Charting new frontiers in IgA nephropathy: a paradigm shift toward precision medicine and early intervention?

Advancements in glomerular transcriptomics offer a promising avenue toward precision medicine in IgA nephropathy. Traditional prognostic biomarkers, including proteinuria, blood pressure, and histomorphometry, fall short at capturing the complexity of IgA nephropathy and can only crudely guide therapeutic decisions. This issue needs to be addressed urgently as pathway-specific treatments become available. Glomerular transcriptomics, although technically challenging, offers an opportunity to refine prognostic precision and identify therapeutic targets, even when apparent risk of disease progression is low.

Using prediction models to improve care and communicate risk: updated modeling for children with IgA nephropathy.

Clinical risk prediction models are being generated at an increasing rate. One important component is the identification of groups for whom such models might require recalibration to retain their desired performance. To this end, an update of the postbiopsy International IgA Nephropathy Prediction Tool for children has been published in this issue of Kidney International. We review the methods used and generalizability in practice, along with broader concepts in model development and application.

Genetics of IgA nephrology: risks, mechanisms, and therapeutic targets.

IgA nephropathy (IgAN) is a genetically complex multifactorial trait. Over the past decade, population-based genome-wide association studies (GWAS) have identified more than 30 IgAN risk loci, providing novel perspectives on both the epidemiology of the disease and its underlying molecular mechanisms. In addition, the association between IgAN and galactose-deficient IgA1 (Gd-IgA1) presented another avenue for genetic exploration due to the heritability of the elevated serum Gd-IgA1 levels. These endeavors also yielded and enabled refinement of polygenic risk scores, which may help identify specific groups of individuals at significantly increased risks, leading to stratifications of medical treatments. In this review, we aim to explore the existing evidence for genetic causation in IgAN. We summarize the state of genetic research in IgAN and how it has led to the reformulation of the new pathogenesis model and novel therapeutic targets.

IgA nephropathy in children: before and after the start of COVID-19.

BACKGROUND: We describe the clinical course of children with IgA nephropathy (IgAN), diagnosed before and after the emergence of COVID-19. We hypothesized that COVID-19 vaccination and/or infection resulted in more children with IgAN to present clinically. METHODS: We conducted a retrospective cohort study of children with IgAN diagnosed on kidney biopsy from 2014-2020 (Period 1) and 2021-2022 (Period 2). Baseline characteristics, clinical presentation, investigations and treatments were compared between patients diagnosed in Period 1 and Period 2, as well as between patients with and without chronic changes on kidney biopsy. Continuous variables were compared using the Wilcoxon rank sum test. Categorical variables were compared using χ2 or Fisher exact tests. RESULTS: Nineteen children with IgAN were diagnosed by kidney biopsy, with 10 during Period 1 and 9 patients during Period 2 (an average of 1-2 patients/year and 4-5 patients/year in Periods 1 and 2, respectively). The most common indication for kidney biopsy is proteinuria with urine protein/creatinine ratio 1.4 (interquartile range [IQR] 1.2-9.0) vs. 0.8 (IQR 0.6-1.5) g/g (p = 0.064) at time of kidney biopsy for patients in Period 1 and 2, respectively. Clinical course was similar in both periods. No patient required acute or chronic kidney replacement therapy. CONCLUSIONS: The rate of diagnosing children with IgAN was higher since the emergence of COVID-19, suggesting that COVID-19 may trigger an immune response responsible for IgAN, similar to other mucosal infections.

Are children with IgA nephropathy different from adult patients?

BACKGROUND: Previously, several studies have indicated that pediatric IgA nephropathy (IgAN) might be different from adult IgAN, and treatment strategies might be also different between pediatric IgAN and adult IgAN. METHODS: We analyzed two prospective cohorts established by pediatric and adult nephrologists, respectively. A comprehensive analysis was performed investigating the difference in clinical and pathological characteristics, treatment, and prognosis between children and adults with IgAN. RESULTS: A total of 1015 children and 1911 adults with IgAN were eligible for analysis. More frequent gross hematuria (88% vs. 20%, p < 0.0001) and higher proteinuria (1.8 vs. 1.3 g/d, p < 0.0001) were seen in children compared to adults. In comparison, the estimated glomerular filtration rate (eGFR) was lower in adults (80.4 vs. 163 ml/min/1.73 m2, p < 0.0001). Hypertension was more prevalent in adult patients. Pathologically, a higher proportion of M1 was revealed (62% vs. 39%, p < 0.0001) in children than in adults. S1 (62% vs. 28%, p < 0.0001) and T1-2 (34% vs. 8%, p < 0.0001) were more frequent in adults. Adjusted by proteinuria, eGFR, and hypertension, children were more likely to be treated with glucocorticoids than adults (87% vs. 45%, p < 0.0001). After propensity score matching, in IgAN with proteinuria > 1 g/d, children treated with steroids were 1.87 (95% CI 1.16-3.02, p = 0.01) times more likely to reach complete remission of proteinuria compared with adults treated with steroids. CONCLUSIONS: Children present significantly differently from adults with IgAN in clinical and pathological manifestations and disease progression. Steroid response might be better in children.

