Immunoglobulin A Nephropathy: Molecular Pathogenesis and Targeted Therapy.

Introduction

Immunoglobulin A (IgA) nephropathy (IgAN), first described by Berger and Hinglais in 1968 [ 1 , 2 , 3 ], remains the most common primary glomerulonephritis worldwide, with a striking geographic disparity in prevalence, accounting for up to 40% of glomerular diseases in Asia but only 10–20% in Western populations [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Characterized by mesangial deposition of galactose‐deficient IgA1 (Gd–IgA1) immune complexes, IgAN progresses to end‐stage kidney disease (ESKD) in 20–40% of patients within two decades, despite optimized supportive care [ 18 , 19 ]. Historically considered benign, recent longitudinal cohorts challenge this view, demonstrating a median kidney failure‐free survival of only 11–12 years even among patients with subnephrotic proteinuria [ 18 , 19 ]. The disease's molecular pathogenesis, rooted in a “multi‐hit” cascade of mucosal immune dysregulation, autoantibody production, and complement activation, has only recently been unraveled, paving the way for mechanism‐driven therapies [ 8 , 9 , 14 ].

The past decade has witnessed a paradigm shift in IgAN management, marked by United States Food and Drug Administration (US FDA) approvals of targeted therapies including targeted‐release formulation budesonide (TRF‐budesonide) (2023), complement inhibitors (iptacopan, accelerated approval 2024), and endothelin (ET) receptor antagonists (ERAs) (sparsentan 2023, atrasentan 2025), alongside emerging strategies such as BAFF (B‐cell activating factor, also known as BLyS, TALL‐1, CD257, or TNFSF13B) and APRIL (A Proliferation‐Inducing Ligand, also known as CD256 or TNFSF13) inhibitors undergoing phase 3 evaluation (sibeprenlimab, telitacicept), and cellular therapies in preclinical exploration [ 20 ].

However, critical challenges persist: (1) Existing therapies like corticosteroids show limited efficacy in high‐risk patients and carry significant safety risks; (2) Renin–angiotensin system inhibitors (RASi), while foundational, fail to halt progression in 20–40% of cases; (3) Novel agents face accuracy limitations in biomarker‐guided patient selection and long‐term safety uncertainties. These gaps underscore three key research questions: (1) How can we optimize risk stratification to identify patients needing early aggressive therapy? (2) What is the optimal sequencing of supportive care, immunosuppression, and targeted agents? (3) Can we develop cost‐effective strategies for global accessibility? This review navigates these controversies—including immunosuppression timing, corticosteroid roles, and therapy integration—amidst an increasingly complex therapeutic landscape, as clinicians now face the challenge of navigating an increasingly complex therapeutic landscape while balancing efficacy, safety, and cost effectiveness.

To ensure methodological transparency, this review employed a systematic literature search strategy. We searched PubMed and Cochrane Library databases (2000–2025) using the following terms: (“IgA nephropathy” OR “IgAN”) AND (“pathogenesis” OR “targeted therapy” OR “biomarkers” OR “clinical trials”). Inclusion criteria encompassed: (1) human studies; (2) randomized controlled trials, cohort studies, or systematic reviews; (3) articles with mechanistic or therapeutic focus. Exclusion criteria: (1) animal‐only studies; (2) case reports (<10 patients); (3) non‐English publications without validated translations.

This review integrates the latest advances in molecular pathogenesis, multiomics, and clinical trials to outline a roadmap for individualized care. Emphasizing the shift from a linear “multi‐hit” model to a dynamic self‐amplifying spiral, we link pathogenic mechanisms (mucosal dysregulation, Gd–IgA1 production, complement activation) to B‐cell, complement, and mucosal‐targeted therapies. We explore how novel biomarkers (e.g., Gd–IgA1, urinary CD163) enable dynamic risk stratification and “treat‐to‐target” (T2T) strategies. Concurrently, we critique controversies like Oxford MEST‐C score (Oxford classification (MEST‐C: mesangial hypercellularity [M], endocapillary hypercellularity [E], segmental sclerosis [S], tubular atrophy/interstitial fibrosis [T], crescent [C]) limitations and immunosuppression hazards, advocating evidence‐based approaches.

The review begins by underscoring the pressing need for more effective therapies through a detailed examination of IgAN's unfavorable long‐term prognosis, highlighting the persistent risk of progression to ESKD despite current standards of care. Building on this foundation, we systematically analyze the molecular mechanisms that drive disease progression, explicitly connecting these pathogenic insights to the therapeutic challenges faced in clinical practice. The subsequent sections critically appraise the latest evidence for supportive interventions, the clinical promise of novel targeted agents, and the potential of innovative modalities such as chimeric antigen receptor (CAT)‐T cell therapy, all within the context of evolving treatment paradigms. The review culminates in a pragmatic framework for initiating and monitoring therapy, emphasizing the integration of mechanistic and clinical data. By weaving together advances from bench to bedside, this work aims to empower clinicians to navigate IgAN's therapeutic transformation and advocates for the adoption of biomarker‐guided trial designs to resolve ongoing uncertainties and optimize patient outcomes.

Poor Prognosis and Global Burden of IgAN

IgAN imposes a substantial global health burden, with striking geographic disparities in prevalence and clinical outcomes. As the most common primary glomerulonephritis worldwide, IgAN accounts for 20–40% of biopsy‐proven glomerular diseases in Asia compared with 10–20% in Western populations [ 12 ]. Recent epidemiological studies estimate an annual incidence of 0.76 per 100,000 in Europe and 2.75 per 100,000 among Asian populations, with a global prevalence ranging from 2.53 per 10,000 in Europe to 10.5 per 100,000 in Australia [ 21 , 22 ]. This geographic variation reflects genetic susceptibility, differential diagnostic practices, and environmental factors influencing mucosal immune dysregulation.

The economic impact of IgAN is profound, particularly in high‐risk populations. In the United States, patients with proteinuria ≥1 g/day incur nearly double the healthcare costs of those with lower proteinuria ($3732 vs. $1457 per patient per month) [ 23 ], driven by frequent hospitalizations and outpatient visits. Advanced chronic kidney disease (CKD) stages exacerbate this burden, with Stage 5 CKD costs exceeding $10,000 monthly. Mirroring this trend in China, the CK‐NET 2017–2018 report revealed that hospitalization costs for CKD patients averaged CNY 18,000 (∼$2600) per admission, with glomerular diseases like IgAN constituting 28.1% of all CKD hospitalizations [ 24 ]. Furthermore, ESKD patients requiring hemodialysis incurred annual expenses exceeding CNY 88,000 (∼$12,700), translating to over $1000 monthly—a catastrophic expenditure for 63% of households. Advanced CKD stages exacerbate this burden globally, with Stage 5 CKD costs exceeding $10,000 monthly in high‐income settings.

Recent long‐term follow‐up data from United Kingdom and Chinese cohorts have revealed a sobering prognosis for IgAN patients [ 18 , 19 ], challenging the historical view of IgAN as a relatively benign condition. The UK National Registry of Rare Kidney Diseases study [ 18 ], analyzing 2299 adults and 140 children with IgAN, demonstrated that 50% of patients reached kidney failure or died within the study period, with a median kidney survival of 11.4 years. Most patients progressed to kidney failure within 10‐15 years across all age groups at diagnosis. Alarmingly, an annual estimated glomerular filtration rate (eGFR) decline of just 1 mL/min per 1.73 m 2 per year would result in approximately 40% of adult patients younger than 50 years at diagnosis reaching kidney failure within their expected lifetime. These findings are corroborated by a large prospective cohort from China [ 19 ], which reported a median kidney survival time of 12.4 years, an annual event rate of ESKD of 41.1 per 1000 person‐years, and a 15‐year kidney survival rate of 40%. These studies suggest that up to 80% of patients may progress to kidney failure within 20 years [ 25 , 26 ], underscoring the chronic and relentless nature of IgAN.

Notably, these poor outcomes persist despite advances in supportive care and the use of RAS inhibitors. Even patients with relatively low levels of proteinuria, traditionally considered with “low‐risk” (0.5–1 g/day), showed significant rates of kidney failure within 10 years [ 18 , 26 ]. These findings highlight the urgent need for more effective, disease‐specific therapies and emphasize the importance of ongoing research into novel therapeutic approaches [ 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. The recognition of IgAN as a disease with such poor long‐term outcomes underscores the critical need for earlier diagnosis, intervention, and better prognostic markers to identify high‐risk patients who might benefit from more aggressive treatment approaches early in the disease course.

Molecular Pathogenesis

The Multi‐Hit Hypothesis: Expanded and Updated

The molecular pathogenesis of IgAN has traditionally been conceptualized through the “multi‐hit hypothesis,” which has significantly influenced therapeutic target discovery and drug development (Figure 1 ) [ 34 , 35 , 36 , 37 , 38 ]. This model outlines four sequential steps: (1) overproduction of Gd–IgA1 due to dysregulated mucosal and systemic immunity; (2) generation of autoantibodies against Gd–IgA1; (3) formation of circulating immune complexes (ICs); and (4) glomerular deposition of these ICs, leading to complement activation, mesangial cell proliferation, and inflammatory injury. Gd–IgA1, defined by aberrant O‐glycosylation in the hinge region, serves as a neoepitope that elicits autoantibody production and IC formation [ 39 , 40 , 41 ]. These immune complexes preferentially deposit in the mesangium via interactions involving IgA, transferrin receptor 1 (CD71), and soluble CD89 (sCD89), forming tripartite complexes (IgA1–sCD89–CD71) that activate mTOR signaling [ 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ]. sCD89 promotes mesangial cell proliferation through PI3K/Akt/mTOR pathways, and glomerular sCD89 deposits correlate with histological markers of disease activity, especially in pediatric IgAN. Experimental models show that recombinant sCD89 injections recapitulate key IgAN features, such as mesangial hypercellularity and proteinuria, and in vitro studies confirm its direct role in triggering inflammatory cytokine release (e.g., IL‐6, TNF‐α) and complement activation [ 52 , 53 ].

Integrating Recent Mechanistic Insights

While the multi‐hit hypothesis remains a cornerstone, recent multiomics and single‐cell studies have revealed a much more intricate interplay of immune and renal cells in IgAN pathogenesis. Expanded populations of mucosal‐associated invariant T cells and CD4+ T helper 17 (Th17) cells have been identified in IgAN patients, promoting B‐cell differentiation into IgA‐secreting plasmablasts via IL‐17 signaling pathways [ 54 , 55 , 56 , 57 , 58 ]. Mendelian randomization and immunophenotyping further implicate dysregulated B‐cell receptor signaling and impaired tolerance checkpoints in transitional B cells, with specific immunophenotypes (e.g., IgD+ CD24− B cells) correlating with disease risk due to altered energy metabolism and defective negative selection [ 59 , 60 , 61 , 62 ]. Elevated BAFF/APRIL levels in IgAN sera drive autoreactive B‐cell survival, supporting these findings [ 63 , 64 , 65 , 66 , 67 ]. Beyond lymphocytes, renal parenchymal cells actively contribute to disease progression: mesangial cells exposed to Gd–IgA1–ICs upregulate Toll‐like receptor (TLR)4 and NLRP3 inflammasomes, activating MAPK/ERK and NF‐κB signaling, which leads to proinflammatory cytokine release (IL‐6, TNF‐α) [ 68 , 69 ]. Glomerular immune complexes containing Gd–IgA1 stabilize alternative pathway (AP) complement activation through properdin‐mediated C3 convertase formation, amplifying mesangial injury via C5a receptor‐mediated inflammation and membrane attack complex (MAC)‐induced cell lysis; this also drives progressive tubulointerstitial fibrosis through C5a‐induced macrophage chemotaxis and endothelial cell activation [ 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 ]. Complement activation in IgAN involves both alternative and lectin pathways, with CFH/CFHR genetic variants propelling AP dysregulation and C3a/C5a‐mediated inflammation perpetuating progression [ 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 ]. Urinary C3a/C5a levels correlate with histological severity and predict eGFR decline, while CFHR1/CFHR5 overexpression amplifies C3 convertase activity, creating a self‐sustaining injury loop. Therapeutic targeting of the complement axis is supported by clinical trials: iptacopan (a factor B inhibitor) reduces proteinuria by 38.5% and slows eGFR decline by 1.1 mL/min/year compared with placebo, while C5a receptor antagonists (such as avacopan) show similar efficacy in early‐phase studies [ 91 ]. Tubular epithelial cells exposed to sustained cytokine stimulation adopt a profibrotic phenotype via TGF‐β/Smad3 signaling, a process exacerbated by epigenetic modifications in fibrotic pathways, such as DNA hypermethylation of C1GALT1 [ 92 , 93 ].

Sustained Pathogenic Cycles and Molecular Mimicry

The chronic progression of IgAN is perpetuated by a self‐reinforcing pathogenic cycle, in which persistent antigenic triggers and molecular mimicry play central roles. The “trigger hypothesis” posits that recurrent mucosal infections, such as streptococcal pharyngitis, provoke episodic surges in aberrant IgA production, which in turn drive disease flares. Recent studies have identified βII‐spectrin as a mesangial autoantigen, sharing structural homology with microbial antigens—particularly the SH3 domain of Streptococcus M proteins—thereby facilitating the formation of cross‐reactive IgA autoantibodies [ 94 , 95 ]. This process is further exacerbated by gut dysbiosis: for example, overgrowth of Akkermansia muciniphila can degrade intestinal MUC1 via bacterial proteases, generating IgA1 neoepitopes that escape immune tolerance. In parallel, TLR9 activation in tonsillar B cells, as demonstrated in Japanese cohorts, induces APRIL overexpression, which sustains Gd–IgA1 synthesis [ 96 , 97 , 98 , 99 , 100 , 101 , 102 ].

Epigenetic and Posttranscriptional Regulation

Epigenetic dysregulation is increasingly recognized as a critical factor in IgAN pathogenesis. For instance, IL‐6–driven overexpression of GALNT14 impairs galactosylation of the IgA1 hinge region, while histone acetylation at TNFRSF13B (TACI) enhances BAFF/APRIL‐mediated plasma cell survival [ 103 , 104 , 105 ]. Furthermore, TRDMT1‐induced RNA 5‐methylcytosine (m5C) modification regulates IgA class switch recombination by modulating activation‐induced cytidine deaminase activity, and miR‐23b downregulation leads to increased pathogenic IgA synthesis [ 106 , 107 ]. These epigenetic mechanisms create a vicious cycle; increased m5C modification exacerbates disease severity in mouse models, while pharmacological inhibition of m5C normalizes IgA levels and ameliorates renal injury.

Innate Immunity and the Renal Inflammatory Niche

Single‐cell multiomics analyses have revealed that these molecular alterations sustain a self‐perpetuating inflammatory niche within the kidney. M2c‐polarized macrophages secrete PDGFB to activate mesangial cells, while injured podocytes release HMGB1, which recruits CD163+ macrophages via TLR4, establishing a feedforward inflammatory loop [ 55 , 57 ]. Clinically, this cycle is reflected in episodic disease flares following infection, with higher urinary sCD163 levels predicting steroid resistance, and glomerular CD206+ macrophage density correlating with treatment response [ 108 , 109 , 110 ]. These findings underscore the clinical utility of integrating urinary sCD163 and glomerular macrophage markers as biomarkers for individualized, niche‐targeted therapeutic strategies, enabling more precise risk stratification and tailored treatment selection.

Limitations of the Multi‐Hit Model

Each infectious trigger transiently elevates circulating pathogenic IgA, which, if not cleared, deposits in glomeruli, activates complement, and recruits inflammatory cells, resulting in a “hit‐and‐run” pattern of injury. Over time, repeated insults cumulatively reduce nephron reserve, accelerating progression to chronic kidney injury despite periods of clinical quiescence between flares. This paradigm mirrors the “trigger‐reload” dynamics observed in autoimmune diseases, where repeated antigenic exposures overwhelm regulatory mechanisms, transforming episodic attacks into relentless kidney destruction.

Despite these advances, significant knowledge gaps remain in our understanding of IgAN pathogenesis. The origin of Gd–IgA1 is still debated: while gut‐associated lymphoid tissue (GALT) is implicated via CCR9+ IgA+ plasmablasts homing to mucosal sites, bone marrow‐derived CD38hi CD27+ plasmablasts also contribute, as evidenced by clonal IgA1 expansions and shared somatic hypermutations between mucosal and systemic compartments in IgAN patients [ 57 , 96 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 ]. Single‐cell RNA sequencing has revealed CXCL12/CXCR4‐mediated crosstalk between these populations, suggesting a dual origin for pathogenic IgA1 [ 57 , 128 , 129 , 130 ].

The role of innate immunity is also undercharacterized. Renal macrophages polarize toward M2c (CD163+ CD206+) and CD14+ CD16+ intermediate subsets, secreting TGF‐β1 and IL‐10 to drive fibrosis, while CD103+ dendritic cells promote Th17 differentiation via IL‐23/IL‐1β, collectively forming a profibrotic niche through PDGF‐B/PDGFRβ signaling and exacerbating mesangial matrix expansion [ 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 ]. The renal microenvironment evolves into a self‐sustaining inflammatory circuit, with injured podocytes releasing HMGB1 that activates TLR4 on tubular epithelial cells, inducing chemokines such as CXCL1/IL‐8 to recruit S100A9+ neutrophils [ 143 , 144 , 145 , 146 , 147 , 148 ]. These neutrophils release neutrophil extracellular traps (NETs) enriched in calprotectin (S100A8/A9) and IgA‐binding proteins, perpetuating immune complex deposition and complement activation via properdin stabilization [ 14 , 149 , 150 ]. Single‐cell multiomics identifies a feedforward loop where NET‐derived histones stimulate TLR9 in B cells, amplifying Gd–IgA1 production [ 57 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 ].

The multi‐hit pathogenesis framework, while foundational, remains incomplete. First, although elevated serum levels of Gd–IgA1 and Gd–IgA1‐specific IgG autoantibodies correlate with disease progression, standardized assays for these biomarkers lack universal clinical validation and their prognostic utility varies across populations [ 34 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 ]. Second, the complement activation paradox remains unresolved: although immune complexes containing IgG typically activate the classical pathway, IgAN predominantly involves alternative and lectin pathways. Recent evidence shows that lectin pathway components (e.g., mannose‐binding lectin [MBL], L‐ficolin) mediate glomerular injury in a subset of patients, with MBL–IgA1 complexes triggering C4d deposition independent of classical pathway activation [ 171 , 172 , 173 ]. Third, the model does not explain why elevated Gd–IgA1 levels in asymptomatic relatives often do not lead to IgAN, despite shared genetic predisposition [ 174 ]. Additional modifiers—such as T‐cell polarization patterns (Th17/Treg imbalance), innate immune cell activation, and tissue‐specific adaptation—may determine clinical progression [ 175 ].

Furthermore, the model's focus on circulatory factors underrepresents renal parenchymal responses—particularly mesangial cell epigenetic reprogramming and local complement activation—that actively shape disease phenotype, as demonstrated by single‐cell transcriptomics of IgAN biopsies [ 58 , 176 , 177 , 178 , 179 ]. The episodic recurrence of proteinuria despite initial immunosuppressive response, exemplified by several trials showing a 40% relapse rate within 3 years post steroid therapy, challenges the linear “hit accumulation” concept [ 180 , 181 , 182 , 183 ]. These conceptual gaps underscore the necessity of expanding the paradigm to include tissue‐specific adaptation mechanisms and dynamic host–environment interactions across disease phases. Given these limitations, a new conceptual framework is required to capture the recurrent and dynamic nature of IgAN pathogenesis.

The Spiral Hypothesis: A Dynamic Model of IgAN Progression

Recent advances in single‐cell and multiomics studies, as well as clinical observations, suggest that the pathogenesis of IgA nephropathy is best conceptualized not as a simple linear cascade, but as a dynamic, self‐perpetuating spiral. We propose a “spiral hypothesis” (Figure 2 ), positing that IgAN progression involves repeated cycles of mucosal immune dysregulation, pathogenic IgA1 production, immune complex formation, and renal injury. Each cycle amplifies both systemic and local immune responses, leading to cumulative nephron loss and irreversible kidney damage over time. This model highlights the interplay between genetic susceptibility, epigenetic regulation, environmental triggers (such as infections and gut microbiota alterations), and renal tissue adaptation. The spiral is driven by recurrent mucosal triggers and sustained by tissue‐level inflammatory and fibrotic responses, resulting in a progressive decline in renal function even during periods of clinical remission. Importantly, this hypothesis underscores the need for therapeutic strategies that interrupt not only the initial pathogenic events but also the recurrent, amplifying cycles that characterize disease progression. By targeting both immune dysregulation and the chronic fibrotic milieu, the spiral hypothesis may provide a more comprehensive framework for understanding clinical heterogeneity and guiding personalized intervention in IgAN.

