fecal samples were collected to detect intestinal microbiota using 16 s rDNA sequencing. Then, we assessed possible correlations among clinical and laboratory findings. Results In patients with IgAN, the levels of Gd-IgA1 both in the serum and urine were higher than that of the healthy control. Furthermore, urine Gd-IgA1 level was positively correlated with the serum creatinine level, 24 h urine protein, and M, S, and T parameters in the Oxford classification. ROC curve analysis showed that urine Gd-IgA1 has a greater diagnostic value (AUC = 0.9714, 95% CI, 0.932–1; P < 0.0001) for IgAN. The best cutoff value for urine Gd-IgA1 was 0.745 ng·l/ml·μmol (sensitivity, 94%; specificity, 95%). The intestinal mucosal barrier damage indexes (DAO, sICAM-1, D-LAC, and LPS) were increased in the patients with IgAN, which were positively correlated with Gd-IgA1 levels (P < 0.05) both in serum and urine. The levels of inflammatory factors in the patients with IgAN were increased. 16 s rDNA analysis showed that the intestinal microbiota in these patients was disordered compared to that observed in the healthy subjects. Actinobacteria, Bifidobacterium, Blautia, Bifidobacteriaceae, and Bifidobacteriales were decreased and Shigella was increased in IgAN. The decreased populations of these flora were negatively and significantly correlated with urine Gd-IgA1 and the levels of DAO, sICAM-1, D-LAC, and LPS. Conclusion The urine Gd-IgA1 levels may be a non-invasive biological marker for evaluating kidney injury in IgAN. Gut flora dysbiosis and intestinal barrier dysfunction may be involved in Gd-IgA1 expression.