Targeting B cells in IgA nephropathy: from pathogenic insight to therapeutic horizon.

INTRODUCTION

Immunoglobulin A nephropathy (IgAN), first described by Jean Berger and Nicole Hinglais in 1968, remains the most common primary glomerulonephritis worldwide [ 1 ]. The estimated global incidence is ≈2.5 cases per 100 000 population [ 2 ]. Across 10 European countries, the age-adjusted annual incidence was 0.76 per 100 000 between 1990 and 2020 [ 3 ].

The hallmark of IgAN is the mesangial deposition of polymeric IgA1-containing immune complexes, which typically present clinically as haematuria and proteinuria. While supportive care, particularly renin–angiotensin–aldosterone system (RAAS) blockade, has been shown to slow disease progression, disease-modifying therapies have, until recently, remained elusive [ 4 ].

A paradigm shift is now under way, driven by refined insights into the role of dysregulated mucosal immunity, particularly the contribution of B cells and plasma cells, in the pathogenesis of IgAN. Immune perturbations in the mucosa-associated lymphoid tissue (MALT) result in an excess of galactose-deficient IgA1 (Gd-IgA1) entering the systemic circulation [ 5 ]. The discovery that the cytokines a proliferation-inducing ligand (APRIL) and B cell activating factor (BAFF) promote B cell survival and trafficking to systemic compartments has further clarified disease mechanisms and revealed new therapeutic targets [ 6 ].

Building on these foundational insights, recent pivotal phase 3 trials targeting mucosal and B cell pathways have begun to reshape the therapeutic landscape. The convergence of molecular understanding and clinical efficacy marks a transformative moment in IgAN management [ 7 ]. These developments are best contextualised through the lens of the updated four-hit model of IgAN pathogenesis.

PATHOGENESIS OF : THE FOUR-HIT MODEL REVISITED

A four-hit model is commonly employed to describe the pathogenesis of IgAN [ 8 ]. It outlines a sequential cascade of immune dysregulation culminating in glomerular injury. Hit 1 is an increase in the levels of Gd-IgA1 in the circulation [ 9 ]. Hit 2 is the presence of IgA and IgG antibodies that recognise and bind to the hinge region of Gd-IgA1 [ 10 ]. These interactions result in Hit 3, the amplification of circulating immune complex formation [ 11 ]. Hit 4 is the deposition of IgA immune complexes in the glomerular mesangium resulting in mesangial cell activation, with downstream effects including complement cascade engagement, pro-inflammatory cytokine release and fibrotic remodelling of the glomerulus [ 12 ].

Recent refinements to this model have emphasised the distinct roles of mucosal versus systemic immune compartments and a genetic predisposition to dysregulation of the gut-associated lymphoid tissue (GALT). These insights have provided a mechanistic rationale for B cell–targeted therapeutic strategies [ 13 ].

THE RATIONALE FOR TARGETING PLASMA CELLS AND B CELLS IN

Emerging evidence underscores the central role of plasma cells and B cells in the immunopathogenesis of IgAN. Dysregulated B cell maturation within the MALT is hypothesised to lead to the increase in circulating Gd-IgA1 observed in patients with IgAN, a key pathogenic driver of immune complex formation [ 14 ]. These B cells are supported by BAFF and APRIL, cytokines secreted by dendritic cells and mucosal epithelial cells that promote IgA class switching recombination and B cell survival and expansion [ 15 ].

Evidence suggests that a proportion of mucosal B cells may mis-home systemically, particularly to the bone marrow, where they have been hypothesised to generate Gd-IgA1, which enters the circulation directly. Roberts et al. [ 16 ] highlighted this compartmental shift, suggesting that IgAN is predominantly driven by both mucosal B cell responses and by long-lived, tissue-resident plasma cells in the kidney and bone marrow.

This mucosal hypothesis is clinically supported by the NEFIGAN phase 2b trial ( NCT01738035 ), in which nefecon (a targeted-release budesonide), designed to act on the GALT of the distal ileum, significantly reduced proteinuria. The observed reduction in the urine protein:creatinine ratio (UPCR) versus placebo supports the notion that modulating GALT-derived immune activity upstream of IgA immune complex deposition can improve kidney outcomes, validating gut-associated B cells as therapeutic targets [ 17 ].