Integrative Summary

In summary, the molecular pathogenesis of IgAN is defined by a complex interplay between mucosal immune dysregulation, pathogenic IgA production, complement activation, and the establishment of a self‐sustaining renal inflammatory niche. While the multi‐hit hypothesis has provided a valuable roadmap for targeted therapy development, recent multiomics and single‐cell studies continue to reveal additional layers of complexity—including the roles of T cell subsets, innate immune mechanisms, epigenetic regulation, and the gut microbiome. The spiral hypothesis better encapsulates the chronic, relapsing, and self‐amplifying features of IgAN, calling for integrated therapeutic strategies that address both the triggers and the perpetuating cycles of immune‐mediated and fibrotic injury.

Current Therapy Dilemma

A paradigm shift has emerged in the management of IgAN, distinguishing between etiological therapies targeting disease mechanisms and general CKD treatments. This evolving approach has sparked considerable debate (Table 1 ), particularly regarding the optimal timing and appropriateness of initiating etiological treatments. The controversy reflects the complex and heterogeneous nature of IgAN, as well as the ongoing challenges in developing effective, targeted therapies for this common glomerular disease.

Proponents of early intervention emphasize that addressing the underlying pathogenic mechanisms at an early stage could potentially alter the disease course and improve long‐term outcomes. This view is supported by accumulating evidence that early immunological events‐such as the production of Gd–IgA1 and the formation of immune complexes‐play a crucial role in disease initiation and progression. By intervening before significant renal damage occurs, early therapy may help prevent or delay the development of CKD and ESKD.

Conversely, some experts urge caution regarding the widespread use of etiological treatments, especially novel agents such as targeted‐release budesonide (Nefecon). Concerns have been raised about the limited long‐term efficacy data and the high costs associated with these therapies. The inclusion of budesonide in broad treatment recommendations has been particularly contentious, with critics arguing that the current evidence base is insufficient to support its widespread adoption as a first‐line therapy. These experts stress the importance of optimizing supportive care‐such as blood pressure control, proteinuria reduction, and cardiovascular risk management‐before considering more aggressive immunomodulatory treatments.

The introduction of sparsentan (US FDA‐approved 2023) [ 184 ] and iptacopan (accelerated approval 2024) [ 185 ] has reshaped the therapeutic landscape. Sparsentan, a dual ET–angiotensin receptor antagonist, reduces proteinuria by 42.8 versus 4.4% with irbesartan at 110 weeks while preserving eGFR (−2.9 vs. −3.9 mL/min/year). Iptacopan [ 186 ], an alternative complement pathway inhibitor, achieves 35% proteinuria reduction and eGFR stabilization in C3d‐positive patients. These agents, alongside targeted‐release budesonide, intensify challenges in patient selection and treatment timing.

Given the heterogeneous clinical presentations and variable progression rates of IgAN, determining which patients are most likely to benefit from specific therapies, and at what point in their disease course, remains a significant challenge [ 187 , 188 ]. The optimal use of these agents—whether as monotherapy or in combination with existing or other novel treatments—has yet to be fully established.

The complex pathogenesis of IgAN, involving multiple “hits” to the immune system and kidneys, suggests that combination therapies targeting different pathways may offer synergistic benefits. For example, combining supportive care with targeted therapies could potentially enhance efficacy. However, such approaches must be balanced against the risk of increased side effects and higher treatment costs.

The controversy between systemic corticosteroids and TRF‐budesonide centers on efficacy‐safety trade‐offs (Table 2 ). While the TESTING trial demonstrated significant eGFR preservation with reduced‐dose methylprednisolone (−2.7 mL/min/year), it reported 16.5% serious infections and 2.1% mortality [ 182 , 183 ]. In contrast, NefIgArd showed comparable proteinuria reduction but superior long‐term eGFR preservation (−2.1 vs. −7.5 mL/min/year in placebo) without steroid‐specific complications [ 186 , 189 , 190 ]. This divergence underscores the value of tissue‐targeted approaches.

Not all patients with IgAN necessarily require etiological treatment. Real‐world evidence and recent guideline updates indicate that patients with mild histological changes or stable, low‐level proteinuria may achieve long‐term stability with optimized supportive care alone [ 191 , 192 ]. For instance, the TESTING trial run‐in phase revealed that 81.8% of patients maintaining proteinuria <1 g/day on RASi avoided progression without immunosuppression [ 193 ]. Although supportive therapies reduce proteinuria by 30–50% and slow CKD progression, longitudinal cohort studies indicate that 30–40% of patients still progress to ESKD within 20 years despite optimal management [ 194 ]. This underscores the need for additive targeted therapies in high‐risk populations, particularly those with active immunological markers (elevated Gd–IgA1, urinary CD163) or aggressive histology (crescents, C4d deposition) [ 195 ].

The advent of new therapies also raises questions about the sequencing and potential combination of treatments. While combination regimens may offer additive benefits, they also necessitate careful monitoring for overlapping toxicities and cost‐effectiveness. Emerging data suggest synergistic effects when combining supportive and targeted therapies. For example, the SPARTACUS trial found that adding sparsentan to sodium‐glucose cotransporter‐2 inhibitors (SGLT2is) yielded additive proteinuria reduction compared with SGLT2i alone [ 196 ]. Conversely, the NefIgArd open‐label extension showed that combining Nefecon with iptacopan‐targeting both Gd–IgA1 production and complement‐mediated injury‐reduced proteinuria more efficiently while stabilizing eGFR [ 197 , 198 ]. However, such regimens require careful monitoring for overlapping toxicities (e.g., infections with complement inhibitors, fluid retention with ET antagonists).

Furthermore, the personalization of treatment strategies is likely to become increasingly important as more therapeutic options become available. Factors such as genetic predisposition, biomarker profiles, and histological findings may play crucial roles in guiding individualized treatment decisions. Elevated serum APRIL levels may predict a response to B‐cell‐targeted therapies like sibeprenlimab, while urinary C3a/C5a ratios correlate with complement inhibitor efficacy. Ongoing phase 3 trials of atrasentan (selective ET‐A antagonist) and zigakibart (APRIL inhibitor) will further clarify the roles of mechanistically distinct agents [ 199 , 200 , 201 , 202 , 203 , 204 ]. Real‐time predictive models that incorporate these factors, alongside clinical parameters, could help tailor therapy to individual patients, maximizing efficacy while minimizing unnecessary exposure to potential side effects.

Ultimately, the goal is to balance immunological control with preservation of renal reserve—a task complicated by IgAN's heterogenous pathogenesis. This heterogeneity necessitates divergent approaches: for chronic, slowly progressive disease, experts advocate step‐up therapy with minimal sequential agents to avoid overtreatment; conversely, in rapidly progressive subgroups, early intensive immunosuppression is critical to counter irreversible glomerulosclerosis. While early intervention in high‐risk patients appears justified, overtreatment of indolent cases remains a concern [ 20 ]. Looking ahead, well‐designed clinical trials comparing treatment strategies—including de‐escalated regimens for low‐risk patients and combination therapies for high‐risk subtypes—will be essential. These studies should address not only short‐term outcomes like proteinuria reduction but also long‐term renal survival and quality of life. Additionally, real‐world evidence tracking risk‐stratified implementation of new therapies will be crucial for refining treatment algorithms.

In summary, while IgAN remains a challenging disease with significant unmet needs, the rapidly evolving therapeutic landscape offers new hope for patients and clinicians. The coming years will be critical in determining how best to integrate these novel therapies into clinical practice, with the ultimate goal of improving renal outcomes and quality of life for patients with this common but potentially devastating kidney disease. As research progresses, the prospect of transforming IgAN from a disease with an uncertain prognosis to a manageable chronic condition with preserved kidney function may become a reality for many patients.

Supporting Therapies

Supportive therapy remains the cornerstone of IgAN management, forming the essential foundation upon which all other interventions are built [ 205 , 206 , 207 ]. Despite significant advances in disease‐specific therapies, optimized supportive care—including lifestyle modification, blood pressure control, and RASi—continues to be the first‐line approach for all patients, irrespective of risk stratification [ 15 , 17 , 20 , 207 , 208 , 209 , 210 ]. This strategy aims not only to slow the progression of CKD but also to reduce cardiovascular morbidity, which constitutes a major cause of mortality in CKD population.

Contemporary treatment algorithms prioritize a stepwise approach: initial optimization of supportive care for 3–6 months, followed by escalation to targeted therapies in nonresponders. As outlined by Praga et al. [ 211 ], this therapeutic hierarchy initiates supportive care with RAS inhibition ± SGLT2i for proteinuria >0.5 g/day, reserving ERAs or immunosuppression for patients with persistent proteinuria >1 g/day despite optimized supportive therapy, histological risk (MEST‐C ≥2), and/or progressive eGFR decline.

The primary therapeutic objectives of supportive care are to achieve rigorous blood pressure control (generally targeting <130/80 mmHg, and <120 mmHg for select high‐risk patients), minimize proteinuria (ideally to <0.5 g/day), and address modifiable lifestyle factors such as obesity, smoking, and dietary sodium intake [ 195 , 212 ]. The efficacy of RAS inhibitors (ACEi/ARB) in reducing proteinuria and preserving renal function is well established [ 213 , 214 , 215 , 216 ], with multiple randomized controlled trials and meta‐analyses showing that maximally tolerated doses confer significant renal protection compared with other antihypertensive agents or placebo. Recent evidence also supports the addition of SGLT2is for patients with persistent proteinuria or declining eGFR despite optimal RAS blockade [ 217 , 218 , 219 , 220 ], with subgroup analyses from DAPA‐CKD and EMPA‐KIDNEY demonstrating substantial reductions in kidney disease progression and ESKD risk in IgAN cohorts.

Practical integration of SGLT2i faces real‐world challenges: cost barriers in low‐resource settings, eGFR eligibility thresholds (typically >20 mL/min), and management of genital infections. Nonetheless, their cardiorenal benefits position them as second‐line agents after RASi, particularly for patients with eGFR decline >2 mL/min/year despite optimized supportive care.

Contemporary supportive care extends beyond traditional agents to incorporate newer pharmacological modalities with pleiotropic effects. ERAs like sparsentan and mineralocorticoid receptor antagonists (MRAs) exhibit dual antiproteinuric and antifibrotic properties through TGF‐β pathway modulation [ 184 , 200 , 201 , 221 , 222 , 223 , 224 , 225 , 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 , 234 , 235 ]. Though mechanistically novel, these agents primarily target downstream pathological processes rather than underlying disease etiology. Their integration into treatment regimens exemplifies the evolution of supportive strategies, complementing rather than replacing foundational RAS inhibition. Sparsentan (US FDA‐approved 2023) now integrates into algorithms for persistent proteinuria without hematuria, while MRAs like finerenone require cautious potassium monitoring, limiting use in advanced CKD. Real‐world implementation is challenged by drug–drug interactions (e.g., NSAIDs) and the absence of head‐to‐head trials against SGLT2i.

The immunomodulatory potential of supportive therapies also warrants emphasis. RAS inhibitors mitigate NF‐κB‐driven inflammation and TGF‐β‐mediated fibrosis, while SGLT2i suppress NLRP3 inflammasome activation and macrophage recruitment [ 236 , 237 , 238 , 239 , 240 , 241 ]. These ancillary properties may explain the 30–40% sustained remission rate observed with optimized supportive care alone. The STOP‐IgAN trial paradigm further validates this approach [ 205 ], demonstrating that 6 months of intensive supportive management enables 40% of initially eligible patients to avoid immunosuppression without compromising outcomes.

For disease‐modifying agents (TRF‐budesonide, BAFF/APRIL inhibitors), supportive care remains the mandatory backbone. Nefecon is prioritized for elderly/comorbid patients intolerant to steroids, while complement inhibitors (e.g., iptacopan) require C3d/Gd–IgA1 biomarkers for patient selection—a significant barrier in regions lacking specialized assays. Cost remains prohibitive: annual pricing exceeds $70,000 for novel agents versus $500–$1200 for RASi/SGLT2i combinations.

It is reasonable to endorse a 1–3 month observation period with optimized supportive therapy before considering immunomodulation, except in cases with high‐risk features: active histological lesions (crescents >25%, fibrinoid necrosis), nephrotic‐range proteinuria (>3.5 g/day), or rapid eGFR decline (>5 mL/min/1.73 m 2 /year) [ 207 ]. This strategic delay allows assessment of treatment responsiveness while minimizing early exposure to immunosuppressive risks.

Nevertheless, even with best‐practice supportive management, a considerable residual risk of CKD progression persists, particularly among patients with persistent proteinuria or high‐risk pathological features. This underscores the need for adjunctive disease‐modifying therapies but also reinforces the principle that supportive care should be maintained as the backbone of all treatment regimens. The integration of novel agents—such as targeted‐release budesonide [ 186 , 190 ] and complement inhibitors [ 185 ]—into the therapeutic landscape does not diminish the foundational role of supportive care; rather, these agents are layered atop optimized supportive measures to maximize renal preservation.

Critical implementation gaps persist: (1) biomarker accessibility limits precision deployment of APRIL inhibitors (e.g., sibeprenlimab requires serum APRIL levels); (2) long‐term safety data for combination regimens (e.g., SGLT2i + ERA) remains incomplete; (3) rural/underserved regions lack infrastructure for rigorous proteinuria monitoring. These disparities necessitate context‐adapted protocols: urban centers may adopt biomarker‐guided escalation, while community clinics prioritize RASi/SGLT2i combinations with quarterly monitoring.

Ultimately, the sustained success of any intervention in IgAN hinges on the continued optimization of supportive therapy as the platform for all subsequent, individualized treatment strategies. As research advances and disease‐modifying therapies become increasingly available, the transition from optimized supportive care to etiology‐targeted interventions should be guided by persistent proteinuria, progressive decline in kidney function, or the presence of high‐risk pathological features. In this way, supportive care not only maximizes the efficacy of new therapies but also ensures that patients receive the most appropriate and effective management at every stage of their disease.

Emerging Targeted Therapies

Targeted‐Release Formulation of Budesonide (TRF‐Budesonide)

Targeted‐release formulation of budesonide (TRF‐budesonide, Nefecon) represents a significant advancement in IgAN treatment [ 186 , 189 , 190 ], addressing its underlying pathogenesis through localized delivery to GALT in the distal ileum—where >70% of mucosal IgA‐producing cells reside. This innovative approach targets the “mucosal origin” hypothesis of IgAN, where dysregulated IgA production occurs in Peyer's patches. Upon ingestion, Nefecon's pH‐dependent enteric coating dissolves in the distal ileum, releasing budesonide directly to GALT. This locally suppresses B‐cell activation, Gd–IgA1 production, and subsequent immune complex formation, while minimizing systemic exposure (Figure 3 ). By interrupting the disease process at its source, TRF‐budesonide offers a mechanistically precise alternative to broad immunosuppression.

The phase 3 NefIgArd trial demonstrated Nefecon's efficacy [ 186 ], showing a 31% reduction in proteinuria compared with placebo after a 9‐month treatment course. Additionally, the study revealed a statistically significant difference in eGFR decline between the Nefecon and placebo groups over a 2‐year period. Notably, the 2‐year eGFR benefit (−2.1 vs. −7.5 mL/min/year in placebo) persisted 9 months posttreatment cessation, suggesting disease‐modifying effects beyond the treatment window. The safety profile of Nefecon was further elucidated during a 15‐month observational follow‐up, where the incidence of treatment‐emergent adverse events (TEAEs) was similar between Nefecon and placebo groups, suggesting that adverse effects are largely confined to the active treatment period.

Common TEAEs associated with Nefecon included peripheral edema (17 vs. 4% placebo), hypertension (12 vs. 3%), muscle spasms (12 vs. 4%), acne (11 vs. 1%), and headache (10 vs. 8%). Of note, four prediabetic participants progressed to diabetes during the 9‐month treatment period, highlighting the importance of glucose monitoring in at‐risk patients. Critically, no instances of adrenal insufficiency, cataracts, or osteoporotic fractures—frequent complications of systemic steroids—were observed. The discontinuation rate due to TEAEs was 9% in the Nefecon group compared with 2% in the placebo group. While this higher rate is notable, it should be contextualized within Nefecon's overall risk–benefit profile, considering its demonstrated efficacy in preserving renal function and reducing proteinuria in IgAN patients.

Cost‐effectiveness analyses reveal nuanced economic implications. At an annual cost of ∼$70,000, Nefecon achieves an incremental cost‐effectiveness ratio (ICER) of $98,000/QALY versus supportive care in high‐risk patients—below the $150,000/QALY US willingness‐to‐pay threshold. However, this exceeds ICERs for SGLT2 inhibitors ($45,000/QALY) and RASi ($12,000/QALY). Budget impact models indicate potential savings by reducing ESKD incidence: treating 100 patients with Nefecon may prevent eight cases of dialysis ($2.4 M savings over 5 years), offsetting 40% of drug costs.

Several critical questions remain regarding the optimal use of TRF‐budesonide in IgAN. A key area for further investigation is the direct comparison between TRF‐budesonide and low‐dose systemic corticosteroids to clarify their relative efficacy and safety [ 182 , 183 ]. While the TESTING trial demonstrated greater proteinuria reduction with systemic steroids, this came at the cost of threefold higher infection rates and significant metabolic toxicity. The NefIgArd extension data suggest TRF's superior long‐term eGFR preservation despite lesser acute proteinuria reduction, highlighting a fundamental efficacy‐safety trade‐off.

While the initial 9‐month treatment course with Nefecon has shown promising results, including a 31% reduction in proteinuria, the durability of its effects and the need for repeated or maintenance therapy remain uncertain. The NefIgArd open‐label extension showed proteinuria rebounded to 82% of baseline 15 months posttreatment, suggesting potential need for retreatment cycles in nonresponders. Long‐term safety data are also essential, particularly concerning extended or repeated treatment courses, even though its targeted delivery system is designed to minimize systemic side effects.

The potential for combining TRF‐budesonide with other immunosuppressive therapies also warrants exploration. Given the complex pathogenesis of IgAN, a multitargeted approach may enhance outcomes by addressing different aspects of the disease. For example, combining TRF‐budesonide with APRIL inhibitors (e.g., sibeprenlimab) or complement blockers (iptacopan) may synergistically target upstream Gd–IgA1 production and downstream inflammatory injury. However, careful evaluation of these combinations is necessary to ensure they do not compromise the favorable safety profile of TRF‐budesonide, particularly regarding risks like infections or metabolic disturbances.

Another priority is identifying patient subgroups most likely to benefit from TRF‐budesonide, either as monotherapy or in combination regimens. Biomarkers such as elevated serum Gd–IgA1, urinary CD163, and mucosal‐homing CCR9+ plasmablasts may help refine patient selection and monitor treatment response. Personalized approaches could optimize outcomes by targeting therapy to those at highest risk of progression while avoiding unnecessary treatment in lower‐risk patients.

B‐Cell Targeted Therapies

Recent advances in understanding the molecular pathogenesis of IgAN have catalyzed the development of B cell‐targeted therapies [ 121 , 166 , 242 , 243 ], which can be broadly categorized into two strategic approaches (Figure 3 ): direct B‐cell depletion and modulation of B‐cell activation pathways. These interventions aim to disrupt the production of Gd–IgA1, a pivotal pathogenic factor in IgAN. Below, we synthesize current evidence and emerging directions, incorporating critical insights from recent literature.

Direct B‐Cell Depletion Strategies

This approach seeks to reduce the populations of B cells and plasma cells responsible for pathogenic Gd–IgA1 production:

Tonsillectomy

Historically considered for its potential to eliminate mucosa‐associated lymphoid tissue (MALT) sources of aberrant IgA, tonsillectomy remains controversial. While Japanese cohort studies initially suggested reduced proteinuria and improved renal outcomes [ 244 , 245 , 246 ], subsequent meta‐analyses reveal inconsistent benefits across diverse populations. Notably, a 2024 systematic review highlighted significant heterogeneity in patient selection and outcome measures, underscoring the lack of consensus on its therapeutic role. Given these limitations and the irreversible nature of the intervention, tonsillectomy cannot be routinely recommended outside select research contexts.