A multi-center randomized controlled trial to investigate potential effects of exercise therapy on renal function stratified by renal disorders and renal pathology: beneficial or harmful effect in immunoglobulin a nephropathy.

BACKGROUND: The effects of exercise therapy (ET) on renal function in chronic kidney disease (CKD) remain unclear. METHODS: In a randomized controlled trial (UMIN-CTR number: UMIN000038415), we investigated whether ET affects renal function in CKD; eligible patients had undergone renal biopsy in the past 3 months. We stratified patients by disease (immunoglobulin A [IgA] nephropathy, n = 16; diabetic nephropathy, n = 4; benign nephrosclerosis, n = 13; and other CKD types, n = 13) and randomized them to 12 weeks' observation and 24 weeks' ET comprising home-based aerobic exercise 3×/week and resistance training 2×/week (intervention group) or usual care (non-intervention group). Primary endpoint was creatinine-based estimated glomerular filtration rate (eGFR) or serum cystatin C-based eGFR (eGFRcys). Secondary endpoints included urinary protein and exercise tolerance. RESULTS: Seventy patients were enrolled, 50 fulfilled the inclusion criteria, but 4 discontinued before randomization. No items significantly differed between week 0 to 24 in either group (intervention group, n = 23; non-intervention group, n = 23) or between groups at week 24 (intention-to-treat population) in the total study population. The eGFRcys slope showed no significant intergroup difference in the observation period, but eGFRcys improved significantly in IgA nephropathy patients (n = 16) in the intervention group (stratified comparison; week 0, 48.3 ± 18.2; week 24, 51.6 ± 17.6; p = 0.043). In these patients, urinary protein was significantly worse at week 24 in the non-intervention group (p = 0.046) and worsened significantly less in the intervention group (p = 0.039). CONCLUSION: ET did not improve renal function overall in CKD patients but might help maintain renal function in patients with IgA nephropathy.

Current understanding and new insights in the treatment of IgA nephropathy.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, and almost all patients are at risk of progression to end-stage kidney disease within their lifetime. The mechanisms responsible for the presentation and development of IgAN are required for the development of highly targeted therapies for this disease. In this review, we first demonstrate the current treatment strategy of IgAN recommended by the 2021 KDIGO guideline. Then, we update the new insights into disease pathogenesis based on the well acknowledged 'multiple-hit hypothesis' and provide the potential therapeutic targets involved in the upstream production of pathogenic IgA1 and the downstream complement activation. Finally, the recent large randomized controlled trials focusing on these novel targets have been summarized, among which Nefecon and Sparsentan have received approval and Telitacicept have been used off-label for IgAN. In the future, emerging treatment approaches for IgAN is likely to evolve, which will signify a shift in the management of the IgAN from traditional immunosuppressive approaches to an era of targeted treatment based on the understanding of the pathogenic mechanisms.

Post-conference review of oral session 6 and short talk in the 17th international IgA nephropathy conference, Tokyo 2023.

Oral session 6 titled 'Clinical Trial 1' and the short talk on 'Landscape of Clinical Trials in IgAN-What's beyond the Horizon?' took place on 30 September 2023 in the symposium venue. The short talk highlighted the increase in IgAN trials in the last decade and the challenges of global clinical trials from the site investigator perspective. The talk also underlined the importance of relooking and repurposing already available and approved therapeutics. There were six oral sessions that focussed mainly on the interim results of ongoing clinical trials as well as early phase results with new investigational agents.

Pathology of IgA nephropathy: A global perspective.