These findings were independently confirmed in the phase 3 NefIgArd trial ( NCT03643965 ), which showed both a significant reduction in proteinuria and a benefit in estimated glomerular filtration rate (eGFR) preservation after 9 months of nefecon treatment. NefIgArd represents the first phase 3 trial to demonstrate significant improvement in both UPCR and eGFR, reinforcing the disease-modifying potential of targeting mucosal B cell activation and plasma cells and the gut–kidney immune axis in IgAN [ 18 , 19 ].

Mechanistically, these clinical benefits are further supported by biomarker analyses from the NEFIGAN and NefIgArd trials, which showed that nefecon significantly reduced serum levels of FABP2 (a marker of gut mucosal damage), systemic IgA antibodies to dietary antigens (gliadin and casein), BAFF, APRIL, secretory IgA, Gd-IgA1 and IgA-containing immune complexes [ 20 ].

These changes indicate that nefecon acts upstream of glomerular injury by suppressing dysregulated GALT-driven B cell and plasma cell activity, providing compelling biological and clinical validation for its role as a disease-modifying agent in IgAN [ 20 ]. Nefecon was the first drug to gain accelerated and then full approval from the US Food and Drug Administration and European Medicines Agency for the treatment of IgAN based on the effects on proteinuria and eGFR.

THERAPEUTIC CLASSES IN LATE-STAGE CLINICAL DEVELOPMENT

Over the past 5 years there has been a rapid expansion in therapeutic strategies aimed at addressing dysregulated B cell activity in IgAN. These novel approaches span several mechanistic classes, each with distinct immunologic targets and clinical potential (Figure 1 ).

BAFF/APRIL pathway inhibitors

One of the most intensively studied areas involves inhibition of the BAFF and/or APRIL pathway. BAFF and APRIL are members of the tumour necrosis factor (TNF) superfamily that play crucial roles in B cell maturation, survival and plasma cell differentiation. BAFF binds three receptors: BAFF receptor (BAFF-R), transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA).

APRIL binds to TACI, which is expressed on activated B cells and plasmablasts, and to BCMA, which is predominantly expressed on plasma cells, supporting their long-term survival. BAFF-R is primarily expressed on mature naïve and memory B cells, supporting their survival and maturation. Together, this receptor network promotes class switching, IgA production and maintenance of both short-lived and long-lived plasma cells [ 14 ]. In IgAN, multiple genome-wide association studies have implicated dysregulation of the BAFF/APRIL–TACI/BCMA/BAFF-R signalling axis, identifying risk loci in TNFSF13 (APRIL) and TNFRSF13B (TACI) [ 21 ]. Elevated APRIL levels, and in several cohorts elevated BAFF levels, have been observed in patients and correlate with disease severity and progression. BAFF-overexpressing mice develop commensal flora–dependent IgAN, supporting a causal role [ 22 ]. These pathophysiological insights have prompted the development and clinical evaluation of multiple therapies targeting the BAFF/APRIL pathway in IgAN (Table 1 ).

Sibeprenlimab is a fully humanised IgG1 monoclonal antibody targeting APRIL, thereby inhibiting plasmablast differentiation and IgA production. In the phase 2 ENVISION trial ( NCT04287985 ; n = 83), sibeprenlimab achieved a dose-dependent reduction in proteinuria, with the highest dose (600 mg monthly) resulting in a 48% reduction versus placebo at week 24. Serum IgG levels decreased by ≈21% but remained within the normal range, with mild upper respiratory tract infections as the most frequent adverse event. An interim analysis of the ongoing phase 3 VISIONARY trial ( NCT05248646 ) presented at the 2025 European Renal Association Congress confirmed significant reductions in proteinuria at week 36 without new safety signals [ 23 ].