GALT Targeting

The development of targeted‐release budesonide (NEFECON) represents a paradigm shift in modulating mucosal immunity. By delivering budesonide to the distal ileum—a hub for Peyer's patches and IgA class‐switching—this agent reduces local B‐cell activation without systemic immunosuppression. The phase 3 NefIgArd trial demonstrated sustained proteinuria reduction (48% at 12 months) and eGFR preservation, positioning it as the first US FDA‐approved therapy for IgAN. This spatially precise approach exemplifies how anatomic targeting can optimize efficacy while minimizing off‐tissue effects.

CD20 Monoclonal Antibodies

The use of CD20 monoclonal antibodies, such as rituximab, in the treatment of progressive IgAN has not shown consistent benefit and is not currently recommended [ 247 , 248 ]. The failure of CD20 monoclonal antibodies in IgAN may be attributed to several factors, including the persistence of long‐lived plasma cells that continue to produce pathogenic IgA1 even after B‐cell depletion, and the potential role of other immune cells in disease progression. This experience emphasizes the need for a more nuanced understanding of the immune dysregulation in IgAN and the importance of developing targeted therapies that address the specific pathogenic mechanisms of the disease.

CD38/CD40 Pathway Inhibition

The use of monoclonal antibodies targeting CD38 or CD40, molecules expressed on B cells and plasma cells, represents a more systemic approach to B cell depletion [ 249 , 250 ]. CD38 is highly expressed on plasma cells, which are responsible for the bulk of antibody production, including pathogenic Gd–IgA1 in IgAN. Monoclonal antibodies against CD38, such as daratumumab, felzartamab, have shown efficacy in multiple myeloma and are being investigated for their potential in IgAN. Early‐phase IgAN trials demonstrate proteinuria reductions (40–60% with felzartamab) but reveal significant toxicity—including cytopenias, opportunistic infections, and cardiotoxicity—offsetting potential benefits while biopsy efficacy awaits confirmation. The plasma cell depletion rationale targeting Gd–IgA1 producers remains biologically plausible despite safety challenges. Similarly, CD40 is a crucial molecule for B cell activation and survival, and blocking CD40–CD40L interactions with monoclonal antibodies could potentially disrupt the production of pathogenic antibodies. However, these approaches are still in early stages of investigation for IgAN ( NCT05065970 ), and their efficacy and safety profiles need to be carefully evaluated, particularly given the broad effects these therapies may have on the immune system.

Modulation of B‐Cell Activation

The second major strategy in targeting B cells in IgAN focuses on modulating B cell activation and the pathways involved in the abnormal production of IgA [ 251 , 252 , 253 ]. This approach aims to fine‐tune the immune response rather than broadly depleting B cells, potentially offering a more nuanced intervention with fewer systemic effects.

Glucocorticoids

Glucocorticoids have long been used in the treatment of IgAN, and their effects on B cell function are well documented. They act through multiple mechanisms, including suppression of B cell proliferation, induction of apoptosis in activated B cells, and modulation of cytokine production. While systemic glucocorticoids have shown efficacy in reducing proteinuria and slowing disease progression in some patients with IgAN, their use is limited by significant side effects associated with long‐term systemic exposure. The development of targeted‐release formulations, as mentioned earlier, aims to harness the beneficial effects of glucocorticoids on mucosal B cells while minimizing systemic exposure.

TLR Modulation

The modulation of TLR signaling represents a novel approach to regulating B cell activation in IgAN. TLRs play a crucial role in innate immunity and can influence B cell activation and antibody production [ 112 , 254 , 255 , 256 , 257 , 258 ]. In IgAN, there is evidence of aberrant TLR signaling contributing to the production of Gd–IgA1 and the overall inflammatory milieu. TLR antagonists are being investigated as potential therapies to dampen this inappropriate immune activation. By targeting specific TLRs implicated in IgAN pathogenesis, such as TLR9, researchers hope to develop more targeted therapies that can modulate B cell function without broadly suppressing the immune system. Hydroxychloroquine (HCQ) has emerged as a promising treatment for IgAN, with its potential mechanism of action of interfering with TLR signaling by directly binding to nucleic acids and inhibiting endosomal TLR activation, particularly TLR9. A randomized controlled trial showed that HCQ, when added to optimized RAAS inhibition, significantly reduced proteinuria by 48.4% over 6 months compared with placebo. Moreover, HCQ exhibited a favorable safety profile with no serious adverse events reported during short‐term use [ 259 , 260 , 261 ]. However, the long‐term renoprotective efficacy and safety of HCQ in IgAN require further investigation. Future research should focus on larger, ethnically diverse randomized controlled trials with extended follow‐up periods to confirm HCQ's long‐term benefits and potential role as an alternative or adjunct to conventional immunosuppressive therapies in IgAN management.

Mycophenolate Mofetil

Mycophenolate Mofetil (MMF) represents an immunomodulatory approach that regulates B‐cell activation and may contribute to reducing pathogenic IgA production in IgAN, though direct evidence for IgA suppression remains limited. By selectively inhibiting inosine monophosphate dehydrogenase, MMF impedes de novo purine synthesis, reducing B‐lymphocyte proliferation and plasma cell differentiation. While the precise impact on Gd–IgA1 antibodies is inferred rather than directly proven, clinical studies demonstrate MMF's efficacy in reducing proteinuria and stabilizing renal function in progressive IgAN [ 262 , 263 , 264 , 265 , 266 , 267 , 268 , 269 , 270 , 271 , 272 , 273 , 274 ], particularly in patients with active inflammation. The MAIN trial demonstrated significant advantages [ 269 ]: MMF combined with supportive care reduced the composite outcome risk by 77% (adjusted hazard ratio 0.23) and slowed eGFR decline (1.2 vs. 3.8 mL/min/1.73 m 2 /year) versus supportive care alone in progressive IgAN. This positions MMF as a viable strategy for modulating aberrant B‐cell responses without broad immunosuppression. Key limitations include rapid loss of renal protection after discontinuation and unresolved questions regarding long‐term safety and generalizability beyond Asian populations. MMF's favorable risk–benefit profile during treatment offers a validated alternative to broad immunosuppression, though its specific mechanistic impact on pathogenic IgA requires further validation.

Proteasome Inhibitors

Proteasome inhibitors represent another innovative approach to modulating B cell function in IgAN. These drugs, such as bortezomib, target the proteasome, a cellular machinery crucial for protein degradation and cell signaling. In the context of B cells and plasma cells, proteasome inhibition can lead to the accumulation of misfolded proteins, triggering the unfolded protein response and ultimately leading to cell death. This approach has shown efficacy in multiple myeloma and is being explored in IgAN due to its potential to selectively target long‐lived plasma cells that may be resistant to other forms of B cell‐directed therapy [ 275 , 276 , 277 ]. Early studies in IgAN have shown promising results in reducing proteinuria [ 278 , 279 , 280 , 281 ], but cytopenias and neuropathy limit long‐term use. Larger clinical trials are needed to establish the efficacy and safety of this approach in the long‐term management of the disease. Next‐generation inhibitors (e.g., carfilzomib) with improved safety profiles are being explored.

APRIL/BAFF Pathway Inhibition

Targeting the APRIL (a proliferation‐inducing ligand) and BAFF pathways has emerged as a promising strategy in modulating B cell activation in IgAN [ 282 , 283 , 284 ]. These cytokines play critical roles in B cell survival, maturation, and antibody production. Elevated levels of APRIL and BAFF have been observed in patients with IgAN, suggesting their involvement in disease pathogenesis. Monoclonal antibodies targeting these cytokines or their receptors are under investigation as potential therapies for IgAN. By interrupting these signaling pathways, the goal is to reduce the survival and activation of autoreactive B cells producing pathogenic Gd–IgA1.

Among the investigational agents, sibeprenlimab, an APRIL‐specific inhibitor, demonstrated promising interim results in the phase 3 APPLAUSE‐IgAN trial ( NCT05248646 ) [ 282 , 283 , 284 ], reporting a 62% reduction in proteinuria at 12 months. Telitacicept, a novel dual inhibitor of BAFF and APRIL, achieved a 49% proteinuria reduction at a 240 mg dosage over 24 weeks in phase 2 studies [ 285 , 286 ]. Similarly, povetacicept, another dual BAFF/APRIL antagonist, yielded over 60% proteinuria reduction at 36 weeks in phase 1/2 trials [ 287 ], alongside associated remission and stable renal function. These agents collectively reduce Gd–IgA1 levels and exhibit safety profiles comparable to placebo, positioning them as potential first‐line disease‐modifying therapies. The compelling efficacy and tolerability have accelerated further development, with multiple BAFF/APRIL inhibitors advancing into phase 3 trials. If approved, these therapies could redefine standard care for IgAN (Tables 3 and 4 ), offering substantial clinical benefits for patients with this progressive kidney disease.

From direct B cell depletion strategies to more nuanced modulation of B cell activation pathways, these emerging therapies offer hope for more effective and potentially safer treatment options for patients with IgAN. The ongoing clinical trials and basic science research in this area promise to shed further light on the most effective ways to target B cells in IgAN.

Complement Inhibitors

Complement inhibitors have emerged as a promising therapeutic approach in IgAN, driven by growing evidence of complement activation's role in disease pathogenesis [ 288 , 289 , 290 , 291 , 292 , 293 ] (Figure 4 ). Glomerular deposition of complement components, particularly C3, is a hallmark of IgAN and correlates with disease severity and progression. Recent mechanistic studies have elucidated mechanisms linking glomerular IgA deposition to complement activation and subsequent inflammation, focusing on the alternative and lectin pathways [ 289 , 294 , 295 ].

The AP has been implicated through increased levels of factor H‐related proteins (CFHRs) in IgAN patients. CFHR1 and CFHR5 compete with factor H for C3b binding, potentially leading to dysregulation and increased complement activation. The lectin pathway's involvement is evidenced by glomerular deposition of MBL and MBL‐associated serine proteases (MASPs) in IgAN kidney biopsies, suggesting activation by aberrantly glycosylated IgA1 molecules. Genetic studies have further supported complement's role, identifying associations between IgAN susceptibility and variants in complement‐encoding genes.

Complement inhibitors can be broadly categorized based on their targets within the complement cascade, including inhibitors of the AP, the lectin pathway (LP), and the terminal pathway (TP). Iptacopan, a factor B inhibitor, prevents C3 convertase formation, reducing overall complement activation [ 185 , 289 ]. In the phase 3 APPLAUSE‐IgAN study, iptacopan demonstrated a 38.3% reduction in proteinuria compared with placebo at 9 months ( p < 0.0001) [ 185 ], with consistent efficacy across key subgroups and good tolerability. Narsoplimab, targeting MASP‐2 in the lectin pathway, showed promise in early‐phase trials [ 296 , 297 ], with a median reduction of 61.4% in 24‐h urine protein excretion during a dose‐extension phase. TP inhibitors, such as avacopan, inhibit C5a receptor signaling to mitigate MAC‐mediated injury, have also shown potential in small pilot studies.

The safety profile of complement inhibitors in IgAN appears to be generally favorable, with most studies reporting good tolerability. However, as with any immunomodulatory therapy, there are potential risks that need to be carefully considered. These may include an increased susceptibility to certain infections, particularly those caused by encapsulated bacteria ( Streptococcus pneumoniae , Neisseria meningitidis , Haemophilus influenzae ), due to the important role of complement in host defense. Prophylactic vaccination and antimicrobial coverage are essential but may not fully mitigate this risk, especially in endemic regions. Long‐term safety data from larger cohorts of patients with IgAN treated with complement inhibitors are still needed to fully characterize the risk–benefit profile of these therapies. The unanswered questions include: chronic immunosuppression and secondary infection vulnerability, potential for compensatory pathway activation (e.g., classical pathway overriding alternative blockade), and renal and hepatic toxicity with extended use, observed in trials of TP inhibitors.

As our understanding of the role of complement in IgAN pathogenesis continues to evolve, and as more clinical data become available, these targeted therapies have the potential to significantly improve outcomes for patients. The coming years will be critical in determining how best to integrate complement inhibitors into clinical practice, with the ultimate goal of reducing disease progression and improving quality of life.

Cellular Therapies

Cellular therapies have emerged as a promising frontier in the treatment of autoimmune disorders [ 298 , 299 , 300 , 301 , 302 , 303 , 304 ], including IgAN. These innovative approaches, encompassing stem cell therapies, CAR‐T cells, CAR‐natural killer (NK) cells, and CAR‐macrophages, represent a paradigm shift in addressing complex immune‐mediated conditions. While still in infancy, the potential application of these therapies to IgAN offers exciting possibilities for this challenging kidney disease (Table 5 ).

Mesenchymal Stem Cell Therapy

Mesenchymal stem cell (MSC) therapy has shown considerable promise in treating autoimmune diseases due to its immunomodulatory properties. In lupus nephritis, clinical trials have demonstrated MSCs' ability to reduce disease activity, improve renal function, and decrease the need for immunosuppressive medications [ 305 , 306 , 307 , 308 ]. The mechanism involves secretion of anti‐inflammatory cytokines, promotion of regulatory T‐cell function, and inhibition of B‐cell and T‐cell proliferation. The success of MSC therapy in lupus nephritis provides a compelling rationale for exploring its potential in IgAN. Both conditions share some common immunological features, including dysregulated B‐cell function and the production of pathogenic antibodies. However, organ‐specific delivery remains a hurdle: only 5–10% of intravenously administered MSCs home to inflamed kidneys. Strategies like intra‐arterial infusion or MSC engineering with kidney‐homing ligands (e.g., CXCR4 overexpression) are under investigation to enhance renal targeting.

CAR‐T Cell Therapy

CAR‐T cell therapy, which has revolutionized the treatment of certain hematological malignancies, is now being investigated for autoimmune diseases. This approach involves genetically modifying T‐cells to express CARs that recognize specific antigens associated with the disease. In the context of autoimmune diseases, CAR‐T cells could be engineered to target autoreactive B‐cells or plasma cells responsible for producing pathogenic antibodies. Early studies in lupus models have shown promising results, with CAR‐T cells targeting CD19 leading to B‐cell depletion and amelioration of disease symptoms [ 302 , 309 , 310 , 311 , 312 , 313 , 314 , 315 ]. Adapting CAR‐T cell therapy for IgAN presents both exciting possibilities and significant challenges. The key would be to identify an appropriate target antigen specific to the pathogenic cells involved in IgAN. Potential targets could include surface markers on the B‐cells or plasma cells producing galactose‐deficient IgA1, or even the aberrant IgA1 molecule itself. However, the risk of off‐target effects and the potential for long‐term B‐cell depletion must be carefully considered, given the important role of IgA in mucosal immunity. For IgAN, potential targets include: Gd–IgA1‐producing plasmablasts (via CD38/BCMA) and autoreactive B‐cell clones (via CD19/CD20). Early‐phase trials in autoimmune conditions show sustained remission after a single infusion, but safety concerns persist. Cytokine release syndrome (CRS) occurs in 15–20% of patients, and prolonged B‐cell depletion increases infection risk. Additionally, manufacturing complexity (3–4 weeks for autologous product generation) and costs (≥$500,000 per treatment) limit accessibility.

CAR‐NK and CAR‐Macrophage Approaches

CAR‐NK cells offer another promising avenue for cellular therapy in autoimmune diseases and potentially IgAN. NK cells are innate immune cells with potent cytotoxic capabilities [ 316 , 317 ]. CAR‐NK cells combine the natural cytotoxicity of NK cells with the specificity of CAR technology. This approach may offer advantages over CAR‐T cells, including a potentially better safety profile due to the limited lifespan of NK cells and their reduced propensity to cause CRS. Their shorter lifespan reduces long‐term immunosuppression concerns, but limited persistence may necessitate repeat dosing.

The concept of CAR‐macrophages represents a recent development in cellular therapies [ 318 ]. Given macrophages' crucial roles in inflammation, tissue repair, and immune regulation, CAR‐macrophages could be engineered to target specific cells or tissues involved in IgAN pathogenesis. This approach could modulate the local immune environment in the kidney, potentially promoting an anti‐inflammatory state and facilitating tissue repair and IgA deposit resolution. CAR‐macrophages can be engineered to phagocytose immune complexes or promote anti‐inflammatory polarization (M2 phenotype). Preclinical data suggest efficacy in resolving glomerular immune complex deposits, but scalable manufacturing and tumorigenicity risks require further validation.

Critical Barriers to Clinical Implementation

While cellular therapies represent a transformative frontier for IgAN, significant translational barriers must be overcome before clinical integration. Foremost is the organ‐specific targeting challenge: intravenous delivery achieves <5% renal parenchymal engraftment due to inefficient homing. This necessitates advanced strategies such as intra‐arterial infusion or engineering homing receptors (e.g., CCR2 for inflamed glomeruli or β2‐spectrin‐specific CARs to enhance renal localization. Long‐term safety concerns include risks of persistent B‐cell aplasia (particularly with CD19‐targeted CAR‐T cells), which may require Ig replacement, and genomic instability from viral vectors. Durability limitations are pronounced in short‐lived CAR‐NK cells, often mandating repeated dosing that escalates cumulative toxicity risks.

Manufacturing complexity presents another major hurdle: autologous CAR‐T production requires specialized good manufacturing practice facilities, elevating costs to $400,000–$1.5 M per patient. Allogeneic “off‐the‐shelf” products, while potentially reducing costs, carry graft‐versus‐host disease risks. Regulatory frameworks for nononcologic cell therapies remain underdeveloped, lacking standardized efficacy benchmarks for IgAN‐specific endpoints like proteinuria reduction or eGFR stability. Additionally, the heterogeneous pathogenesis of IgAN demands combination strategies—such as MSC‐primed immunotolerant microenvironments paired with CAR‐T/NK cells targeting Gd–IgA1‐producing plasmablasts—which introduce further clinical trial design complexities.

The organ‐specific nature of IgAN (primarily manifesting in the kidneys) underscores the need for precise targeting. Strategies like kidney‐homing peptides or localized administration techniques require development to improve efficacy. Long‐term safety, durability of treatment effects, and potential need for repeated interventions must be rigorously evaluated. Given the complexity of IgAN pathogenesis, combination approaches may be reasonable—for example, integrating MSC therapy to modulate systemic immune environments with CAR‐T/NK cytotoxicity against pathogenic B‐cell clones. Such synergies could simultaneously dampen inflammation and eliminate disease‐driving cell populations.

Regulatory and manufacturing challenges include standardizing production protocols and advancing allogeneic platforms to improve accessibility. International consortia (e.g., KDIGO) are now defining IgAN‐specific efficacy endpoints to guide regulatory pathways. Future directions may include developing kidney‐targeted CARs against mesangial‐specific antigens (e.g., β2‐spectrin) to enhance renal specificity while sparing extrarenal tissues, cost‐reduction tactics like automated bioreactors (potentially lowering expenses by 60–70%), and leveraging deeper pathogenesis insights to move beyond symptom management toward disease modification. As cellular technologies advance, these therapies hold promises for fundamentally altering IgAN progression, offering hope for improved outcomes.

Relevant Preclinical Animal Experiments and Clinical Trials

The integration of preclinical animal models and clinical trials has been pivotal in advancing our understanding of IgAN pathogenesis and accelerating therapeutic development. Animal models recapitulate key aspects of human IgAN, including mesangial IgA deposition, hematuria, proteinuria, and progressive renal injury. These models have elucidated critical pathophysiological mechanisms, such as aberrant IgA glycosylation, immune complex formation, complement activation, and mucosal immune dysregulation. Concurrently, insights from preclinical studies have directly informed the design of clinical trials targeting these pathways, resulting in a rapidly evolving therapeutic landscape.