Worldwide adoption of the Oxford Classification of IgA nephropathy (IgAN) has enabled comparison of pathology data from clinicopathological studies in different regions of the world. It is apparent that the frequency of Oxford Classification MEST-C scores shows geographic variations. These in part reflect differences in the stage of disease at diagnosis, criteria for performing biopsies and inclusion in clinical studies, and pathologist reporting practice. However, there appears to be a true geographic difference in the frequency of glomerular inflammation and crescents with a 2-3 fold greater proportion of patients showing these changes in East Asia when compared to Europe and North America. This indicates that the pathology of IgAN is influenced by genetic background. Geographic differences in the pathology of IgAN might underly the reported differences in clinical presentation and outcome in different regions of the world, and has important implications for clinical trials and patient management.

My journey on the path to understanding IgA nephropathy: From bench to bedside.

When Berger et al. first reported IgA nephropathy in 1968, the prognosis was generally thought to be benign. However, as more case data were accumulated, it became evident that not all patients with IgA nephropathy necessarily had a good prognosis. IgA nephropathy has a significant morbidity, culminating in end-stage kidney disease (ESKD) in about 40% of patients without treatment within 20 years of the diagnosis. Although almost 20% of patients remain stable in their renal function, 30%-40% of patients develop ESKD from its onset. The important factors of renal outcome in patients with IgA nephropathy is the severity of histopathological findings, heavy proteinuria, long duration of proteinuria, haematuria and hypertension.

Review on epidemiology, disease burden, and treatment patterns of IgA nephropathy in select APAC countries.

BACKGROUND: Immunoglobulin type A (IgA) nephropathy is the most common primary glomerulonephritis (GN) worldwide with higher rates in East and Pacific Asia compared to North America and Europe. Despite high reported prevalence of IgAN in these countries, the overall disease prevalence across Asia is not available. Treatment patterns of IgAN patients across Asian countries have also not been summarized. The aim of this study was to review and summarize evidence on IgA nephropathy prevalence, treatment patterns, and humanistic and economic burden in mainland China, Taiwan, South Korea, Japan, and Australia. METHODS: A targeted literature review was conducted in PubMed and local databases in China (including Taiwan), South Korea, Japan, and Australia between January 2010-December 2021. Website literature searches were conducted using Google Scholar and Baidu. RESULTS: Sixty-nine publications and 3 clinical guidelines were included. Incidence ranged from 0 to 10.7 per 100 000 people per year in Australia, Japan, and Taiwan, and ranged from 6.3 to 24.70% among patients who underwent renal biopsy in mainland China. Prevalence and diagnosis rates ranged from 0 to 72.1% in mainland China, South Korea, Taiwan, Japan, and Australia. Mortality rates in mainland China, South Korea, and Japan varied widely. The top 3 commonly used therapies were angiotensin-converting enzyme inhibitor/angiotensin receptor blockers (0.9-99.6%), corticosteroids (3.5-100%), and immunosuppressants (1.6-85.5%) in Japan, mainland China, and South Korea. Patient quality of life was measured by different tools, and annual hospitalization costs ranged from $1 284.73 to $2 252.12 (2015-2018) in China. CONCLUSIONS: The prevalence of IgA nephropathy among the general population in select countries/regions is not commonly available, despite evidence from studies and clinical guidelines. In addition, it is observed across geographic regions that heterogeneity exists in prevalence rates, and large variations exist in treatment patterns. There is need to fill in these gaps to understand the contributing factors behind the differences through population-based, multi-center, and real-world studies.

Long-term renal survival in patients with IgA nephropathy: a systematic review.

The management strategy for IgA nephropathy (IgAN), has undergone constant improvements since the disease entity was first described 50 years ago. However, it is still unknown how these changes affected the long-term renal survival of IgAN patients. We systematically evaluate changes in IgAN renal survival by searching PubMed, Embase, and the Cochrane Library Database of Systematic Reviews from inception to 19 May 2024. We included a large sample of 103076 IgAN cases from 158 studies. Renal survival rates were 94.16% (95% CI: 94.02% to 94.31%), 88.68% (95% CI: 88.48% to 88.87%), and 78.13% (95% CI: 77.82% to 78.43%) at three, five, and ten-year, respectively. Over the past few decades, there haven't been any sound changes in the 3-year and 5-year renal survival rates. The kidney survival rate in developed countries is higher than in developing countries. Researchers consistently show that while proteinuria < 1.0 g/24 h, renal survival rates increase dramatically. In IgAN, long-term renal survival fluctuated rather than continuously improving over time. Our system review's findings indicate that supportive care-the most important recommendation for managing IgAN has shown promising results. The long-term outcomes of IgAN could be significantly improved by the latest developed treatment options.