Zigakibart (BION-1301) is also an anti-APRIL monoclonal antibody. In an open-label phase 1/2 study, zigakibart achieved a 55% mean reduction in proteinuria at week 36, with sustained reductions out to 100 weeks and stable eGFR. No serious infections were reported. Based on these results, a global phase 3 trial is currently ongoing to assess long-term efficacy and safety [ 24 ].

Atacicept is a recombinant fusion protein comprising the extracellular domain of TACI linked to the Fc portion of human IgG1. By binding and neutralising both BAFF and APRIL, atacicept prevents their interaction with TACI, BCMA and BAFF-R, reducing B cell survival, maturation and differentiation into plasma cells. This leads to decreased production of immunoglobulins, including Gd-IgA1. In the ORIGIN phase 2 study ( NCT04716231 ), atacicept reduced proteinuria by 45% at week 24 with stable eGFR over 36 weeks. Serum IgG decreased by ≈18% without clinically significant infections [ 25 ]. In the 96-week phase 2b open-label extension, atacicept achieved sustained reductions in Gd-IgA1 (≈66%), UPCR (≈52%) and haematuria (in 75% of participants with baseline haematuria), with eGFR remaining stable (annualized slope −0.6 ml/min/1.73 m 2 /year) and no new safety concerns [ 26 ]. A global phase 3 trial is ongoing to confirm these findings in a larger population.

Telitacicept is another recombinant TACI–IgG fusion protein targeting both BAFF and APRIL. In a randomised, double-blind phase 2 trial conducted in China, telitacicept reduced proteinuria by 42% at week 24, with sustained reductions through 48 weeks in extension cohorts. Mild, reversible thrombocytopenia was observed in ≈5% of patients, with no severe infections. Currently a phase 3 trial is ongoing in China to evaluate long-term efficacy and safety [ 27 ].

Povetacicept (ALPN-303) is a next-generation fusion protein based on an engineered TACI domain designed for enhanced dual inhibition of BAFF and APRIL. In the RUBY-3 trial (phase 1b/2a, open label, multicohort; NCT05732402 ), patients with IgAN received 80 mg or 240 mg subcutaneously every 4 weeks. At 36 weeks, the 80-mg dose achieved a reduction of ≈64% in UPCR and ≈69% in Gd-IgA1; haematuria resolved in all with baseline haematuria and renal function remained stable. Updated data demonstrated reductions of >60% in proteinuria, haematuria resolution and stable eGFR [ 28 ]. The ( NCT06564142 ) trial is a global, randomized, placebo-controlled phase 3 study in IgAN (≈480 patients), investigating povetacicept 80 mg subcutaneously every 4 weeks versus placebo added to standard of care [ 29 ].

Notably, data from the sibeprenlimab and atacicept phase 2 trials suggest that proteinuria returns to baseline following treatment discontinuation, indicating a pharmacodynamic effect tied to sustained pathway inhibition [ 30 , 31 ].

CD38-targeting monoclonal antibodies

Another emerging strategy in IgAN immunotherapy involves CD38-targeting monoclonal antibodies, which deplete long-lived plasma cells, a likely source of sustained Gd-IgA1 and IgA/IgG anti-Gd-IgA1 antibody production [ 32 ]. These therapies aim to achieve deeper and more durable suppression of antibody production and are currently being evaluated in phase 3 clinical trials (Table 2 ).

Two investigational agents are in development:

Felzartamab, a fully human IgG1 monoclonal antibody, was evaluated in the randomised, double-blind, placebo-controlled IGNAZ phase 2a trial ( NCT05065970 ). Interim and recent results indicate that intravenous felzartamab administered in a nine-dose regimen led to a rapid, sustained reduction in proteinuria, up to 44% at 9 months, maintained through a 24-month follow-up, with serum IgA reductions lasting up to 19 months post-treatment, with IgG levels recovering by 6–9 months post-therapy. Felzartamab was generally well tolerated, with the most common adverse events being grade 1–2 infusion-related reactions; infection rates were similar to those of placebo and no severe infections were reported [ 33 ].