Preclinical Animal Models: Mechanistic Insights and Contributions

Several animal models have been instrumental in dissecting IgAN pathogenesis [ 6 , 9 , 11 , 14 , 15 , 17 , 319 , 320 , 321 , 322 ]. The ddY mouse model, particularly its subgroup the grouped ddY (gddY) strain, spontaneously develops IgAN‐like features, including mesangial IgA–IgG–C3 deposition, proteinuria, and glomerulosclerosis [ 58 , 94 , 112 , 140 , 258 , 323 , 324 , 325 , 326 ]. This model has been foundational for studying the role of TLRs. Activation of TLR9 by microbial DNA analogs exacerbates IgAN in gddY mice, driving the production of Gd–IgA1 and immune complexes via the MyD88–NF‐κB pathway. Subsequent work demonstrated that HCQ, a TLR7/9 inhibitor, suppresses aberrant IgA glycosylation and renal injury in this model [ 58 , 112 ], providing preclinical rationale for its clinical evaluation in IgAN patients. The gddY model also illuminated the role of APRIL (a proliferation‐inducing ligand). APRIL overexpression in gddY mice promotes pathogenic IgA synthesis, while anti‐APRIL antibodies reduce serum Gd–IgA1, mesangial deposition, and proteinuria [ 326 ]. This directly supported the development of anti‐APRIL therapies now in clinical trials. Complementary models, such as the β‐1,4‐galactosyltransferase‐I‐deficient mouse [ 327 ], highlighted the significance of aberrant IgA glycosylation, while humanized models (e.g., α1KICD89Tg mice expressing human IgA1 and CD89) confirmed the role of Fcα receptor‐mediated mesangial injury [ 328 , 329 , 330 ]. ET‐1 signaling was identified as a key mediator of podocyte injury and proteinuria, leading to preclinical testing of ERAs like sparsentan, which preserved podocyte integrity and reduced glomerulosclerosis [ 331 ]. Using bacterial lipocalin‐type prostaglandin D synthase (LCWE) to induce immune complexes, it demonstrated that complement activation (via the AP) is essential for glomerular deposition and injury. This model validated the “multi‐hit” hypothesis, showing that Gd–IgA1–IgG complexes trigger endothelial glycocalyx disruption, facilitating mesangial migration and inflammation [ 332 ]. These models collectively underscore the importance of mucosal immune dysregulation (e.g., TLR/BAFF/APRIL pathways), nephritogenic immune complex formation (Gd–IgA1–autoantibody interactions), and downstream effectors (complement, ET, and inflammatory cytokines).

Animal models have not only identified therapeutic targets but also enabled combination therapy testing. For example, gddY studies showed that SGLT2 inhibitors (e.g., dapagliflozin) synergize with ET antagonists to mitigate proteinuria and glomerular hyperfiltration, prompting trials like NCT05856760 (SPARTACUS) evaluating sparsentan with SGLT2 inhibitors.

Recent models have also emphasized disease heterogeneity. Genetic analyses of gddY mice revealed subphenotypes with distinct TLR/APRIL dysregulation, suggesting personalized therapeutic approaches. This approach is consistent with current clinical strategies to stratify patients using biomarkers (such as serum Gd–IgA1 and APRIL levels) in ongoing trials, including NCT05732402 (RUBY‐3).

Preclinical models remain indispensable for deconstructing IgAN pathogenesis and validating therapeutic targets. Their translation to clinical trials has yielded multiple targeted therapies, with three agents (nefecon, sparsentan, iptacopan) approved and dozens in late‐phase testing. Future directions include leveraging models to optimize combination regimens, identify predictive biomarkers, and address advanced‐disease populations.

Human Clinical Trials: Translation of Preclinical Insights

The mechanistic insights derived from animal models have directly informed an unprecedented expansion in clinical trial activity for IgAN, fundamentally transforming the therapeutic landscape. The translation from bench to bedside has been particularly successful, with multiple pathways identified in preclinical studies now being targeted in phases 2 and 3 clinical trials. This robust pipeline represents the culmination of decades of animal model research that elucidated key pathogenic mechanisms, providing the scientific rationale for mechanism‐based therapeutic interventions.

Mucosal‐targeted therapies represent the first successful translation from animal models to clinical practice. The observation that gddY mice maintained in germ‐free conditions did not develop IgAN, coupled with the demonstration that GALT plays a central role in aberrant IgA production [ 333 ], provided the foundation for developing targeted‐release budesonide (nefecon). This approach specifically targets IgA synthesis in Peyer's patches of the terminal ileum, where pathogenic IgA1 is predominantly produced. The NefIgArd phase 3 trial demonstrated that nefecon significantly reduced proteinuria and slowed eGFR decline, leading to regulatory approval as the first disease‐specific therapy for IgAN [ 186 ]. The success of this gut‐targeted approach validated decades of animal research demonstrating the central role of mucosal immunity in IgAN pathogenesis.

B‐cell modulation strategies have emerged as particularly promising therapeutic approaches based on extensive preclinical validation. The discovery that APRIL overexpression in gddY mice promotes pathogenic IgA synthesis, while anti‐APRIL antibodies reduce serum Gd–IgA1 and mesangial deposition, provided compelling rationale for clinical development [ 112 ]. Sibeprenlimab, a humanized anti‐APRIL monoclonal antibody, demonstrated remarkable efficacy in the phase 2 ENVISION trial, with 47%–62% proteinuria reduction across different dose levels and stabilization of eGFR compared with progressive decline in the placebo group [ 282 , 283 ]. The VISIONARY phase 3 trial has completed enrollment and will provide definitive evidence for this mechanism. Similarly, zigakibart (BION‐1301), another anti‐APRIL antibody [ 334 ], showed 53% proteinuria reduction in phase 1/2 studies and is advancing to the BEYOND phase 3 trial.

The success of dual APRIL/BAFF inhibition in preclinical models led to clinical testing of TACI‐Fc fusion proteins. Atacicept demonstrated dose‐dependent proteinuria reduction and kidney function stabilization in the phase 2b ORIGIN trial, with concurrent reductions in serum Gd–IgA1 levels confirming target engagement [ 335 , 336 ]. The ORIGIN 3 phase 3 trial is currently recruiting patients worldwide. Telitacicept, approved for systemic lupus erythematosus in China, showed similar efficacy in IgAN with significant reductions in plasma Gd–IgA1 and IgG–IgA immune complexes, providing direct confirmation of the pathogenic mechanisms identified in animal models [ 285 , 337 ]. Povetacicept, featuring a reengineered TACI domain with enhanced potency, demonstrated 53.5% proteinuria reduction in early‐phase studies, with the RAINIER phase 3 trial in development [ 64 ].

Complement inhibition represents another successful translation from preclinical research. The demonstration in LCWE‐complement models that AP activation is essential for glomerular deposition and injury provided strong rationale for targeting this cascade [ 332 ]. Iptacopan, an oral factor B inhibitor, achieved 43.8% proteinuria reduction in the phase 2 trial and has received US FDA accelerated approval based on interim phase 3 results from the APPLAUSE‐IgAN study [ 20 , 91 , 289 , 338 ]. The antisense oligonucleotide RO7434656, which reduces hepatic factor B production, demonstrated 45% proteinuria reduction in phase 2 studies and is advancing to the IMAGINATION phase 3 trial. Terminal complement inhibition with ravulizumab showed 29.8% proteinuria reduction in the SANCTUARY trial, leading to the initiation of the ICAN phase 3 study [ 90 , 195 ].

ERA emerged from animal studies demonstrating that ET‐1 signaling mediates podocyte injury and proteinuria in IgAN models. The gddY mouse studies showing that ET antagonists preserve podocyte integrity and reduce glomerulosclerosis provided direct preclinical validation for this approach [ 331 , 339 , 340 ]. Sparsentan, a dual ET/angiotensin receptor antagonist, demonstrated superior eGFR preservation compared with irbesartan in the rigorous PROTECT phase 3 trial, leading to regulatory approval. The mechanism‐of‐action studies in animal models, showing protection of glomerular glycocalyx and prevention of immune complex migration into the mesangium, were directly confirmed by biomarker studies in the clinical trial. Atrasentan, a selective ETA receptor antagonist [ 200 , 202 , 234 , 341 ], achieved 36.1% proteinuria reduction in the ALIGN trial interim analysis.

Plasma cell depletion strategies, based on observations that rituximab failed to reduce Gd–IgA1 levels due to its inability to target tissue‐resident plasma cells, led to development of anti‐CD38 therapies. Felzartamab demonstrated sustained reductions in proteinuria and Gd–IgA1 levels extending beyond 10 months after dosing completion in the IGNAZ trial, confirming that plasma cells are indeed critical sources of pathogenic IgA1 [ 342 , 343 ].

The comprehensive clinical trial portfolio shown in Table 6 illustrates the breadth of mechanism‐based approaches now under investigation. Three therapies (nefecon, sparsentan, iptacopan) have achieved regulatory approval, with multiple others in late‐phase development. The consistency between preclinical predictions and clinical outcomes validates the utility of animal models in IgAN research and demonstrates the power of mechanism‐based drug development. Current trials are exploring combination approaches, building on animal studies showing synergistic effects between different therapeutic targets, with the goal of achieving more profound and durable treatment responses for patients with this progressive kidney disease.

Factors Influencing Treatment Initiation

The poor prognosis associated with IgAN in many patients necessitates a more proactive approach to treatment, particularly given the substantial lifetime risk of kidney failure in high‐risk populations. Recent evidence supports a paradigm shift toward earlier intervention, moving beyond reactive strategies to integrated management that simultaneously targets both immune‐mediated pathogenesis and CKD components [ 344 , 345 , 346 ]. Initiating etiological therapy should be based on a comprehensive assessment of clinical presentation, disease activity, and biomarkers indicative of active renal inflammation. This personalized strategy aims to identify patients most likely to benefit from early intervention while avoiding unnecessary exposure to potentially harmful therapies in those with a more benign course (Figure 5 ).

Key clinical factors must be evaluated holistically. Disease severity—manifested as persistent proteinuria exceeding 0.5 g/day despite ≥3 months of optimized supportive care (including maximal RASi, blood pressure control, and lifestyle modifications)—remains a critical indicator of progression risk. A declining eGFR trajectory, even in the absence of heavy proteinuria, warrants urgent attention. Histological findings from the Oxford Classification (MEST‐C score) provide essential context: active lesions like mesangial hypercellularity (M1), endocapillary proliferation (E1), crescents (C1/2), or chronic changes such as segmental sclerosis (S1) and tubulointerstitial fibrosis (T1/2) stratify risk and guide therapeutic intensity. Notably, the presence of persistent microhematuria (>20 RBC/HPF) may signal ongoing glomerular inflammation and synergistically worsens prognosis when combined with proteinuria, necessitating consideration for immunosuppressive or targeted immunomodulatory therapies.

Emerging biomarkers [ 347 , 348 ], while promising, require cautious interpretation. Gd–IgA1 is mechanistically central to IgAN pathogenesis, yet its utility as a standalone clinical biomarker remains controversial [ 111 , 114 , 170 , 349 , 350 , 351 , 352 , 353 , 354 ]. Although elevated serum Gd–IgA1 correlates with disease susceptibility and progression in some cohorts, inconsistencies in its relationship with real‐time disease activity limit its reliability for individual treatment decisions. This controversy stems from unresolved questions about whether Gd–IgA1 is a direct pathogenic driver or merely a marker of systemic immune dysregulation, compounded by methodological variability in assays and lack of standardized thresholds. Other biomarkers—such as urinary soluble CD163 (reflecting macrophage activation), complement activation products (e.g., C5b‐9), and autoantibodies against Gd–IgA1—may offer complementary insights but require further validation for routine clinical use. Thus, biomarker integration should augment—not replace—clinical and histological assessments, particularly in borderline cases.

Patient‐specific factors critically modulate treatment choices. Younger patients face higher cumulative lifetime risks, justifying earlier aggressive intervention to preserve kidney function. Conversely, older individuals or those with significant comorbidities (e.g., diabetes, cardiovascular disease) may prioritize safety, favoring conservative management or targeted therapies with lower toxicity profiles. Genetic and ethnic factors also influence outcomes, with Asian populations often exhibiting more aggressive disease. A transformative shift in therapeutic sequencing is emerging: rather than reserving immunosuppression for “supportive care–resistant” cases, high‐risk patients may benefit from concurrent initiation of etiological agents alongside optimized CKD management. This dual approach addresses both upstream immune dysregulation (e.g., via gut‐immune axis modulators like budesonide or APRIL/BAFF inhibitors) and downstream glomerular hyperfiltration/fibrosis pathways (e.g., SGLT2 inhibitors or ET antagonists) to maximize nephron preservation.

In summary, treatment initiation hinges on dynamic risk stratification: proteinuria >0.5 g/day, eGFR decline, high‐risk histology, and hematuria constitute major triggers. Biomarkers like Gd–IgA1 provide mechanistic insights but lack standalone decisional utility. The evolving landscape—emphasizing early, combination‐based strategies—reflects a move toward personalized, proactive management to achieve complete remission (proteinuria <0.3 g/day, stable eGFR, and hematuria resolution) while mitigating long‐term kidney failure risk.

Concept of T2T in IgAN

The T2T strategy represents a paradigm shift in chronic disease management, emphasizing systematic treatment adjustments at predefined intervals to achieve specific, clinically meaningful endpoints. This approach has demonstrated superior outcomes compared with conventional care in conditions like diabetes, hypertension, and rheumatoid arthritis through large, randomized trials. While T2T remains conceptually underdeveloped in IgAN, emerging evidence supports its applicability. Current understanding identifies critical therapeutic targets: proteinuria reduction to <0.5 g/day (ideally <0.3 g/day), blood pressure control <130/80 mmHg, stabilization of eGFR decline to <1 mL/min/1.73 m 2 /year, and resolution of persistent hematuria. These targets reflect the multifactorial nature of IgAN progression and will evolve alongside advances in pathogenesis understanding [ 20 , 211 ].

The timing and sequence of therapeutic interventions are crucial considerations within T2T frameworks. Traditional stepwise escalation—beginning with supportive care (lifestyle modifications and maximally tolerated RAS blockade) before introducing immunosuppression—faces challenges in high‐risk patients. Recent evidence advocates for earlier, integrated intervention targeting both immune‐mediated pathogenesis and CKD components simultaneously. This approach recognizes that delayed immunosuppression in rapidly progressive cases may permit irreversible nephron loss, while isolated supportive care often fails to modify underlying immunological drivers. For example, patients with proteinuria >0.5 g/day despite optimized RAS inhibition and significant hematuria (>20 RBC/HPF) may benefit from concurrent initiation of gut‐targeted immunomodulators (e.g., budesonide) or APRIL/BAFF inhibitors alongside SGLT2 inhibitors or ET antagonists rather than sequential trials of monotherapies.

T2T success necessitates biomarker‐guided personalization. Beyond conventional parameters (proteinuria, eGFR slope), integration of histopathological risk stratification (Oxford MEST‐C scores) and emerging biomarkers (galactose‐deficient IgA1, urinary sCD163, complement activation products) allows dynamic risk assessment. Persistent microhematuria, particularly when coexisting with proteinuria, signals ongoing glomerular inflammation and should trigger therapy escalation independent of proteinuria thresholds. The paradigm also demands regular monitoring intervals (e.g., 3‐month assessments during induction, 6‐month thereafter) to evaluate target attainment and guide therapy adjustments. Future T2T frameworks will likely incorporate molecular targets such as reduction of pathogenic IgA1 levels, modulation of mucosal immune responses, and complement pathway inhibition, enabling precision medicine approaches.

Notably, the T2T model must balance urgency of intervention against therapeutic risks. While aggressive early combination therapy shows promise in preserving kidney function, patient‐specific factors (age, comorbidities, genetic background) modulate risk–benefit calculations. Younger patients with active histological lesions warrant rapid dual‐pathway intervention, whereas older individuals with comorbidities may prioritize safer immunomodulatory agents like targeted‐release budesonide over systemic corticosteroids. This individualized strategy—combining clinical, histological, and biomarker data—represents the cornerstone of effective T2T implementation in IgAN.

Conclusion and Prospects

The landscape of IgAN management is undergoing profound transformation, driven by advances in molecular pathogenesis understanding and targeted therapeutic development. Historically, treatment relied heavily on proteinuria thresholds and reactive escalation, but emerging evidence supports a paradigm shift toward early, dual‐pathway intervention addressing both immune‐mediated glomerular injury and progressive CKD mechanisms. This integrated approach recognizes that delaying immunomodulation in high‐risk patients risks irreversible nephron loss, while isolated supportive care often fails to modify underlying immunological drivers. The approval of disease‐specific agents—sparsentan (dual ET/angiotensin inhibition), nefecon (targeted mucosal immunomodulation), and iptacopan (complement blockade)—alongside repurposed CKD therapies (e.g., SGLT2 inhibitors) enables synergistic combinations for complete remission.

Critical to this evolution is refined risk stratification beyond proteinuria alone. Histological activity (Oxford MEST‐C scores), persistent microhematuria (>20 RBC/HPF), and biomarkers like galactose‐deficient IgA1 or urinary sCD163 provide nuanced insights into progression risk. For instance, hematuria resolution—spontaneous or treatment‐induced—strongly correlates with renal survival, making it a key therapeutic target alongside proteinuria reduction and eGFR stabilization. This heterogeneity necessitates divergent approaches: for chronic, slowly progressive disease, step‐up therapy with minimal sequential agents avoids overtreatment; in rapidly progressive subgroups, early intensive immunosuppression counters irreversible glomerulosclerosis. While early intervention in high‐risk patients is justified, overtreatment of indolent cases remains a concern.

Looking ahead, three priorities define the next era:

Comparative treatment trials evaluating de‐escalated regimens for low‐risk patients and combination therapies for high‐risk subtypes (e.g., APRIL inhibitors with SGLT2i/ET antagonists), measuring not only short‐term proteinuria reduction but also long‐term renal survival and quality of life.

Biomarker‐driven algorithms incorporating dynamic risk assessment (e.g., urinary C5b‐9 monitoring during complement blockade) with real‐world evidence tracking risk‐stratified implementation to refine precision dosing.

Generating evidence for populations facing therapeutic voids—particularly those historically excluded from trials due to complexity (e.g., rapidly progressive crescentic IgAN, pregnancy, or posttransplant recurrence)—through dedicated registry studies and real‐world data initiatives.

Ultimately, the convergence of molecular insights, targeted therapies, and pragmatic trial designs promises to transform IgAN into a manageable disease with definable remission endpoints. Success requires multidisciplinary collaboration to validate surrogate endpoints (complete remission: proteinuria <0.3 g/day, hematuria resolution, eGFR slope <−1 mL/min/year) and ensure equitable access. Well‐designed trials and real‐world evidence will be essential to balance immunological control with renal reserve preservation, replacing reactive, proteinuria‐centric dogma with proactive, pathophysiology‐driven strategies prioritizing long‐term kidney survival.

Author Contributions

Xu‐Jie Zhou : conceptualization, data curation, writing, and visualization. The author has approved the final manuscript.

Ethics Statement

The author has nothing to report.

Conflicts of Interest

The author declares no conflicts of interest.

Acknowledgments

The author gratefully acknowledges the use of BioRender ( www.biorender.com ) for figure creation.

Zhou X.‐J., “Immunoglobulin A Nephropathy: Molecular Pathogenesis and Targeted Therapy.” MedComm 6, no. 9 (2025): 6, e70382. 10.1002/mco2.70382

Funding : Support was provided by National Science Foundation of China (82370709); National Key Research and Development Program of China (2024YFC2511000); Beijing Nova Program Interdisciplinary Cooperation Project (20230484426); National High Level Hospital Clinical Research Funding (Interdisciplinary Clinical Research Project of Peking University First Hospital, 2024IR35, 2022CR41); Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2019‐I2M‐5‐046, 2020‐JKCS‐009); and the Joint Institute (JI) Collaboration Scholars Program at the University of Michigan Medical School. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

1. Berger J. and Hinglais N., “[Intercapillary deposits of IgA‐IgG],” Journal D urologie Et De Nephrologie 74 (1968): 694–695.

2. Trimarchi H., Barratt J., Monteiro R. C., and Feehally J., “IgA Nephropathy: "State of the Art": A Report From the 15th International Symposium on IgA Nephropathy Celebrating the 50th Anniversary of Its First Description,” Kidney International 95 (2019): 750–756.

3. Pattrapornpisut P., Avila‐Casado C., and Reich H. N., “IgA Nephropathy: Core Curriculum 2021,” American Journal of Kidney Diseases 78 (2021): 429–441.

4. Stamellou E., Seikrit C., Tang S., et al., “IgA Nephropathy,” Nature reviews Disease primers 9 (2023): 67.

5. Cheung C. K., Alexander S., Reich H. N., Selvaskandan H., Zhang H., and Barratt J., “The Pathogenesis of IgA Nephropathy and Implications for Treatment,” Nature Reviews Nephrology 21 (2025): 9–23.

6. Parlato B., “The Journey to Advocacy: Celebrating the IgA Nephropathy Foundation's 20th Anniversary,” Seminars in Nephrology 44 (2024): 151575.

7. Kamal F., Kim J., and Lafayette R., “Current Biomarkers of IgA Nephropathy,” Seminars in Nephrology 44 (2024): 151572.

8. Zhou X. and Zhang H., “The Genetics of IgA Nephropathy: Implications for Future Therapies,” Seminars in Nephrology 44 (2024): 151567.