Prognosis of IgA nephropathy patient with proteinuria remission by supportive therapy: cohort from screening failed Chinese patients in TESTING study.

BACKGROUND: During the run-in phase of the TESTING study, approximately half of patients with IgA nephropathy (IgAN) were excluded due to proteinuria below 1 g/24 h after intensive supportive therapy. The long-term prognosis of these patients needs further investigation. METHODS: 112 screening failed patients in the TESTING study from 10 centers in China were enrolled in this retrospective study. The prognosis of 88 patients, who were excluded because of proteinuria below 1 g/24 h, was analyzed by Landmark Kaplan-Meier analysis. The composite kidney endpoint was defined by a ≥ 50% reduction in eGFR, ESKD (eGFR <15 mL/min per 1.73 m2), chronic dialysis for at least 6 months, or renal transplantation. RESULTS: In total, 88 patients were excluded due to proteinuria less than 1 g/24 h. During the follow-up, 73/88 (83.0%) patients received renin-angiotensin system blocker. 72/88 (81.8%) had stable proteinuria remission and did not receive immunosuppressive therapy (IST), and 16/88 (18.2%) received IST because of a relapse of proteinuria. Landmark Kaplan-Meier analysis revealed that, the kidney survival from dialysis or composite kidney outcome of these excluded patients with IST was similar to those without IST during the early stages of follow-up (dialysis, before 60 months, p = 0.778; composite kidney outcome, before 48 months, p = 0.862); whereas the risk for dialysis of patients receiving IST was significantly higher than those without IST after 60 months (OR = 11.3, p = 0.03). Similarly, the risk for the composite kidney outcome of patients receiving IST was also significantly higher than those without IST after 48 months (OR = 5.92, p = 0.029). CONCLUSIONS: IgAN patients who maintained a persistent remission of proteinuria after intensive supportive therapy had a much better long-term kidney outcome than those who experienced a relapse of proteinuria and needed IST.

IgA nephropathy in adults-treatment standard.

Immunoglobulin A nephropathy (IgAN) is the most common primary form of glomerular disease worldwide and carries a high lifetime risk of kidney failure. The underlying pathogenesis of IgAN has been characterized to a sub-molecular level; immune complexes containing specific O-glycoforms of IgA1 are central. Kidney biopsy remains the gold-standard diagnostic test for IgAN and histological features (i.e. MEST-C score) have also been shown to independently predict outcome. Proteinuria and blood pressure are the main modifiable risk factors for disease progression. No IgAN-specific biomarker has yet been validated for diagnosis, prognosis or tracking response to therapy. There has been a recent resurgence of investigation into IgAN treatments. Optimized supportive care with lifestyle interventions and non-immunomodulatory drugs remains the backbone of IgAN management. The menu of available reno-protective medications is rapidly expanding beyond blockade of the renin-angiotensin-aldosterone system to include sodium-glucose cotransporter 2 and endothelin type A receptor antagonism. Systemic immunosuppression can further improve kidney outcomes, although recent randomized controlled trials have raised concerns regarding infectious and metabolic toxicity from systemic corticosteroids. Studies evaluating more refined approaches to immunomodulation in IgAN are ongoing: drugs targeting the mucosal immune compartment, B-cell promoting cytokines and the complement cascade are particularly promising. We review the current standards of treatment and discuss novel developments in pathophysiology, diagnosis, outcome prediction and management of IgAN.

Prognostic factors of IgA nephropathy presenting with mild proteinuria at the time of diagnosis (a multicenter cohort study).