Mezagitamab, another fully humanised anti-CD38 IgG1 monoclonal antibody, is administered subcutaneously and acts via antibody-dependent cellular cytotoxicity [ 34 , 35 ]. At the 2025 ERA Congress, 48-week data from the open-label phase 1b study in IgAN showed that mezagitamab reduced serum IgA by 52.4%, Gd-IgA1 by 57.8% and proteinuria by 54.1%, with eGFR remaining stable. The treatment was well tolerated, with no serious infections, opportunistic infections or discontinuations due to adverse events [ 36 ].

By focusing on CD38, which is selectively upregulated on mature plasma cells, these therapies aim to spare naïve and memory B cells, offering a more targeted depletion of the disease-driving effector cell pool.

CD19- and CD20-targeting monoclonal antibodies

Monoclonal antibodies targeting CD20 are commonly used to deplete pathogenic B cell subsets in autoimmune diseases [ 37 ]. In IgAN, CD20 depletion failed to show efficacy, possibly reflecting differences in target coverage and tissue accessibility.

Rituximab, a chimeric anti-CD20 monoclonal antibody, was evaluated in a US multicentre, randomised controlled trial of 34 adults with biopsy-proven IgAN (proteinuria >1 g/day, eGFR <90 ml/min/1.73 m 2 ) [ 38 ]. Despite effective peripheral B cell depletion, rituximab failed to reduce proteinuria or improve eGFR over 1 year compared with placebo. Levels of Gd-IgA1 and anti-Gd-IgA1 antibodies remained unchanged. These results were attributed to rituximab’s limited tissue penetration and inability to deplete mucosal CD20-negative plasmablasts, which are hypothesised to be the key producers of pathogenic Gd-IgA1 [ 39 , 40 ].

In contrast, next-generation anti-CD20 and now anti-CD19 monoclonal antibodies offer broader depletion of the B cell lineage, including plasmablasts. While data in IgAN are currently lacking, this pharmacodynamic profile supports their evaluation in IgAN, where broader B cell lineage targeting (including mucosal and systemic compartments) may be advantageous [ 41 , 42 ].

Targeting intracellular B cell pathways

Targeting intracellular signalling cascades in B cells represents an alternative strategy for disrupting the production of pathogenic IgA1 and downstream inflammatory responses in IgAN. This includes inhibition of kinases involved in B cell receptor (BCR) signalling, such as spleen tyrosine kinase (SYK) and Bruton’s tyrosine kinase (BTK), as well as proteasome pathways required for plasma cell survival, such as those targeted by bortezomib.

Fostamatinib, an oral SYK inhibitor, has been evaluated in a randomized, placebo-controlled phase 2 trial in 76 patients with IgAN receiving optimized RAAS blockade [ 43 , 44 ]. At 24 weeks, fostamatinib did not significantly reduce proteinuria in the overall population; however, in a pre-specified subgroup with baseline proteinuria >1 g/day, a dose-dependent trend was observed, with reductions of ≈27% (100 mg twice daily) and 36% (150 mg twice daily) versus 14% with placebo [ 45 ]. Renal function remained stable and repeat biopsies in a subset showed reduced SYK staining per glomerulus, consistent with target engagement [ 46 ]. The drug was generally well tolerated, with common adverse events including diarrhoea, hypertension and elevated liver enzymes [ 44 , 46 ].

Several selective BTK inhibitors have entered early-stage trials for autoimmune diseases, targeting downstream signalling of the BCR. Covalent inhibitors such as evobrutinib and tolebrutinib (both in phase 3 trials) and the reversible, non-covalent inhibitor fenebrutinib have demonstrated promising pharmacodynamic effects across multiple autoimmune settings [ 47 ]. In relapsing multiple sclerosis, fenebrutinib significantly reduced new T1 gadolinium-enhancing lesions and maintained a favourable safety profile through 96 weeks [ 48 ]. Early BTK inhibitors like spebrutinib (NCT04599917) were evaluated in trials for autoimmune conditions such as rheumatoid arthritis, demonstrating the potential of this class of drugs. However, its clinical development was ultimately discontinued.