9. Novak J., Reily C., Steers N. J., et al., “Emerging Biochemical and Immunologic Mechanisms in the Pathogenesis of IgA Nephropathy,” Seminars in Nephrology 44 (2024): 151565.

10. Ong S. C. and Julian B. A., “Post‐transplant IgA Nephropathy,” Seminars in Nephrology 44 (2024): 151570.

11. Rizk D. V., “Updates on IgA Nephropathy,” Seminars in Nephrology 44 (2024): 151574.

12. Ghaddar M., Canney M., and Barbour S. J., “IgA Nephropathy: Epidemiology and Disease Risk across the World,” Seminars in Nephrology 44 (2024): 151564.

13. Peruzzi L. and Coppo R., “IgAN Across the Age Spectrum: The Pediatric Perspective,” Seminars in Nephrology 44 (2024): 151569.

14. Gleeson P. J. and Monteiro R. C., “The Role of Mucosal Immunity: What Can We Learn from Animal and Human Studies?,” Seminars in Nephrology 44 (2024): 151566.

15. Haas M., “The Pathology of IgA Nephropathy: How Can It Inform Management?,” Seminars in Nephrology 44 (2024): 151568.

16. Pillebout E., “IgA Vasculitis and IgA Nephropathy: Two Sides of the Same Coin?,” Seminars in Nephrology 44 (2024): 151571.

17. Cheung C. K. and Barratt J., “The Rapidly Changing Treatment Landscape of IgA Nephropathy,” Seminars in Nephrology 44 (2024): 151573.

18. Pitcher D., Braddon F., Hendry B., et al., “Long‐Term Outcomes in IgA Nephropathy,” Clinical Journal of the American Society of Nephrology 18 (2023): 727–738.

19. Shen X., Chen P., Liu M., et al., “Long‐term Outcomes of IgA Nephropathy in China,” Nephrology, Dialysis, Transplantation 40, no. 6 (2024): 1137–1146.

20. Floege J., Bernier‐Jean A., Barratt J., and Rovin B., “Treatment of Patients With IgA Nephropathy: A Call for a New Paradigm,” Kidney International 107 (2025): 640–651.

21. Willey C. J., Coppo R., Schaefer F., Mizerska‐Wasiak M., Mathur M., and Schultz M. J., “The Incidence and Prevalence of IgA Nephropathy in Europe,” Nephrology, Dialysis, Transplantation 38 (2023): 2340–2349.

22. Kiryluk K., Freedberg D. E., Radhakrishnan J., et al., “Global Incidence of IgA Nephropathy by Race and Ethnicity: A Systematic Review,” Kidney360 4 (2023): 1112–1122.

23. Lerma E. V., Bensink M. E., Thakker K. M., et al., “Impact of Proteinuria and Kidney Function Decline on Health Care Costs and Resource Utilization in Adults with IgA Nephropathy in the United States: A Retrospective Analysis,” Kidney Medicine 5 (2023): 100693.

24. Yang C., Gao B., Wang F., et al., “Executive Summary for the China Kidney Disease Network (CK‐NET) 2017‐2018 Annual Data Report,” Kidney International 107 (2025): 980–984.

25. Selvaskandan H. and Barratt J., “Dynamic Individualized Risk Prediction in IgA Nephropathy: Entering the Era of Artificial Intelligence,” Clinical Journal of the American Society of Nephrology 19 (2024): 826–828.

26. Bharati J. and Jhaveri K. D., “Prognosis of IgA Nephropathy: A Lifetime Story,” Clinical Journal of the American Society of Nephrology 18 (2023): 699–701.

27. Caster D. J. and Lafayette R. A., “The Treatment of Primary IgA Nephropathy: Change, Change, Change,” American Journal of Kidney Diseases 83 (2024): 229–240.

28. Kronbichler A., Bajema I., Geetha D., and Säemann M., “Novel Aspects in the Pathophysiology and Diagnosis of Glomerular Diseases,” Annals of the Rheumatic Diseases 82 (2023): 585–593.

29. Kunter U., Seikrit C., and Floege J., “Novel Agents for Treating IgA Nephropathy,” Current Opinion in Nephrology and Hypertension 32 (2023): 418–426.

30. Glassock R. J., “IgA Nephropathy: "the Times They Are a‐Changin",” Glomerular Diseases 2 (2022): 4–14.

31. Gleeson P. J., O'Shaughnessy M. M., and Barratt J., “IgA Nephropathy in Adults‐treatment Standard,” Nephrology, Dialysis, Transplantation 38 (2023): 2464–2473.

32. Zhang Y. and Zhang H., “Current Understanding and New Insights in the Treatment of IgA Nephropathy,” Nephrology (Carlton, Vic.) 29, no. Suppl 2 (2024): 75–79.

33. Schena F. P. and Cox S. N., “Biomarkers and Precision Medicine in IgA Nephropathy,” Seminars in Nephrology 38 (2018): 521–530.

34. Suzuki H., “Biomarkers for IgA Nephropathy on the Basis of Multi‐hit Pathogenesis,” Clinical and Experimental Nephrology 23 (2019): 26–31.

35. Wu M., Chen C., Yiang G., et al., “The Emerging Role of Pathogenesis of IgA Nephropathy,” Journal of Clinical Medicine 7 (2018): 225.

36. Tortajada A., Gutierrez E., Pickering M. C., Praga Terente M., and Medjeral‐Thomas N., “The Role of Complement in IgA Nephropathy,” Molecular Immunology 114 (2019): 123–132.

37. Gutiérrez E., Carvaca‐Fontán F., Luzardo L., Morales E., Alonso M., and Praga M., “A Personalized Update on IgA Nephropathy: A New Vision and New Future Challenges,” Nephron 144 (2020): 555–571.

38. Zhang H. and Barratt J., “Is IgA Nephropathy the Same Disease in Different Parts of the World?,” Seminars in Immunopathology 43 (2021): 707–715.

39. Bechtler C., Barneoud‐Rousset O., Pang L., et al., “Optimized Synthesis, Polymer Conjugation, and Proof‐of‐concept Studies of the gd‐IgA1 Epitope for Antibody‐scavenging Therapies in IgA Nephropathy,” Chemical Biology and Drug Design 102 (2023): 580–586.

40. Suzuki Y., Suzuki H., Yasutake J., and Tomino Y., “Paradigm Shift in Activity Assessment of IgA Nephropathy—optimizing the next Generation of Diagnostic and Therapeutic Maneuvers via Glycan Targeting,” Expert Opinion on Biological Therapy 15 (2015): 583–593.

41. Yamasaki K., Suzuki H., Yasutake J., Yamazaki Y., and Suzuki Y., “Galactose‐Deficient IgA1‐Specific Antibody Recognizes GalNAc‐Modified Unique Epitope on Hinge Region of IgA1,” Monoclon Antib Immunodiagn Immunother 37 (2018): 252–256.

42. Gornowicz‐Porowska J., Seraszek‐Jaros A., Bowszyc‐Dmochowska M., Kaczmarek E., and Dmochowski M., “Immunoexpression of IgA Receptors (CD89, CD71) in Dermatitis Herpetiformis,” Folia Histochemica Et Cytobiologica 55 (2017): 212–220.

43. Haddad E., Moura I. C., Arcos‐Fajardo M., Macher M., Baudouin V., and Alberti C., “Enhanced Expression of the CD71 Mesangial IgA1 Receptor in Berger Disease and Henoch‐Schönlein Nephritis: Association Between CD71 Expression and IgA Deposits,” Journal of the American Society of Nephrology 14 (2003): 327–337.

44. Lechner S. M., Papista C., Chemouny J. M., Berthelot L., and Monteiro R. C., “Role of IgA Receptors in the Pathogenesis of IgA Nephropathy,” Journal of Nephrology 29 (2016): 5–11.

45. Tamouza H., Chemouny J. M., Raskova Kafkova L., Berthelot L., Flamant M., and Demion M., “The IgA1 Immune Complex‐mediated Activation of the MAPK/ERK Kinase Pathway in Mesangial Cells Is Associated With Glomerular Damage in IgA Nephropathy,” Kidney International 82 (2012): 1284–1296.

46. Abbad L., Monteiro R. C., and Berthelot L., “Food Antigens and Transglutaminase 2 in IgA Nephropathy: Molecular Links Between Gut and Kidney,” Molecular Immunology 121 (2020): 1–6.

47. Floege J., Moura I. C., and Daha M. R., “New Insights Into the Pathogenesis of IgA Nephropathy,” Seminars in immunopathology 36 (2014): 431–442.

48. Jhee J. H., Nam B. Y., Park J. T., et al., “CD71 mesangial IgA1 Receptor and the Progression of IgA Nephropathy,” Translational Research 230 (2021): 34–43.

49. Monteiro R. C., Moura I. C., Launay P., et al., “Pathogenic Significance of IgA Receptor Interactions in IgA Nephropathy,” Trends in Molecular Medicine 8 (2002): 464–468.

50. Launay P., Grossetête B., Arcos‐Fajardo M., et al., “Fcalpha Receptor (CD89) Mediates the Development of Immunoglobulin A (IgA) Nephropathy (Berger's disease). Evidence for Pathogenic Soluble Receptor‐Iga Complexes in Patients and CD89 Transgenic Mice,” Journal of Experimental Medicine 191 (2000): 1999–2009.

51. Cambier A., Da Silva J., Bex J., et al., “Blockade of mTOR Ameliorates IgA Nephropathy by Correcting CD89 and CD71 Dysfunctions in Humanized Mice,” BioRxiv (2025): 2021–2025.

52. Cambier A., Gleeson P. J., Abbad L., et al., “Soluble CD89 Is a Critical Factor for Mesangial Proliferation in Childhood IgA Nephropathy,” Kidney International 101 (2022): 274–287.

53. Xu L., Li B., Huang M., et al., “Critical Role of Kupffer Cell CD89 Expression in Experimental IgA Nephropathy,” PLoS ONE 11 (2016): e0159426.

54. Lee H., Shin Y., Fang X., et al., “Single‐cell RNA Sequencing Revealed the Role of the Th17 Pathway in the Development of Anti‐ human Leukocyte Antigen Antibodies in a Highly Sensitized Mouse Model,” Kidney Research and Clinical Practice (2024).

55. Xia M., Li Y., Liu Y., Dong Z., and Liu H., “Single‐Cell RNA‐Sequencing Analysis Provides Insights Into IgA Nephropathy,” Biomolecules 15 (2025): 191.

56. Qing J., Li C., Zhi H., Zhang L., Wu J., and Li Y., “Exploring Macrophage Heterogeneity in IgA Nephropathy: Mechanisms of Renal Impairment and Current Therapeutic Targets,” International Immunopharmacology 140 (2024): 112748.

57. Chen X., Wang T., Chen L., et al., “Cross‐species Single‐cell Analysis Uncovers the Immunopathological Mechanisms Associated With IgA Nephropathy Progression,” JCI Insight 9 (2024): e173651.

58. Zambrano S., He L., Kano T., et al., “Molecular Insights Into the Early Stage of Glomerular Injury in IgA Nephropathy Using Single‐cell RNA Sequencing,” Kidney International 101 (2022): 752–765.

59. Du W., Gao C., You X., et al., “Increased Proportion of Follicular Helper T Cells Is Associated With B Cell Activation and Disease Severity in IgA Nephropathy,” Frontiers in immunology 13 (2022): 901465.

60. Tang W., Li Q., Yang X., and Yang H., “Causal Relationships Between Immune Cell Phenotypes and Primary Glomerular Diseases: Genetic Evidence From Bidirectional Mendelian Randomization Study,” Clinical Kidney Journal 18 (2025): sfaf057.

61. Huang H., Chen B., Feng C., Chen W., and Wu D., “Exploring the Mediating Role of Immune Cells in the Pathogenesis of IgA Nephropathy Through the Inflammatory Axis of Gut Microbiota From a Genomic Perspective,” Mammalian Genome 36 (2025): 306–316.

62. Shu J., Ge Y., and Wu Y., “Causal Role of Immune Cells in IgA Nephropathy: A Mendelian Randomization Study,” Renal Failure 46 (2024): 2381593.

63. Meffre E. and Wardemann H., “B‐cell Tolerance Checkpoints in Health and Autoimmunity,” Current Opinion in Immunology 20 (2008): 632–638.

64. Davies R., Peng S. L., Lickliter J., et al., “A First‐in‐human, Randomized Study of the Safety, Pharmacokinetics and Pharmacodynamics of Povetacicept, an Enhanced Dual BAFF/APRIL Antagonist, in Healthy Adults,” Clinical and Translational Science 17 (2024): e70055.

65. Martín‐Penagos L., Benito‐Hernández A., San Segundo D., Sango C., Azueta A., and Gómez‐Román J., “A Proliferation‐inducing Ligand Increase Precedes IgA Nephropathy Recurrence in Kidney Transplant Recipients,” Clinical Transplantation 33 (2019): e13502.

66. Sun J., Cheng Y., Zhang W., et al., “TACI Ig Fusion Protein Inhibits TLR4/MyD88/NF‐κB Pathway Alleviates Renal Injury in IgA Nephropathy Rats,” Iranian Journal of Kidney Diseases 18 (2024): 326–336.

67. Jin Y., Zhu J., Sheng A., et al., “Telitacicept as a BAFF/APRIL Dual Inhibitor: Efficacy and Safety in Reducing Proteinuria for Refractory Childhood IgA Vasculitis Nephritis,” Pediatric Nephrology 40, no. 8 (2025): 2561–2569.

68. Luvizotto M. J., Menezes‐Silva L., Woronik V., Monteiro R. C., and Câmara N. O. S., “Gut‐kidney Axis in IgA Nephropathy: Role on Mesangial Cell Metabolism and Inflammation,” Frontiers in Cell and Developmental Biology 10 (2022): 993716.

69. Popova A., Slisere B., Racenis K., et al., “IgA Class‐switched CD27‐CD21+ B Cells in IgA Nephropathy,” Nephrology, Dialysis, Transplantation 40 (2025): 505–515.

70. Xu Z., Zhan H., Zhang J., et al., “New Biomarkers in IgA Nephropathy,” Clinical Immunology 274 (2025): 110468.

71. Nurmi M. S., Pérez‐Alós L., Garred P., Fellström B., Gabrysch K., and Lundberg S., “Urine Complement‐related Proteins in IgA Nephropathy and IgA Vasculitis Nephritis, Possible Biomarkers of Disease Activity,” Clinical Kidney Journal 18 (2025): sfae395.

72. Wang D., Wu C., Chen S., et al., “Urinary Complement Profile in IgA Nephropathy and Its Correlation With the Clinical and Pathological Characteristics,” Frontiers in Immunology 14 (2023): 1117995.

73. Gan T., Qu L., Qu S., et al., “Unveiling Biomarkers and Therapeutic Targets in IgA Nephropathy Through Large‐scale Blood Transcriptome Analysis,” International Immunopharmacology 132 (2024): 111905.

74. Yu B. C., Park J. H., Lee K. H., et al., “Urinary C5b‐9 as a Prognostic Marker in IgA Nephropathy,” Journal of Clinical Medicine 11 (2022): 820.

75. Cetinkaya H., Gursu M., Yazici H., et al., “Could Mesangial C3 Deposition be an Independent Prognostic Marker in Immunoglobulin A Nephropathy?,” Journal of Nephrology 37 (2024): 923–932.

76. Dixon B. P., Greenbaum L. A., Huang L., et al., “Clinical Safety and Efficacy of Pegcetacoplan in a Phase 2 Study of Patients With C3 Glomerulopathy and Other Complement‐Mediated Glomerular Diseases,” Kidney International Reports 8 (2023): 2284–2293.

77. Tesař V., Radhakrishnan J., Charu V., and Barratt J., “Challenges in IgA Nephropathy Management: An Era of Complement Inhibition,” Kidney International Reports 8 (2023): 1730–1740.

78. Yu G., Zhao J., Wang M., et al., “Urinary C4d and Progression of Kidney Disease in IgA Vasculitis,” Nephrology, Dialysis, Transplantation 39 (2024): 1642–1648.

79. Dong Y., Wang Z., Guo W., et al., “Association Between Urinary C4d Levels and Disease Progression in IgA Nephropathy,” Nephrology, Dialysis, Transplantation 39 (2024): 1279–1287.

80. Wang Z., Jiang Y., Chen P., et al., “The Level of Urinary C4d Is Associated With Disease Progression in IgA Nephropathy With Glomerular Crescentic Lesions: A Cohort Study,” Nephrology, Dialysis, Transplantation 37 (2022): 2119–2127.

81. Tringali E., Vetrano D., Tondolo F., et al., “Role of Serum Complement C3 and C4 on Kidney Outcomes in IgA Nephropathy,” Scientific Reports 14 (2024): 16224.

82. Guo W., Liu Q., Zhu L., et al., “Coding and Noncoding Variants in CFH Act Synergistically for Complement Activation in Immunoglobulin A Nephropathy,” American Journal of the Medical Sciences 356 (2018): 114–120.

83. Kang Y., Xu B., Shi S., et al., “Mesangial C3 Deposition, Complement‐Associated Variant, and Disease Progression in IgA Nephropathy,” Clin J Am Soc Nephrol 18 (2023): 1583–1591.

84. Li Y., Ni X., Li X., et al., “Glomerular Mesangial Cells Derived Complement Factor H Regulates Complement Activation, Influences Cell Proliferation, and Maintains Actin Cytoskeleton,” International Immunopharmacology 154 (2025): 114544.

85. Hou W., Shi S., Zhou X., et al., “Complement Factor H Variants Are Associated With Microangiopathy Lesions in IgA Nephropathy,” International Immunopharmacology 112 (2022): 109234.

86. Xie J., Kiryluk K., Li Y., et al., “Fine Mapping Implicates a Deletion of CFHR1 and CFHR3 in Protection From IgA Nephropathy in Han Chinese,” Journal of the American Society of Nephrology 27 (2016): 3187–3194.

87. Zhai Y., Meng S., Zhu L., et al., “Rare Variants in the Complement Factor H‐Related Protein 5 Gene Contribute to Genetic Susceptibility to IgA Nephropathy,” Journal of the American Society of Nephrology 27 (2016): 2894–2905.

88. Zhu L., Zhai Y., Wang F., et al., “Variants in Complement Factor H and Complement Factor H‐Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy,” Journal of the American Society of Nephrology 26 (2015): 1195–1204.

89. Jia M., Zhu L., Zhai Y., et al., “Variation in Complement Factor H Affects Complement Activation in Immunoglobulin A Vasculitis With Nephritis,” Nephrology (Carlton, Vic.) 25 (2020): 40–47.

90. Caravaca‐Fontán F., Gutiérrez E., Sevillano Á. M., and Praga M., “Targeting Complement in IgA Nephropathy,” Clinical Kidney Journal 16 (2023): ii28–ii39.

91. Rizk D. V., Rovin B. H., Zhang H., et al., “Targeting the Alternative Complement Pathway with Iptacopan to Treat IgA Nephropathy: Design and Rationale of the APPLAUSE‐IgAN Study,” Kidney International Reports 8 (2023): 968–979.

92. Wang P., Luo M., Song E., et al., “Long Noncoding RNA Lnc‐TSI Inhibits Renal Fibrogenesis by Negatively Regulating the TGF‐β/Smad3 Pathway,” Science Translational Medicine 10 (2018): eaat2039.

93. Mucha K., Pac M., and Pączek L., “Omics Are Getting Us Closer to Understanding IgA Nephropathy,” Archivum Immunologiae Et Therapiae Experimentalis 71 (2023): 12.

94. Nihei Y., Haniuda K., Higashiyama M., et al., “Identification of IgA Autoantibodies Targeting Mesangial Cells Redefines the Pathogenesis of IgA Nephropathy,” Science Advances 9 (2023): eadd6734.

95. Higashiyama M., Haniuda K., Nihei Y., et al., “Oral Bacteria Induce IgA Autoantibodies Against a Mesangial Protein in IgA Nephropathy Model Mice,” Life Science Alliance 7 (2024): e202402588.

96. Jemelkova J., Stuchlova Horynova M., Kosztyu P., Zachova K., Zadrazil J., and Galuszkova D., “GalNAc‐T14 May Contribute to Production of Galactose‐Deficient Immunoglobulin A1, the Main Autoantigen in IgA Nephropathy,” Life Sci Alliance 8 (2023): 1068–1075.

97. Wang X., Zhou X., Qiao X., Falchi M., Liu J., and Zhang H., “The Evolving Understanding of Systemic Mechanisms in Organ‐specific IgA Nephropathy: A Focus on Gut‐kidney Crosstalk,” Theranostics 15 (2025): 656–681.