BACKGROUND: Clinical factors affecting renal prognosis in patients with immunoglobulin A nephropathy (IgAN) and low urinary protein excretion (U-Prot) remain unclear. This study evaluated such factors in patients with clinical grade I (CG-I) IgAN with U-Prot < 0.5 g/day. METHODS: This secondary analysis of a previous retrospective study included 394 patients with CG-I IgAN. The primary outcome was the first occurrence of a 1.5-fold increase in serum creatinine levels from baseline. Factors related to renal prognosis were examined using univariate and multivariate Cox regression analyses. CG-I was divided into C-Grade Ia (CG-Ia) (n = 330) with baseline eGFR ≥ 60 ml/min/1.73 m2, and C-Grade Ib (CG-Ib) (n = 64) with baseline eGFR < 60 ml/min/1.73 m2. Outcome incidence was compared between conservative and aggressive therapy (corticosteroids and/or tonsillectomy) groups. RESULTS: Overall outcome incidence was significantly higher in CG-Ib than in CG-Ia; the cumulative incidence was significantly higher in CG-Ib (hazard ratio, 9.67; 95% confidence interval, 2.90-32.23). Older age, higher IgA levels, eGFR < 60 mL/min/1.73 m2, lower eGFR at baseline were independent prognostic factors for CG-I. Older age, lower eGFR, higher IgA levels at baseline, and U-Prot remission at 1-year post-diagnosis were independent prognostic factors for CG-Ib. Aggressive therapy tended to suppress the cumulative outcome incidence compared with conservative therapy in CG-Ib (p = 0.087). CONCLUSION: An eGFR < 60 mL/min/1.73 m2 is a significant predictor of renal prognosis in patients with IgAN and U-Prot < 0.5 g/day.

IgA nephropathy in adults with epidermolysis bullosa.

Epidermolysis bullosa (EB) is a devastating genetic condition caused by mutations in genes that give rise to aberrant proteins. There are 16 different such proteins implicated in EB that are important in maintaining the integrity of the dermoepidermal junction. It is classified into four major subtypes: (i) EB simplex; (ii) junctional EB (JEB); (iii) dystrophic EB (DEB); and (iv) Kindler EB. Renal disease is a recognized complication of EB and the aetiology is complex. We describe our experience of managing five patients with EB and IgA nephropathy. We recommend that patients with recessive DEB and JEB routinely have the following monitored: renal function, urinary albumin/creatinine ratio, urine analysis, serum albumin levels and immunoglobulins; specifically serum IgA. Management of IgA nephropathy in the context of EB should be tailored to the individual and be carried out within a specialist multidisciplinary team. Our case series provides important insights into the treatment of IgA nephropathy in patients with EB and will help inform treatment in this rare genetic disease. Case series and reports like ours are key in gaining real-life data to quantify the actual risk of morbidity and mortality from each of the treatment modalities discussed.

Chimeric Fusion between Clostridium Ramosum IgA Protease and IgG Fc Provides Long-Lasting Clearance of IgA Deposits in Mouse Models of IgA Nephropathy.

BACKGROUND: IgA nephropathy is a common primary glomerulonephritis caused by mesangial deposition of poly-IgA complexes. The disease follows a variable course of clinical progression, with a high risk of kidney failure. Although no specific therapy is available, enzymatic strategies to clear IgA deposits are being considered for the treatment of rapidly progressive IgA nephropathy. METHODS: We chose an IgA protease of commensal bacterium Clostridium ramosum, termed AK183, as the template for constructing a recombinant biologic. To extend the t1/2 in blood, we fused AK183 to the Fc segment of human IgG1. Activities of this Fc-AK183 fusion protein toward the cleavage and subsequent clearance of IgA were tested in mouse models. RESULTS: First, we discovered an autocleavage activity of AK183 that separates the N-terminal protease from its C-terminal autotransporter ß domain. Therefore, we grafted Fc to the N terminus of AK183 and demonstrated its week-long enzymatic activity in mice. In addition, the proteolytic fragments of IgA generated in the reaction with Fc-AK183 were effectively removed from circulation via kidney filtration. The combined actions of Fc-AK183-mediated cleavage and subsequent renal clearance of IgA resulted in a lasting obliteration of blood IgA, as demonstrated in a human IgA-injection model and in a humanized α1KI transgenic model. Fc-AK183 was also able to remove chronic IgA and associated complement C3 deposits in the glomerulus. CONCLUSION: We constructed a chimeric fusion of IgA protease with Fc and demonstrated its long-lasting efficacy as a promising targeted therapy for IgA nephropathy in mouse models.

Efficacy and Safety of Plasma Exchange as an Adjunctive Therapy for Rapidly Progressive IgA Nephropathy and Henoch-Schönlein Purpura Nephritis: A Systematic Review.