98. Tejedor Vaquero S., Neuman H., Comerma L., et al., “Immunomolecular and Reactivity Landscapes of Gut IgA Subclasses in Homeostasis and Inflammatory Bowel Disease,” Journal of Experimental Medicine 221 (2024): e20230079.

99. Hong M., Song E., Yoon H. J., Chung W., Seo H. Y., and Kim D., “Clade‐specific Extracellular Vesicles From Akkermansia Muciniphila Mediate Competitive Colonization via Direct Inhibition and Immune Stimulation,” Nature Communications 16 (2025): 2708.

100. Gleeson P. J., Benech N., Chemouny J., et al., “The Gut Microbiota Posttranslationally Modifies IgA1 in Autoimmune Glomerulonephritis,” Science Translational Medicine 16 (2024): eadl6149.

101. Muto M., Manfroi B., Suzuki H., et al., “Toll‐Like Receptor 9 Stimulation Induces Aberrant Expression of a Proliferation‐Inducing Ligand by Tonsillar Germinal Center B Cells in IgA Nephropathy,” Journal of the American Society of Nephrology 28 (2017): 1227–1238.

102. Chang S. and Li X., “The Role of Immune Modulation in Pathogenesis of IgA Nephropathy,” Frontiers in Medicine (Lausanne) 7 (2020): 92.

103. Prakash S., Steers N. J., Li Y., et al., “Loss of GalNAc‐T14 Links O‐glycosylation Defects to Alterations in B Cell Homing in IgA Nephropathy,” Journal of Clinical Investigation 135, no. 10 (2025): e181164.

104. Hong J., Adam S. Y., Wang S., et al., “Melatonin Modulates ZAP70 and CD40 Transcripts via Histone Modifications in Canine Ileum Epithelial Cells,” Veterinary Sciences 12 (2025): 87.

105. Kanswal S., Katsenelson N., Selvapandiyan A., Bram R. J., and Akkoyunlu M., “Deficient TACI Expression on B Lymphocytes of Newborn Mice Leads to Defective Ig Secretion in Response to BAFF or APRIL,” Journal of Immunology 181 (2008): 976–990.

106. Quinn G. Z. and Susztak K., “Is IgA Class Switching Epigenetically Wired?: Untangling the Evidence,” Journal of the American Society of Nephrology 35 (2024): 1630–1632.

107. Yu S., Li X., Wang T., et al., “B‐Cell Epigenetic Modulation of IgA Response by 5‐Azacytidine and IgA Nephropathy,” Journal of the American Society of Nephrology 35 (2024): 1686–1701.

108. Xie D., Zhao H., Xu X., et al., “Intensity of Macrophage Infiltration in Glomeruli Predicts Response to Immunosuppressive Therapy in Patients With IgA Nephropathy,” Journal of the American Society of Nephrology 32 (2021): 3187–3196.

109. Li J., Lv J., Wong M. G., et al., “Correlation of Urinary Soluble CD163 Levels with Disease Activity and Treatment Response in IgA Nephropathy,” Kidney International Reports 9 (2024): 3016–3026.

110. Liu Y., Gong Y., and Xu G., “The Role of Mononuclear Phagocyte System in IgA Nephropathy: Pathogenesis and Prognosis,” Frontiers in immunology 14 (2023): 1192941.

111. Cheung C. K. and Barratt J., “Further Evidence for the Mucosal Origin of Pathogenic IgA in IgA Nephropathy,” Journal of the American Society of Nephrology 33 (2022): 873–875.

112. Makita Y., Suzuki H., Kano T., et al., “TLR9 activation Induces Aberrant IgA Glycosylation via APRIL‐ and IL‐6‐mediated Pathways in IgA Nephropathy,” Kidney International 97 (2020): 340–349.

113. Buren M., Yamashita M., Suzuki Y., Tomino Y., and Emancipator S. N., “Altered Expression of Lymphocyte Homing Chemokines in the Pathogenesis of IgA Nephropathy,” Contributions to Nephrology 157 (2007): 50–55.

114. Zachova K., Jemelkova J., Kosztyu P., et al., “Galactose‐Deficient IgA1 B Cells in the Circulation of IgA Nephropathy Patients Carry Preferentially Lambda Light Chains and Mucosal Homing Receptors,” Journal of the American Society of Nephrology 33 (2022): 908–917.

115. Sallustio F., Curci C., Chaoul N., et al., “High Levels of Gut‐homing Immunoglobulin A+ B Lymphocytes Support the Pathogenic Role of Intestinal Mucosal Hyperresponsiveness in Immunoglobulin A Nephropathy Patients,” Nephrology, Dialysis, Transplantation 36 (2021): 452–464.

116. Popova A., Slisere B., Racenis K., et al., “Enhanced Differentiation of IgA+ Class‐switched CD27‐CD21+ B Cells in Patients With IgA Nephropathy,” Medrxiv (2024): 2024.

117. van den Wall Bake A. W., Daha M. R., Evers‐Schouten J., and van Es L. A., “Serum IgA and the Production of IgA by Peripheral Blood and Bone Marrow Lymphocytes in Patients With Primary IgA Nephropathy: Evidence for the Bone Marrow as the Source of Mesangial IgA,” American Journal of Kidney Diseases 12 (1988): 410–414.

118. De Fijter J. W., Daha M. R., Schroeijers W. E., van Es L. A., and Van Kooten C., “Increased IL‐10 Production by Stimulated Whole Blood Cultures in Primary IgA Nephropathy,” Clinical and Experimental Immunology 111 (1998): 429–434.

119. Aizawa M., Suzuki Y., Suzuki H., et al., “Roles of Bone Marrow, Mucosa and Lymphoid Tissues in Pathogenesis of Murine IgA Nephropathy,” Contributions to Nephrology 157 (2007): 164–168.

120. Meng H., Ohtake H., Ishida A., Ohta N., Kakehata S., and Yamakawa M., “IgA Production and Tonsillar Focal Infection in IgA Nephropathy,” Journal of Clinical and Experimental Hematopathology 52 (2012): 161–170.

121. Suzuki Y., “B Cell Targeting in IgA Nephropathy,” Nephrology (Carlton, Vic.) 29, no. Suppl 2 (2024): 39–43.

122. Wang Y., Zhang L., Zhao P., et al., “Functional Implications of Regulatory B Cells in human IgA Nephropathy,” Scandinavian Journal of Immunology 79 (2014): 51–60.

123. Chen D., Zhang Z., Yang Y., Hong Q., Li W., and Zhuo L., “High‐throughput Sequencing Analysis of Genes Encoding the B‐lymphocyte Receptor Heavy‐chain CDR3 in Renal and Peripheral Blood of IgA Nephropathy,” Bioscience Reports 39 (2019): BSR20190482.

124. Zhang X., Zeng J., Tong Y., et al., “CDR3 sequences in IgA Nephropathy Are Shorter and Exhibit Reduced Diversity,” FEBS Open Bio 10 (2020): 2702–2711.

125. Du S. W., Jacobs H. M., Arkatkar T., Rawlings D. J., and Jackson S. W., “Integrated B Cell, Toll‐Like, and BAFF Receptor Signals Promote Autoantibody Production by Transitional B Cells,” Journal of Immunology 201 (2018): 3258–3268.

126. Ou M., Zheng F., Zhang X., et al., “Integrated Analysis of B‑Cell and T‑Cell Receptors by High‑Throughput Sequencing Reveals Conserved Repertoires in IgA Nephropathy,” Molecular Medicine Reports 17 (2018): 7027–7036.

127. Huang C., Li X., Wu J., et al., “The Landscape and Diagnostic Potential of T and B Cell Repertoire in Immunoglobulin A Nephropathy,” Journal of Autoimmunity 97 (2019): 100–107.

128. Zheng Y., Lu P., Deng Y., et al., “Single‐Cell Transcriptomics Reveal Immune Mechanisms of the Onset and Progression of IgA Nephropathy,” Cell Reports 33 (2020): 108525.

129. Chen X., Li M., Zhu S., et al., “Proteomic Profiling of IgA Nephropathy Reveals Distinct Molecular Prognostic Subtypes,” Iscience 26 (2023): 105961.

130. Chen L., Chen X., Cai G., Jiang H., Chen X., and Zhang M., “An Inflammatory Cytokine Signature Predicts IgA Nephropathy Severity and Progression,” MedComm 5 (2024): e783.

131. Nachiappa Ganesh R., Garcia G., and Truong L., “Monocytes and Macrophages in Kidney Disease and Homeostasis,” International Journal of Molecular Sciences 25 (2024): 3763.

132. Paust H., Turner J., Steinmetz O. M., et al., “The IL‐23/Th17 Axis Contributes to Renal Injury in Experimental Glomerulonephritis,” Journal of the American Society of Nephrology 20 (2009): 969–979.

133. Yano N., Endoh M., Nomoto Y., Sakai H., Fadden K., and Rifai A., “Phenotypic Characterization of Cytokine Expression in Patients With IgA Nephropathy,” Journal of Clinical Immunology 17 (1997): 396–403.

134. Hotta O., Yusa N., Ooyama M., Unno K., Furuta T., and Taguma Y., “Detection of Urinary Macrophages Expressing the CD16 (Fc gamma RIII) Molecule: A Novel Marker of Acute Inflammatory Glomerular Injury,” Kidney International 55 (1999): 1927–1934.

135. Cox S. N., Serino G., Sallustio F., et al., “Altered Monocyte Expression and Expansion of Non‐classical Monocyte Subset in IgA Nephropathy Patients,” Nephrology, Dialysis, Transplantation 30 (2015): 1122–1232.

136. Eljaszewicz A., Kleina K., Grubczak K., et al., “Elevated Numbers of Circulating Very Small Embryonic‐Like Stem Cells (VSELs) and Intermediate CD14++CD16+ Monocytes in IgA Nephropathy,” Stem Cell Reviews and Reports 14 (2018): 686–693.

137. Qing J., Li C., Hu X., et al., “Differentiation of T Helper 17 Cells May Mediate the Abnormal Humoral Immunity in IgA Nephropathy and Inflammatory Bowel Disease Based on Shared Genetic Effects,” Frontiers in Immunology 13 (2022): 916934.

138. Zhang Y., Liu X., Zhou X., et al., “A Functional Variant rs3093023 in CCR6 Is Associated with IgA Nephropathy by Regulating Th17 Cells in a North Han Chinese Population,” Frontiers in Immunology 12 (2021): 600598.

139. Liu K., Yang Y., Chen Y., Li S., Gong Y., and Liang Y., “The Therapeutic Effect of Dendritic Cells Expressing Indoleamine 2,3‐dioxygenase (IDO) on an IgA Nephropathy Mouse Model,” International Urology and Nephrology 52 (2020): 399–407.

140. Chou Y., Chen H., Hsu B., et al., “Galectin‐3 Contributes to Pathogenesis of IgA Nephropathy,” Kidney International 106 (2024): 658–670.

141. Bicanski B., Wenderdel M., Mertens P. R., et al., “PDGF‐B Gene Single‐nucleotide Polymorphisms Are Not Predictive for Disease Onset or Progression of IgA Nephropathy,” Clinical Nephrology 67 (2007): 65–72.

142. Stein‐Oakley A. N., Maguire J. A., Dowling J., Perry G., and Thomsom N. M., “Altered Expression of Fibrogenic Growth Factors in IgA Nephropathy and Focal and Segmental Glomerulosclerosis,” Kidney International 51 (1997): 195–204.

143. O'Sullivan K. M., Ford S. L., Longano A., Kitching A. R., and Holdsworth S. R., “Intrarenal Toll‐Like Receptor 4 and Toll‐Like Receptor 2 Expression Correlates With Injury in Antineutrophil Cytoplasmic Antibody‐associated Vasculitis,” American Journal of Physiology. Renal Physiology 315 (2018): F1283–F1294.

144. Peng Z., Huang X., Pan Y., et al., “USP22 promotes Angiotensin II‐induced Podocyte Injury by Deubiquitinating and Stabilizing HMGB1,” Cell. Signalling 131 (2025): 111771.

145. Datta S., Rahman M. A., Koka S., and Boini K. M., “High Mobility Group Box 1 (HMGB1) Mediates Nicotine‐induced Podocyte Injury,” Frontiers in Pharmacology 15 (2024): 1540639.

146. Liu J., Zhao T., Cui H., et al., “HMGB1 Encapsulated in Podocyte‐Derived Exosomes Plays a Central Role in Glomerular Endothelial Cell Injury in Lupus Nephritis by Regulating TRIM27 Expression,” Laboratory Investigation 105 (2025): 104096.

147. Sprenkeler E. G. G., Zandstra J., van Kleef N. D., et al., “S100A8/A9 Is a Marker for the Release of Neutrophil Extracellular Traps and Induces Neutrophil Activation,” Cells 11 (2022): 236.

148. Pepper R. J., Wang H., Rajakaruna G. K., et al., “S100A8/A9 (calprotectin) is Critical for Development of Glomerulonephritis and Promotes Inflammatory Leukocyte‐renal Cell Interactions,” American Journal of Pathology 185 (2015): 1264–1274.

149. Ebefors K., Liu P., Lassén E., Elvin J., Candemark E., and Levan K., “Mesangial Cells From Patients With IgA Nephropathy Have Increased Susceptibility to Galactose‐deficient IgA1,” BMC Nephrology [Electronic Resource] 17 (2016): 40.

150. Srsen S., Held M., Sestan M., et al., “Serum Levels of S100A8/A9 as a Biomarker of Disease Activity in Patients With IgA Vasculitis,” Biomedicines 12 (2024): 750.

151. Panda S. K., Facchinetti V., Voynova E., et al., “Galectin‐9 Inhibits TLR7‐mediated Autoimmunity in Murine Lupus Models,” Journal of Clinical Investigation 128 (2018): 1873–1887.

152. Gestermann N., Di Domizio J., Lande R., et al., “Netting Neutrophils Activate Autoreactive B Cells in Lupus,” Journal of Immunology 200 (2018): 3364–3371.

153. Capolunghi F., Cascioli S., Giorda E., et al., “CpG Drives human Transitional B Cells to Terminal Differentiation and Production of Natural Antibodies,” Journal of Immunology 180 (2008): 800–808.

154. Chen X., Tu L., Tang Q., Huang L., and Qin Y., “An Emerging Role for Neutrophil Extracellular Traps in IgA Vasculitis: A Mini‐Review,” Frontiers in Immunology 13 (2022): 912929.

155. Gimpel A., Maccataio A., Unterweger H., Sokolova M. V., Schett G., and Steffen U., “IgA Complexes Induce Neutrophil Extracellular Trap Formation More Potently than IgG Complexes,” Frontiers in Immunology 12 (2021): 761816.

156. Chen X., Tu L., Zou J., Zhu S., Zhao Y., and Qin Y., “The Involvement of Neutrophil Extracellular Traps in Disease Activity Associated with IgA Vasculitis,” Frontiers in Immunology 12 (2021): 668974.

157. Mayer‐Hain S., Gebhardt K., Neufeld M., et al., “Systemic Activation of Neutrophils by Immune Complexes Is Critical to IgA Vasculitis,” Journal of Immunology 209 (2022): 1048–1058.

158. Aleyd E., Al M., Tuk C. W., van der Laken C. J., and van Egmond M., “IgA Complexes in Plasma and Synovial Fluid of Patients With Rheumatoid Arthritis Induce Neutrophil Extracellular Traps via FcαRI,” Journal of Immunology 197 (2016): 4552–4559.

159. Tuz A. A., Ghosh S., Karsch L., et al., “Stroke and Myocardial Infarction Induce Neutrophil Extracellular Trap Release Disrupting Lymphoid Organ Structure and Immunoglobulin Secretion,” Nature Cardiovascular Research 3 (2024): 525–540.

160. Chen X., Tu L., Tang Q., Zou J., Yun X., and Qin Y., “DNase I Targeted Degradation of Neutrophil Extracellular Traps to Reduce the Damage on IgAV Rat,” PLoS ONE 18 (2023): e0291592.

161. Chen X., Zou J., Tu L., Yun X., and Qin Y., “Neutrophil Extracellular Traps Involved in the Pathogenesis of IgA Vasculitis: Confirmed in Two IgAV Rat Models,” PLoS ONE 18 (2023): e0288538.

162. Stacey H. D., Golubeva D., Posca A., et al., “IgA Potentiates NETosis in Response to Viral Infection,” PNAS 118 (2021): e2101497118.

163. Berthoux F., Suzuki H., Thibaudin L., et al., “Autoantibodies Targeting Galactose‐deficient IgA1 Associate With Progression of IgA Nephropathy,” Journal of the American Society of Nephrology 23 (2012): 1579–1587.

164. Maixnerova D., Ling C., Hall S., et al., “Galactose‐deficient IgA1 and the Corresponding IgG Autoantibodies Predict IgA Nephropathy Progression,” PLoS ONE 14 (2019): e0212254.

165. Placzek W. J., Yanagawa H., Makita Y., et al., “Serum Galactose‐deficient‐IgA1 and IgG Autoantibodies Correlate in Patients With IgA Nephropathy,” PLoS ONE 13 (2018): e0190967.

166. Nihei Y., Suzuki H., and Suzuki Y., “Current Understanding of IgA Antibodies in the Pathogenesis of IgA Nephropathy,” Frontiers in Immunology 14 (2023): 1165394.

167. Ohyama Y., Yamaguchi H., Ogata S., et al., “Racial Heterogeneity of IgA1 Hinge‐region O‐glycoforms in Patients With IgA Nephropathy,” Iscience 25 (2022): 105223.

168. Ohyama Y., Renfrow M. B., Novak J., and Takahashi K., “Aberrantly Glycosylated IgA1 in IgA Nephropathy: What We Know and What We Don't Know,” Journal of Clinical Medicine 10 (2021): 3467.

169. Gaber L. W., Khan F. N., Graviss E. A., et al., “Prevalence, Characteristics, and Outcomes of Incidental IgA Glomerular Deposits in Donor Kidneys,” Kidney International Reports 5 (2020): 1914–1924.

170. Matsumoto Y., Aryal R. P., Heimburg‐Molinaro J., et al., “Identification and Characterization of Circulating Immune Complexes in IgA Nephropathy,” Science Advances 8 (2022): eabm8783.

171. Roos A., Rastaldi M. P., Calvaresi N., et al., “Glomerular Activation of the Lectin Pathway of Complement in IgA Nephropathy Is Associated With More Severe Renal Disease,” Journal of the American Society of Nephrology 17 (2006): 1724–1734.

172. Rizk D. V., Maillard N., Julian B. A., et al., “The Emerging Role of Complement Proteins as a Target for Therapy of IgA Nephropathy,” Frontiers in immunology 10 (2019): 504.

173. Duval A., Caillard S., and Frémeaux‐Bacchi V., “The Complement System in IgAN: Mechanistic Context for Therapeutic Opportunities,” Nephrology, Dialysis, Transplantation 38 (2023): 2685–2693.

174. Cheung C. K., Barratt J., Liew A., Zhang H., Tesar V., and Lafayette R., “The Role of BAFF and APRIL in IgA Nephropathy: Pathogenic Mechanisms and Targeted Therapies,” Frontiers in Nephrology 3 (2023): 1346769.

175. Yanagawa H., Suzuki H., Suzuki Y., et al., “A Panel of Serum Biomarkers Differentiates IgA Nephropathy From Other Renal Diseases,” PLoS ONE 9 (2014): e98081.

176. Zeng H., Wang L., Li J., et al., “Single‐cell RNA‐sequencing Reveals Distinct Immune Cell Subsets and Signaling Pathways in IgA Nephropathy,” Cell & Bioscience 11 (2021): 203.

177. Xu C., Zhang Y., Zhou J., et al., “Integrated Temporal Transcriptional and Epigenetic Single‐cell Analysis Reveals the Intrarenal Immune Characteristics in an Early‐stage Model of IgA Nephropathy During Its Acute Injury,” Frontiers in Immunology 15 (2024): 1405748.

178. Tang R., Meng T., Lin W., et al., “A Partial Picture of the Single‐Cell Transcriptomics of Human IgA Nephropathy,” Frontiers in Immunology 12 (2021): 645988.

179. Schena F. P., Rossini M., Abbrescia D. I., and Zaza G., “The Molecular Mechanisms of Inflammation and Scarring in the Kidneys of Immunoglobulin A Nephropathy: Gene Involvement in the Mechanisms of Inflammation and Scarring in Kidney Biopsy of IgAN Patients,” Seminars in Immunopathology 43 (2021): 691–705.

180. Rauen T., Fitzner C., Eitner F., et al., “Effects of Two Immunosuppressive Treatment Protocols for IgA Nephropathy,” Journal of the American Society of Nephrology 29 (2018): 317–325.

181. Rauen T., Wied S., Fitzner C., et al., “After Ten Years of Follow‐up, no Difference Between Supportive Care plus Immunosuppression and Supportive Care Alone in IgA Nephropathy,” Kidney International 98 (2020): 1044–1052.

182. Lv J., Wong M. G., Hladunewich M. A., et al., “Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients with IgA Nephropathy: The TESTING Randomized Clinical Trial,” Jama 327 (2022): 1888–1898.

183. Lv J., Zhang H., Wong M. G., et al., “Effect of Oral Methylprednisolone on Clinical Outcomes in Patients with IgA Nephropathy: The TESTING Randomized Clinical Trial,” Jama 318 (2017): 432–442.

184. Rovin B. H., Barratt J., Heerspink H. J. L., Alpers C. E., Bieler S., and Chae D., “Efficacy and Safety of sparsentan versus irbesartan in Patients With IgA Nephropathy (PROTECT): 2‐year Results From a Randomised, Active‐controlled, Phase 3 Trial,” Lancet 402 (2023): 2077–2090.

185. Perkovic V., Barratt J., Rovin B., et al., “Alternative Complement Pathway Inhibition With Iptacopan in IgA Nephropathy,” New England Journal of Medicine (2024).

186. Lafayette R., Kristensen J., Stone A., et al., “Efficacy and Safety of a Targeted‐release Formulation of budesonide in Patients With Primary IgA Nephropathy (NefIgArd): 2‐year Results From a Randomised Phase 3 Trial,” Lancet 402 (2023): 859–870.

187. Selvaskandan H. and Barratt J., “Charting New Frontiers in IgA Nephropathy: A Paradigm Shift Toward Precision Medicine and Early Intervention?,” Kidney International 105 (2024): 659–661.

188. Radhakrishnan J. and Cattran D. C., “The KDIGO Practice Guideline on Glomerulonephritis: Reading Between the (guide)Lines–application to the Individual Patient,” Kidney International 82 (2012): 840–856.

189. Wyatt R. J., “Are We Ready for Targeted Therapy for IgA Nephropathy?,” Lancet 389 (2017): 2083–2084.

190. Fellström B. C., Barratt J., Cook H., et al., “Targeted‐release Budesonide versus Placebo in Patients With IgA Nephropathy (NEFIGAN): A Double‐blind, Randomised, Placebo‐controlled Phase 2b Trial,” Lancet 389 (2017): 2117–2127.

191. Maixnerova D., Hartinger J., and Tesar V., “Expanding Options of Supportive Care in IgA Nephropathy,” Clinical Kidney Journal 16 (2023): ii47–ii54.

192. Grabe D. W., “Preventing Progression in IgA Nephropathy: A Managed Care Focus on Emerging Therapies,” American Journal of Managed Care 29 (2023): S31–S43.

193. Guo Y., Shi S., Zhao J., et al., “Prognosis of IgA Nephropathy Patient With Proteinuria Remission by Supportive Therapy: Cohort From Screening Failed Chinese Patients in TESTING Study,” Renal Failure 46 (2024): 2398826.

194. Gomes A. M., Schau B., and Farinha A., “Emerging Perspectives in the Management of IgA Nephropathy: A Comprehensive Review,” Porto Biomedical Journal 9 (2024): 264.

195. Filippone E. J., Gulati R., and Farber J. L., “The Road Ahead: Emerging Therapies for Primary IgA Nephropathy,” Frontiers in Nephrology 5 (2025): 1545329.

196. Schanz M., Seikrit C., Hohenstein B., et al., “First Real‐world Evidence of Sparsentan Efficacy in Patients With IgA Nephropathy Treated With SGLT2 Inhibitors,” Clinical Kidney Journal 18 (2025): sfae394.

197. Barratt J., Stone A. M., Reich H. N., and Lafayette R. A., “eGFR Slope Modelling Predicts Long‐term Clinical Benefit With Nefecon in a Real‐world IgAN Population,” Clinical Kidney Journal 18 (2025): sfae404.

198. Barratt J., Kristensen J., Pedersen C., and Jerling M., “Insights on Nefecon(®), a Targeted‐Release Formulation of Budesonide and Its Selective Immunomodulatory Effects in Patients With IgA Nephropathy,” Drug Design, Development and Therapy 18 (2024): 3415–3428.

199. Tian Z., Yang Y., Mei J., et al., “Efficacy and Safety of Endothelin A Receptor Antagonists in IgA Nephropathy: A Systematic Review and Meta‐analysis,” Clinical Kidney Journal 18 (2025): sfaf066.

200. Heerspink H. J. L., Jardine M., Kohan D. E., et al., “Study Design and Baseline Characteristics of ALIGN, a Randomized Controlled Study of Atrasentan in Patients with IgA Nephropathy,” Kidney International Reports 10 (2025): 217–226.

201. Willcocks L., “ALIGNing the Treatment of IgA Nephropathy: Reducing Proteinuria With Endothelin A Receptor Inhibition,” Med 6 (2025): 100564.

202. Hunter‐Dickson M. and Wong M. G., “The Role of Endothelin Receptor Antagonists in IgA Nephropathy,” Nephrology (Carlton, Vic.) 29, no. Suppl 2 (2024): 30–33.

203. Yeo S. C. and Barratt J., “The Contribution of a Proliferation‐inducing Ligand (APRIL) and Other TNF Superfamily Members in Pathogenesis and Progression of IgA Nephropathy,” Clinical Kidney Journal 16 (2023): ii9–ii18.

204. Kooienga L., Lee E. Y., Kim S. G., et al., “Zigakibart Demonstrates Clinical Safety and Efficacy in a Phase 1/2 Trial of Healthy Volunteers and Patients With IgA Nephropathy,” Kidney International (2025). S0085‐2538(25)00414‐4.

205. Rauen T., Eitner F., Fitzner C., et al., “Intensive Supportive Care plus Immunosuppression in IgA Nephropathy,” New England Journal of Medicine 373 (2015): 2225–2236.

206. Pozzi C., “Pro: STOP Immunosuppression in IgA Nephropathy?,” Nephrology, Dialysis, Transplantation 31 (2016): 1766–1770.

207. Rovin B. H., Adler S. G., Barratt J., et al., “Executive Summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases,” Kidney International 100 (2021): 753–779.

208. Floege J., Rauen T., and Tang S. C. W., “Current Treatment of IgA Nephropathy,” Seminars in immunopathology 43 (2021): 717–728.

209. Floege J., Jayne D. R. W., Sanders J. F., et al., “Executive Summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA‐Associated Vasculitis,” Kidney International 105 (2024): 447–449.

210. Rovin B. H., Ayoub I. M., Chan T. M., Liu Z., Mejía‐Vilet J. M., and Balk E. M., “Executive Summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus Nephritis,” Kidney International 105 (2024): 31–34.

211. Praga M., Caravaca‐Fontán F., Da Silva I., Fernández‐Juárez G., Gutiérrez E., and Sevillano A. M., “Tailored Management Strategies for IgA Nephropathy Based on Clinical Presentations,” Nephrology, Dialysis, Transplantation 40 (2025): 874–883.

212. Reich H. N. and Floege J., “How I Treat IgA Nephropathy,” Clinical Journal of the American Society of Nephrology 17 (2022): 1243–1246.

213. Li P. K., Kwan B. C., Chow K., Leung C., and Szeto C., “Treatment of Early Immunoglobulin A Nephropathy by Angiotensin‐converting Enzyme Inhibitor,” American Journal of Medicine 126 (2013): 162–168.

214. Li P. K., Leung C. B., Chow K. M., et al., “Hong Kong Study Using valsartan in IgA Nephropathy (HKVIN): A Double‐blind, Randomized, Placebo‐controlled Study,” American Journal of Kidney Diseases 47 (2006): 751–760.

215. Praga M., Gutiérrez E., González E., Morales E., and Hernández E., “Treatment of IgA Nephropathy With ACE Inhibitors: A Randomized and Controlled Trial,” Journal of the American Society of Nephrology 14 (2003): 1578–1583.

216. Bagchi S., Mani K., Swamy A., et al., “Supportive Management of IgA Nephropathy with Renin‐Angiotensin Blockade, the AIIMS Primary IgA Nephropathy Cohort (APPROACH) Study,” Kidney International Reports 6 (2021): 1661–1668.

217. Nuffield Department of Population Health Renal Studies Group; SGLT2 inhibitor Meta‐Analysis Cardio‐Renal Trialists' Consortium . Impact of Diabetes on the Effects of Sodium Glucose co‐transporter‐2 Inhibitors on Kidney Outcomes: Collaborative Meta‐analysis of Large Placebo‐controlled Trials. Lancet 2022; 400:1788–1801.

218. Wheeler D. C., Toto R. D., Stefánsson B. V., et al., “A Pre‐specified Analysis of the DAPA‐CKD Trial Demonstrates the Effects of dapagliflozin on Major Adverse Kidney Events in Patients With IgA Nephropathy,” Kidney International 100 (2021): 215–224.

219. Hwang J. H. and Hsu C., “In CKD, empagliflozin Reduced Kidney Disease Progression at a Median 2 y, Regardless of Primary Kidney Disease Type,” Annals of Internal Medicine 177 (2024): JC40.

220. EMPA‐KIDNEY Collaborative Group . “Impact of Primary Kidney Disease on the Effects of empagliflozin in Patients With Chronic Kidney Disease: Secondary Analyses of the EMPA‐KIDNEY Trial,” The Lancet Diabetes & Endocrinology 12 (2024): 51–60.

221. Riggleman A., Harvey J., and Baylis C., “Endothelin Mediates Some of the Renal Actions of Acutely Administered Angiotensin II,” Hypertension 38 (2001): 105–109.

222. Boffa J. J., Tharaux P. L., Dussaule J. C., and Chatziantoniou C., “Regression of Renal Vascular Fibrosis by Endothelin Receptor Antagonism,” Hypertension 37 (2001): 490–496.

223. Iñigo P., Campistol J. M., Lario S., et al., “Effects of losartan and Amlodipine on Intrarenal Hemodynamics and TGF‐beta(1) Plasma Levels in a Crossover Trial in Renal Transplant Recipients,” Journal of the American Society of Nephrology 12 (2001): 822–827.

224. Enevoldsen F. C., Sahana J., Wehland M., Grimm D., Infanger M., and Krüger M., “Endothelin Receptor Antagonists: Status Quo and Future Perspectives for Targeted Therapy,” Journal of Clinical Medicine 9 (2020): 824.

225. Hocher B., George I., Diekmann F., et al., “ETA Receptor Blockade Induces Fibrosis of the Clipped Kidney in Two‐kidney‐one‐clip Renovascular Hypertensive Rats,” Journal of Hypertension 18 (2000): 1807–1814.

226. Raina R., Chauvin A., Chakraborty R., et al., “The Role of Endothelin and Endothelin Antagonists in Chronic Kidney Disease,” Kidney Dis (Basel) 6 (2020): 22–34.

227. Bomback A. S., Kshirsagar A. V., Amamoo M. A., and Klemmer P. J., “Change in Proteinuria After Adding Aldosterone Blockers to ACE Inhibitors or Angiotensin Receptor Blockers in CKD: A Systematic Review,” American Journal of Kidney Diseases 51 (2008): 199–211.

228. Chung E. Y., Ruospo M., Natale P., et al., “Aldosterone Antagonists in Addition to Renin Angiotensin System Antagonists for Preventing the Progression of Chronic Kidney Disease,” Cochrane Database of Systematic Reviews (Online) 10 (2020): CD007004.

229. Alexandrou M., Papagianni A., Tsapas A., et al., “Effects of Mineralocorticoid Receptor Antagonists in Proteinuric Kidney Disease: A Systematic Review and Meta‐analysis of Randomized Controlled Trials,” Journal of Hypertension 37 (2019): 2307–2324.

230. Gao Q., Lin H., Zhao Z., et al., “Effectiveness and Safety of finerenone in the Treatment of IgA Nephrology Patients: A Retrospective, Real‐world Study,” International Urology and Nephrology (2025).

231. Tang C., Si F., Chen P., et al., “Effectiveness and Safety of finerenone in Non‐diabetic Patients With IgA Nephropathy,” Journal of Nephrology (2025).

232. Longhitano E., Calabrese V., Casuscelli C., et al., “Proteinuria and Progression of Renal Damage: The Main Pathogenetic Mechanisms and Pharmacological Approach,” Medicina (Kaunas, Lithuania) 60 (2024): 1821.

233. Kohan D. E., Barratt J., Heerspink H. J. L., et al., “Targeting the Endothelin A Receptor in IgA Nephropathy,” Kidney International Reports 8 (2023): 2198–2210.

234. Heerspink H. J. L., Jardine M., Kohan D. E., et al., “Atrasentan in Patients With IgA Nephropathy,” New England Journal of Medicine 392 (2025): 544–554.

235. Heerspink H. J. L., Du X., Xu Y., et al., “The Selective Endothelin Receptor Antagonist SC0062 in IgA Nephropathy: A Randomized Double‐Blind Placebo‐Controlled Clinical Trial,” Journal of the American Society of Nephrology 36 (2025): 657–667.

236. Müller D. N. and Luft F. C., “Renin Receptor Blockade: A Better Strategy for Renal Protection Than Renin‐angiotensin System Inhibition?,” Current Hypertension Reports 10 (2008): 405–409.

237. Yoshiji H., Kuriyama S., and Fukui H., “Blockade of Renin‐angiotensin System in Antifibrotic Therapy,” Journal of Gastroenterology and Hepatology 22, no. Suppl 1 (2007): S93–S95.

238. Kok H. M., Falke L. L., Goldschmeding R., and Nguyen T. Q., “Targeting CTGF, EGF and PDGF Pathways to Prevent Progression of Kidney Disease,” Nature Reviews Nephrology 10 (2014): 700–711.

239. Lee S., Kim S. I., and Choi M. E., “Therapeutic Targets for Treating Fibrotic Kidney Diseases,” Translational Research 165 (2015): 512–530.

240. Akunjee M. M., Khosla S. G., Nylen E. S., and Sen S., “SGLT2 inhibitors Use in Kidney Disease: What Did We Learn?,” American Journal of Physiology. Endocrinology and Metabolism 328, no. 6 (2025): E856–E868.

241. Chen X., Hocher C., Shen L., Krämer B. K., and Hocher B., “Reno‐ and Cardioprotective Molecular Mechanisms of SGLT2 Inhibitors Beyond Glycemic Control: From Bedside to Bench,” American Journal of Physiology Cell Physiology 325 (2023): C661–C681.

242. Muto M., Suzuki H., and Suzuki Y., “New Insights and Future Perspectives of APRIL in IgA Nephropathy,” International Journal of Molecular Sciences 25 (2024): 10340.

243. Shimizu Y., Tomino Y., and Suzuki Y., “IgA Nephropathy: Beyond the Half‐Century,” Medicina (Kaunas, Lithuania) 60 (2023): 54.

244. Liu L. L., Wang L. N., Jiang Y., et al., “Tonsillectomy for IgA Nephropathy: A Meta‐analysis,” American Journal of Kidney Diseases 65 (2015): 80–87.

245. Komatsu H., Fujimoto S., Hara S., Sato Y., Yamada K., and Kitamura K., “Effect of Tonsillectomy plus Steroid Pulse Therapy on Clinical Remission of IgA Nephropathy: A Controlled Study,” Clinical Journal of the American Society of Nephrology 3 (2008): 1301–1307.

246. Hirano K., Matsuzaki K., Yasuda T., et al., “Association between Tonsillectomy and Outcomes in Patients with Immunoglobulin A Nephropathy,” JAMA Network Open 2 (2019): e194772.

247. Jefferson J. A., “Complications of Immunosuppression in Glomerular Disease,” Clinical Journal of the American Society of Nephrology 13 (2018): 1264–1275.

248. Lafayette R. A., Canetta P. A., Rovin B. H., et al., “A Randomized, Controlled Trial of Rituximab in IgA Nephropathy With Proteinuria and Renal Dysfunction,” Journal of the American Society of Nephrology 28 (2017): 1306–1313.

249. Del V. L., Allinovi M., Comolli S., Peiti S., Rimoldi C., and Locatelli F., “Drugs in Development to Treat IgA Nephropathy,” Drugs 84 (2024): 503–525.

250. Maixnerova D., El M. D., Rizk D. V., Zhang H., and Tesar V., “New Treatment Strategies for IgA Nephropathy: Targeting Plasma Cells as the Main Source of Pathogenic Antibodies,” Journal of Clinical Medicine 11 (2022): 2810.

251. Selvaskandan H., Jhaveri K. D., and Rizk D. V., “Primary IgA Nephropathy: New Insights and Emerging Therapies,” Advances in Kidney Disease and Health 31 (2024): 180–193.

252. Rajasekaran A., Julian B. A., and Rizk D. V., “IgA Nephropathy: An Interesting Autoimmune Kidney Disease,” American Journal of the Medical Sciences 361 (2021): 176–194.

253. Mathur M., Sahay M., Pereira B., and Rizk D. V., “State‐of‐Art Therapeutics in IgA Nephropathy,” Indian Journal of Nephrology 34 (2024): 417–430.

254. Rao I. R., Kolakemar A., Shenoy S. V., et al., “Hydroxychloroquine in Nephrology: Current Status and Future Directions,” Journal of Nephrology 36 (2023): 2191–2208.

255. Zheng N., Xie K., Ye H., et al., “TLR7 in B Cells Promotes Renal Inflammation and Gd‐IgA1 Synthesis in IgA Nephropathy,” JCI Insight 5 (2020): e136965.

256. Lee M., Suzuki H., Ogiwara K., et al., “The Nucleotide‐sensing Toll‐Like Receptor 9/Toll‐Like Receptor 7 System Is a Potential Therapeutic Target for IgA Nephropathy,” Kidney International 104 (2023): 943–955.

257. Wang Y. N., Gan T., Qu S., et al., “MTMR3 risk Alleles Enhance Toll like Receptor 9‐induced IgA Immunity in IgA Nephropathy,” Kidney International 104 (2023): 562–576.

258. Kano T., Suzuki H., Makita Y., Fukao Y., and Suzuki Y., “Nasal‐associated Lymphoid Tissue Is the Major Induction Site for Nephritogenic IgA in Murine IgA Nephropathy,” Kidney International 100 (2021): 364–376.

259. Liu L. J., Yang Y. Z., Shi S. F., et al., “Effects of Hydroxychloroquine on Proteinuria in IgA Nephropathy: A Randomized Controlled Trial,” American Journal of Kidney Diseases 74 (2019): 15–22.

260. Barr B. and Barbour S., “New Therapies for Immunoglobulin A Nephropathy: What's the Standard of Care in 2023?,” Current Opinion in Nephrology and Hypertension 33 (2024): 311–317.

261. Chen P. and Lv J., “Low Dose Glucocorticoids, Mycophenolate Mofetil and Hydroxychloroquine in IgA Nephropathy, an Update of Current Clinical Trials,” Nephrology (Carlton, Vic.) 29, no. Suppl 2 (2024): 25–29.

262. Hou J., Le W., Chen N., Wang W., Liu Z., and Liu D., “Mycophenolate Mofetil Combined with Prednisone versus Full‐Dose Prednisone in IgA Nephropathy with Active Proliferative Lesions: A Randomized Controlled Trial,” American Journal of Kidney Diseases 69 (2017): 788–795.

263. Hogg R. J., Bay R. C., Jennette J. C., et al., “Randomized Controlled Trial of Mycophenolate Mofetil in Children, Adolescents, and Adults With IgA Nephropathy,” American Journal of Kidney Diseases 66 (2015): 783–791.

264. Yan B., Tie X., Wang L., Qiao X., and Su X., “Enteric‐coated Mycophenolate Sodium plus Hydroxychloroquine therApy versus Hydroxychloroquine for the Remission of Proteinuria in IgA Nephropathy (EMSAR‐IgAN trial): Study Protocol for a Randomised Trial,” BMJ Open 15 (2025): e098688.

265. Peng X., Zheng W., Fu R., et al., “Efficacy and Safety of Mycophenolate Mofetil in the Treatment for IgA Nephropathy: A Meta‐analysis of Randomized Controlled Trials,” Clinical and Experimental Nephrology 25 (2021): 788–801.