Patients with IgA nephropathy (IgAN), including Henoch-Schönlein purpura nephritis (HSP), who present with rapidly progressive glomerulonephritis (RPGN) have a poor prognosis despite aggressive immunosuppressive therapy. The utility of plasmapheresis/plasma exchange (PLEX) for IgAN/HSP is not well established. This systematic review aims to assess the efficacy of PLEX for IgAN and HSP patients with RPGN. A literature search was conducted using MEDLINE, EMBASE, and through Cochrane Database from inception through September 2022. Studies that reported outcomes of PLEX in IgAN or HSP patients with RPGN were enrolled. The protocol for this systematic review is registered with PROSPERO (no. CRD42022356411). The researchers systematically reviewed 38 articles (29 case reports and 9 case series articles) with a total of 102 RPGN patients (64 (62.8%) had IgAN and 38 (37.2%) had HSP). The mean age was 25 years and 69% were males. There was no specific PLEX regimen utilized in these studies, but most patients received at least 3 PLEX sessions that were titrated based on the patient's response/kidney recovery. The number of PLEX sessions ranged from 3 to 18, and patients additionally received steroids and immunosuppressive treatment (61.6% of patients received cyclophosphamide). Follow-up time ranged from 1 to 120 months, with the majority being followed for at least 2 months after PLEX. Among IgAN patients treated with PLEX, 42.1% (n = 27/64) achieved remission; 20.3% (n = 13/64) achieved complete remission (CR) and 18.7% (n = 12/64) partial remission (PR). 60.9% (n = 39/64) progressed to end-stage kidney disease (ESKD). Among HSP patients treated with PLEX, 76.3% (n = 29/38) achieved remission; of these, 68.4% (n = 26/38) achieved CR and 7.8% achieved (n = 3/38) PR. 23.6% (n = 9/38) progressed to ESKD. Among kidney transplant patients, 20% (n = 1/5) achieved remission and 80% (n = 4/5) progressed to ESKD. Adjunctive plasmapheresis/plasma exchange with immunosuppressive therapy showed benefits in some HSP patients with RPGN and possible benefits in IgAN patients with RPGN. Future prospective, multi-center, randomized clinical studies are needed to corroborate this systematic review's findings.

Assessing prognosis in IgA nephropathy.

Assessing the prognosis is essential in chronic diseases, such as IgA nephropathy. The 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend the "International IgAN Prediction Tool" (available at www.qxmd.com) for this. The key limitation was that the tool was only validated at the time of the kidney biopsy. An improved algorithm is now described, which allows assessing the prognosis at 1 or 2 years after biopsy. Herein, we review the strengths, limitations, and potential clinical usefulness of this new prediction tool.

Probiotics ameliorate IgA nephropathy by improving gut dysbiosis and blunting NLRP3 signaling.

BACKGROUND: Recently, a few studies have indicated a relationship between the gut microbiota and IgA nephropathy (IgAN). Whether the gut microbiota participates in the pathogenesis of IgAN and whether probiotics are effective in treating IgAN are still controversial. Therefore, this study aimed to identify the differences in the structure of the gut microbiota between IgAN and controls and to evaluate the efficacy and mechanism of probiotics in the treatment of IgAN. METHODS: To address this question, 35 IgAN patients and 25 healthy volunteers were enrolled, and a mouse IgAN model was also constructed. The stool microbes were analyzed by 16S rRNA high-throughput sequencing to identify the differential strains between IgAN and healthy controls. The impact of probiotics on the structure of the intestinal flora and the efficacy of the probiotics in the treatment of IgAN were evaluated. RESULTS: Although the microflora structure of mice and humans was not the same, both patients and mice with IgAN exhibited gut microbiota dysbiosis, with all subjects presenting an evident decrease in Bifidobacterium levels. The Bifidobacterium proportion was negatively correlated with proteinuria and hematuria levels, indicating that the decreased Bifidobacterium abundance could be related to IgAN severity. Probiotic treatment containing Bifidobacterium in IgAN mice could significantly alleviate gut dysbiosis, specifically by increasing the proportion of beneficial bacteria and reducing the abundance of potentially pathogenic bacteria. Moreover, both probiotics and their metabolites, short-chain fatty acids (SCFAs), could attenuate IgAN clinicopathological manifestations by inhibiting the NLRP3/ASC/Caspase 1 signaling pathway. CONCLUSIONS: Supplementation with probiotics mainly containing Bifidobacterium could markedly improve gut dysbiosis in IgAN. Moreover, both probiotics and their SCFA metabolites could attenuate the clinicopathological manifestations of IgAN by inhibiting the NLRP3/ASC/Caspase 1 signaling pathway. Therefore, probiotics have potential as an adjunctive therapy for IgAN.