266. Zheng J., Bi T., Zhu L., and Liu L., “Efficacy and Safety of Mycophenolate Mofetil for IgA Nephropathy: An Updated Meta‐analysis of Randomized Controlled Trials,” Experimental and Therapeutic Medicine 16 (2018): 1882–1890.

267. Rasche F. M., Keller F., von Müller L., Sailer L., Karges W., and Czock D., “Mycophenolic Acid Therapy After Cyclophosphamide Pulses in Progressive IgA Nephropathy,” Journal of Nephrology 19 (2006): 465–472.

268. Dal Canton A., Amore A., Barbano G., et al., “One‐year Angiotensin‐converting Enzyme Inhibition plus Mycophenolate Mofetil Immunosuppression in the Course of Early IgA Nephropathy: A Multicenter, Randomised, Controlled Study,” Journal of Nephrology 18 (2005): 136–140.

269. Hou F. F., Xie D., Wang J., et al., “Effectiveness of Mycophenolate Mofetil among Patients with Progressive IgA Nephropathy: A Randomized Clinical Trial,” JAMA Network Open 6 (2023): e2254054.

270. Tang S., Leung J. C. K., Chan L. Y. Y., et al., “Mycophenolate Mofetil Alleviates Persistent Proteinuria in IgA Nephropathy,” Kidney International 68 (2005): 802–812.

271. Maes B. D., Oyen R., Claes K., et al., “Mycophenolate Mofetil in IgA Nephropathy: Results of a 3‐year Prospective Placebo‐controlled Randomized Study,” Kidney International 65 (2004): 1842–1849.

272. Carney E. F., “Clinical Trial: Lack of Benefit of MMF in IgAN,” Nature Reviews Nephrology 11 (2015): 567.

273. Tan J., Dong L., Ye D., et al., “The Efficacy and Safety of Immunosuppressive Therapies in the Treatment of IgA Nephropathy: A Network Meta‐analysis,” Scientific Reports 10 (2020): 6062.

274. Tan C. H. R., Loh P. T., Yang W. S., and Chan C. M., “Mycophenolate Mofetil in the Treatment of IgA Nephropathy: A Systematic Review,” Singapore Medical Journal 49 (2008): 780–785.

275. Zhou X. J., Cheng F. J., Zhu L., et al., “Association of Systemic Lupus Erythematosus Susceptibility Genes With IgA Nephropathy in a Chinese Cohort,” Clinical Journal of the American Society of Nephrology 9 (2014): 788–797.

276. Gan T., Li Y., Zhou X. J., and Zhang H., “Immunoproteasome in IgA Nephropathy: State‐of‐Art and Future Perspectives,” International Journal of Biological Sciences 16 (2020): 2518–2526.

277. Xu L. L., Gan T., Li Y., et al., “Combined Genetic Association and Differed Expression Analysis of UBE2L3 Uncovers a Genetic Regulatory Role of (Immuno)Proteasome in IgA Nephropathy,” Kidney Diseases (Basel) 10 (2024): 167–180.

278. Tang S. C. and Lai K. N., “The Ubiquitin‐proteasome Pathway and IgA Nephropathy: A Novel Link?,” Kidney International 75 (2009): 457–459.

279. Coppo R., Camilla R., Alfarano A., et al., “Upregulation of the Immunoproteasome in Peripheral Blood Mononuclear Cells of Patients With IgA Nephropathy,” Kidney International 75 (2009): 536–541.

280. Hartono C., Chung M., Perlman A. S., et al., “Bortezomib for Reduction of Proteinuria in IgA Nephropathy,” Kidney International Reports 3 (2018): 861–866.

281. Coppo R., “Proteasome Inhibitors in Progressive Renal Diseases,” Nephrology, Dialysis, Transplantation 29, no. Suppl 1 (2014): i25–i30.

282. Lemley K. V. and Glassock R. J., “APRIL—Springtime for New IgA Nephropathy Therapy?,” New England Journal of Medicine 390 (2024): 80–81.

283. Mathur M., Barratt J., Chacko B., et al., “A Phase 2 Trial of Sibeprenlimab in Patients With IgA Nephropathy,” New England Journal of Medicine 390 (2024): 20–31.

284. Wang M., “Targeting APRIL to Slow Progression of IgA Nephropathy,” Nature Reviews Nephrology 20 (2024): 6.

285. Zan J., Liu L., Li G., et al., “Effect of Telitacicept on Circulating Gd‐IgA1 and IgA‐Containing Immune Complexes in IgA Nephropathy,” Kidney International Reports 9 (2024): 1067–1071.

286. Liu L., Liu Y., Li J., et al., “Efficacy and Safety of Telitacicept in IgA Nephropathy: A Retrospective, Multicenter Study,” Nephron (2024): 1–10.

287. Evans L. S., Lewis K. E., DeMonte D., et al., “Povetacicept, an Enhanced Dual APRIL/BAFF Antagonist That Modulates B Lymphocytes and Pathogenic Autoantibodies for the Treatment of Lupus and Other B Cell‐Related Autoimmune Diseases,” Arthritis Rheumatol 75 (2023): 1187–1202.

288. Miwa T., Sato S., Golla M., and Song W. C., “Expansion of Anticomplement Therapy Indications From Rare Genetic Disorders to Common Kidney Diseases,” Annual Review of Medicine 75 (2024): 189–204.

289. Zhang H., Rizk D. V., Perkovic V., et al., “Results of a Randomized Double‐blind Placebo‐controlled Phase 2 Study Propose iptacopan as an Alternative Complement Pathway Inhibitor for IgA Nephropathy,” Kidney International 105 (2024): 189–199.

290. Floege J. and Daha M. R., “IgA Nephropathy: New Insights Into the Role of Complement,” Kidney International 94 (2018): 16–18.

291. Medjeral‐Thomas N. R., Lomax‐Browne H. J., Beckwith H., et al., “Circulating Complement Factor H‐related Proteins 1 and 5 Correlate With Disease Activity in IgA Nephropathy,” Kidney International 92 (2017): 942–952.

292. Tortajada A., Gutiérrez E., Goicoechea D. J. E., et al., “Elevated Factor H‐related Protein 1 and Factor H Pathogenic Variants Decrease Complement Regulation in IgA Nephropathy,” Kidney International 92 (2017): 953–963.

293. Wada T. and Nangaku M., “Novel Roles of Complement in Renal Diseases and Their Therapeutic Consequences,” Kidney International 84 (2013): 441–450.

294. Barratt J., Lafayette R. A., Zhang H., et al., “IgA Nephropathy: The Lectin Pathway and Implications for Targeted Therapy,” Kidney International 104 (2023): 254–264.

295. Zhu L., Guo W. Y., Shi S. F., et al., “Circulating Complement Factor H‐related Protein 5 Levels Contribute to Development and Progression of IgA Nephropathy,” Kidney International 94 (2018): 150–158.

296. Lafayette R. A., Rovin B. H., Reich H. N., Tumlin J. A., Floege J., and Barratt J., “Safety, Tolerability and Efficacy of Narsoplimab, a Novel MASP‐2 Inhibitor for the Treatment of IgA Nephropathy,” Kidney International Reports 5 (2020): 2032–2041.

297. Selvaskandan H., Kay C. C., Dormer J., et al., “Inhibition of the Lectin Pathway of the Complement System as a Novel Approach in the Management of IgA Vasculitis‐Associated Nephritis,” Nephron 144 (2020): 453–458.

298. Migliorini A., Nostro M. C., and Sneddon J. B., “Human Pluripotent Stem Cell‐derived Insulin‐producing Cells: A Regenerative Medicine Perspective,” Cell Metabolism 33 (2021): 721–731.

299. Leonard W. J. and Lin J. X., “Strategies to Therapeutically Modulate Cytokine Action,” Nature Reviews Drug Discovery 22 (2023): 827–854.

300. McNerney M. P., Doiron K. E., Ng T. L., Chang T. Z., and Silver P. A., “Theranostic Cells: Emerging Clinical Applications of Synthetic Biology,” Nature Reviews Genetics 22 (2021): 730–746.

301. Mohan C., Zhang T., and Putterman C., “Pathogenic Cellular and Molecular Mediators in Lupus Nephritis,” Nature Reviews Nephrology 19 (2023): 491–508.

302. Schett G., Müller F., Taubmann J., et al., “Advancements and Challenges in CAR T Cell Therapy in Autoimmune Diseases,” Nature Reviews Rheumatology 20 (2024): 531–544.

303. Fasano S., Milone A., Nicoletti G. F., Isenberg D. A., and Ciccia F., “Precision Medicine in Systemic Lupus Erythematosus,” Nature Reviews Rheumatology 19 (2023): 331–342.

304. Baker D. J., Arany Z., Baur J. A., Epstein J. A., and June C. H., “CAR T Therapy Beyond Cancer: The Evolution of a Living Drug,” Nature 619 (2023): 707–715.

305. Alunno A., Bistoni O., Montanucci P., Basta G., Calafiore R., and Gerli R., “Umbilical Cord Mesenchymal Stem Cells for the Treatment of Autoimmune Diseases: Beware of Cell‐to‐cell Contact,” Annals of the Rheumatic Diseases 77 (2018): e14.

306. Deng D., Zhang P., Guo Y., and Lim T. O., “A Randomised Double‐blind, Placebo‐controlled Trial of Allogeneic Umbilical Cord‐derived Mesenchymal Stem Cell for Lupus Nephritis,” Annals of the Rheumatic Diseases 76 (2017): 1436–1439.

307. Liang J., Zhang H., Hua B., et al., “Allogenic Mesenchymal Stem Cells Transplantation in Refractory Systemic Lupus erythematosus: A Pilot Clinical Study,” Annals of the Rheumatic Diseases 69 (2010): 1423–1429.

308. Tyndall A. and Houssiau F. A., “Mesenchymal Stem Cells in the Treatment of Autoimmune Diseases,” Annals of the Rheumatic Diseases 69 (2010): 1413–1414.

309. Abeles I., Palma C., Meednu N., Payne A. S., Looney R. J., and Anolik J. H., “B Cell‐Directed Therapy in Autoimmunity,” Annual Review of Immunology 42 (2024): 103–126.

310. Gremese E., Bruno D., and Ferraccioli G., “CAR T‐cell Perspectives in Lupus,” Lancet 404 (2024): 336.

311. Krickau T., Naumann‐Bartsch N., Aigner M., et al., “CAR T‐cell Therapy Rescues Adolescent With Rapidly Progressive Lupus Nephritis From Haemodialysis,” Lancet 403 (2024): 1627–1630.

312. Schett G., Mackensen A., and Mougiakakos D., “CAR T‐cell Therapy in Autoimmune Diseases,” Lancet 402 (2023): 2034–2044.

313. Lungova K. and Putman M., “Barriers to CAR T‐cell Therapy in Rheumatology,” The Lancet Rheumatology (2024).

314. Mackensen A., Müller F., Mougiakakos D., et al., “Anti‐CD19 CAR T Cell Therapy for Refractory Systemic Lupus Erythematosus,” Nature Medicine 28 (2022): 2124–22132.

315. Mullard A., “CAR T Cell Therapies Raise Hopes—and Questions—for Lupus and Autoimmune Disease,” Nature Reviews Drug Discovery 22 (2023): 859–861.

316. Moles M. W., Erdlei H., Menzel L., et al., “CXCR4 has a Dual Role in Improving the Efficacy of BCMA‐redirected CAR‐NK Cells in Multiple Myeloma,” Frontiers in Immunology 15 (2024): 1383136.

317. Hassan S. H., Alshahrani M. Y., Saleh R. O., et al., “A New Vision of the Efficacy of both CAR‐NK and CAR‐T Cells in Treating Cancers and Autoimmune Diseases,” Medical Oncology 41 (2024): 127.

318. Shu J., Xie W., Chen Z., Offringa R., Hu Y., and Mei H., “The Enchanting Canvas of CAR Technology: Unveiling Its Wonders in Non‐neoplastic Diseases,” Med 5 (2024): 495–529.

319. Foster M. H., “Optimizing the Translational Value of Animal Models of Glomerulonephritis: Insights From Recent murine Prototypes,” American Journal of Physiology. Renal Physiology 311 (2016): F487–F495.

320. Moszczuk B., Mucha K., Kucharczyk R., and Zagożdżon R., “The Role of Glomerular and Serum Expression of Lymphocyte Activating Factors BAFF and APRIL in Patient With Membranous and IgA Nephropathies,” Archivum Immunologiae Et Therapiae Experimentalis 73 (2025).

321. Ma T. K., McAdoo S. P., and Tam F. W. K., “Targeting the Tyrosine Kinase Signalling Pathways for Treatment of Immune‐mediated Glomerulonephritis: From Bench to Bedside and Beyond,” Nephrology, Dialysis, Transplantation 32 (2017): i129–i138.

322. Monteiro R. C. and Suzuki Y., “Are There Animal Models of IgA Nephropathy?,” Seminars in immunopathology 43 (2021): 639–648.

323. Suzuki H., Suzuki Y., Novak J., and Tomino Y., “Development of Animal Models of Human IgA Nephropathy,” Drug Discovery Today: Disease Models 11 (2014): 5–11.

324. Kano T., Suzuki H., Makita Y., et al., “Lessons From IgA Nephropathy Models,” International Journal of Molecular Sciences 25 (2024): 11484.

325. Okazaki K., Suzuki Y., Otsuji M., et al., “Development of a Model of Early‐onset IgA Nephropathy,” Journal of the American Society of Nephrology 23 (2012): 1364–1374.

326. Myette J. R., Kano T., Suzuki H., et al., “A Proliferation Inducing Ligand (APRIL) Targeted Antibody Is a Safe and Effective Treatment of Murine IgA Nephropathy,” Kidney International 96 (2019): 104–116.

327. Nishie T., Miyaishi O., Azuma H., et al., “Development of Immunoglobulin A Nephropathy‐ Like Disease in Beta‐1,4‐galactosyltransferase‐I‐deficient Mice,” American Journal of Pathology 170 (2007): 447–456.

328. Lechner S. M., Abbad L., Boedec E., Papista C., Le Stang M., and Moal C., “IgA1 Protease Treatment Reverses Mesangial Deposits and Hematuria in a Model of IgA Nephropathy,” Journal of the American Society of Nephrology 27 (2016): 2622–2629.

329. Chemouny J. M., Gleeson P. J., Abbad L., Lauriero G., Boedec E., and Le Roux K., “Modulation of the Microbiota by Oral Antibiotics Treats Immunoglobulin A Nephropathy in Humanized Mice,” Nephrology, Dialysis, Transplantation 34 (2019): 1135–1144.

330. Gleeson P. J., Benech N., Chemouny J., Metallinou E., Berthelot L., and Da Silva J., “The Gut Microbiota Posttranslationally Modifies IgA1 in Autoimmune Glomerulonephritis,” Science Translational Medicine 16 (2024): eadl6149.

331. Nagasawa H., Ueda S., Suzuki H., et al., “Sparsentan Is Superior to losartan in the gddY Mouse Model of IgA Nephropathy,” Nephrology, Dialysis, Transplantation 39 (2024): 1494–1503.

332. Li R., Wang M., Li J., et al., “Lactobacillus Casei Cell Wall Extract and Production of Galactose‐Deficient IgA1 in a Humanized IGHA1 Mouse Model,” Journal of the American Society of Nephrology 36 (2025): 60–72.

333. Suzuki H., Fan R., Zhang Z., et al., “Aberrantly Glycosylated IgA1 in IgA Nephropathy Patients Is Recognized by IgG Antibodies With Restricted Heterogeneity,” Journal of Clinical Investigation 119 (2009): 1668–1677.

334. Kooienga L., Lee E. Y., Kim S. G., et al., “Zigakibart Demonstrates Clinical Safety and Efficacy in a Phase 1/2 Trial of Healthy Volunteers and Patients With IgA Nephropathy,” Kidney International (2025).

335. Lafayette R., Barbour S., Israni R., et al., “A Phase 2b, Randomized, Double‐blind, Placebo‐controlled, Clinical Trial of atacicept for Treatment of IgA Nephropathy,” Kidney International 105 (2024): 1306–1315.

336. Barratt J., Tumlin J., Suzuki Y., et al., “Randomized Phase II JANUS Study of Atacicept in Patients with IgA Nephropathy and Persistent Proteinuria,” Kidney International Reports 7 (2022): 1831–1841.

337. Lv J., Liu L., Hao C., et al., “Randomized Phase 2 Trial of Telitacicept in Patients with IgA Nephropathy with Persistent Proteinuria,” Kidney International Reports 8 (2023): 499–506.

338. Perkovic V., Barratt J., Rovin B., et al., “Alternative Complement Pathway Inhibition With Iptacopan in IgA Nephropathy,” New England Journal of Medicine 392 (2025): 531–543.

339. Nakamura T., Ebihara I., Fukui M., Tomino Y., and Koide H., “Effect of a Specific Endothelin Receptor A Antagonist on Glomerulonephritis of ddY Mice With IgA Nephropathy,” Nephron 72 (1996): 454–460.

340. Michinaga S., Nagase M., Matsuyama E., et al., “Amelioration of Cold Injury‐induced Cortical Brain Edema Formation by Selective Endothelin ETB Receptor Antagonists in Mice,” PLoS ONE 9 (2014): e102009.

341. Moedt E., Wasehuus V. S., and Heerspink H. J. L., “Selective endothelin A Receptor Antagonism in Chronic Kidney Disease: Improving Clinical Application,” Nephrology, Dialysis, Transplantation 40 (2025): i37–i46.

342. Maixnerova D. and Tesar V., “Emerging Role of Monoclonal Antibodies in the Treatment of IgA Nephropathy,” Expert Opinion on Biological Therapy 23 (2023): 419–427.

343. Mayer K. A., Budde K., Schatzl M., et al., “CD38 monoclonal Antibody felzartamab for Late Antibody‐mediated Rejection: A Phase II Drug Evaluation,” Expert Opinion on Investigational Drugs 34 (2025): 1–10.

344. Tang C., Chen P., Si F. L., et al., “Time‐Varying Proteinuria and Progression of IgA Nephropathy: A Cohort Study,” American Journal of Kidney Diseases 84 (2024): 170–178.

345. Johnson R. J., Hurtado A., Merszei J., Rodriguez‐Iturbe B., and Feng L., “Hypothesis: Dysregulation of Immunologic Balance Resulting From Hygiene and Socioeconomic Factors May Influence the Epidemiology and Cause of Glomerulonephritis Worldwide,” American Journal of Kidney Diseases 42 (2003): 575–581.

346. Rodrigues J. C., Haas M., and Reich H. N., “IgA Nephropathy,” Clinical Journal of the American Society of Nephrology 12 (2017): 677–686.

347. Duan Z. Y., Zhang C., Chen X. M., and Cai G. Y., “Blood and Urine Biomarkers of Disease Progression in IgA Nephropathy,” Biomarker Research 12 (2024): 72.

348. Schena F. P., Manno C., and Strippoli G., “Understanding Patient Needs and Predicting Outcomes in IgA Nephropathy Using Data Analytics and Artificial Intelligence: A Narrative Review,” Clinical Kidney Journal 16 (2023): ii55–ii61.

349. Zhao L., Peng L., Yang D., et al., “Immunostaining of Galactose‐deficient IgA1 by KM55 Is Not Specific for Immunoglobulin A Nephropathy,” Clinical Immunology 217 (2020): 108483.

350. Zhang X., Lv J., Liu P., et al., “Poly‐IgA Complexes and Disease Severity in IgA Nephropathy,” Clinical Journal of the American Society of Nephrology 16 (2021): 1652–1664.

351. Chen P., Yu G., Zhang X., et al., “Plasma Galactose‐Deficient IgA1 and C3 and CKD Progression in IgA Nephropathy,” Clinical Journal of the American Society of Nephrology 14 (2019): 1458–1465.

352. Wang Y. N., Zhou X. J., Chen P., et al., “Interaction Between GALNT12 and C1GALT1 Associates With Galactose‐Deficient IgA1 and IgA Nephropathy,” Journal of the American Society of Nephrology 32 (2021): 545–552.

353. Reily C., Rice T., Crossman D. K., and Rizk D. V., “Phosphatase Control of Cytokine‐mediated Overproduction of Galactose‐deficient IgA1, the Main Autoantigen in IgA Nephropathy,” Journal of Autoimmunity 132 (2022): 102883.

354. Suzuki H. and Novak J., “IgA Glycosylation and Immune Complex Formation in IgAN,” Seminars in immunopathology 43 (2021): 669–678.

Associated Data

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.