In addition to tyrosine kinase inhibition, proteasome blockade offers a distinct intracellular pathway for depleting long-lived plasma cells. The proteasome inhibitor bortezomib demonstrated modest efficacy, measured by reductions in proteinuria in small IgAN cohorts, but with less-specific targeting and a less favourable safety profile [ 49 , 50 ]. By promoting plasma cell apoptosis, bortezomib reduces Gd-IgA1 and circulating antibody levels, although its toxicity profile limits widespread use. Nonetheless, bortezomib provides an important proof of concept that intracellular targeting of plasma cell survival pathways can be effective in modulating IgAN pathogenesis. Together, these intracellular approaches (SYK/BTK inhibition and proteasome disruption) expand the therapeutic toolbox beyond surface-targeted antibodies, offering strategies that may be useful in resistant disease characterised by entrenched humoral activity.

Cellular and bispecific platforms

Emerging cellular and bispecific technologies, including adoptive anti-BCMA chimeric antigen receptor T (CAR-T) cell therapies, bispecific T cell engagers (e.g. teclistamab) and antibody–drug conjugates, represent the translational frontier between oncology and autoimmunity [ 51 ]. These platforms offer the potential for deep, durable B cell depletion or functional reset, raising the possibility of ‘one-shot’ therapies for selected patients with immune-mediated kidney disease. However, safety in the transplant-eligible chronic kidney disease (CKD) population remains a key concern [ 52 , 53 ].

Encouraging data from CD19-directed CAR-T cell studies in systemic lupus erythematosus (SLE) and other autoimmune diseases have demonstrated robust efficacy with low rates of cytokine release syndrome and minimal neurotoxicity. In patients with pre-existing CKD, these therapies have caused only mild and reversible kidney injury, supporting cautious optimism for their future evaluation in IgAN [ 54 ].

B CELLS IN FIBROSIS: RATIONALE FOR B CELL–TARGETED THERAPIES

As IgAN progresses, chronic tissue remodelling and fibrosis become dominant pathological features. Evidence increasingly implicates B cells not just in antibody production, but as direct contributors to fibrotic damage via cytokine release and immune cell cross-talk:

In chronic allograft damage models, intrarenal B cells formed tertiary lymphoid structures and secreted GRO-α (CXCL1), RANTES (CCL5), interleukon-6 and monocyte chemoattractant protein-1 (MCP-1; CCL2). These factors promoted tubular loss, interstitial fibrosis and immune infiltration. B cell depletion (anti-CD20) improved outcomes, especially when administered post-transplant [ 55 ].

In IgG4-related disease, patient-derived CD19 + B cells and plasmablasts promoted fibroblast-driven collagen production by secreting platelet-derived growth factor subunit B and lysyl oxidase like 2 and induced fibroblast release of CCL-4, CCL-5 and CCL-11. These data show plasmablasts possess intrinsic pro-fibrotic properties [ 56 ].

In systemic sclerosis (SSc), B cells drove profibrotic macrophage differentiation. B cell depletion (anti-CD20) significantly reduced skin and lung fibrosis in a bleomycin mouse model. The extent of macrophage skewing by B cells correlated with fibrosis severity in SSc patients [ 57 ].

In kidney-specific fibrosis models using unilateral ureteral obstruction, B cell–deficient and anti-CD20-treated mice showed reduced macrophage infiltration and tubulointerstitial fibrosis. B cells were shown to be a key source of CCL2 (MCP-1), driving monocyte recruitment and TNF-α/vascular cell adhesion molecule-1 upregulation. Blocking CCL2 reduced fibrosis [ 58 ].

These findings suggest B cells contribute to fibrosis through multiple mechanisms: directly activating fibroblasts and promoting extracellular matrix deposition, inducing pro-fibrotic macrophage phenotypes and amplifying inflammatory chemokine cascades. The therapeutic implication is that B cell–targeted approaches may, in addition to targeting immunoglobulin production, disrupt intrarenal survival niches and chronic fibrotic cascades, thereby reducing kidney disease progression independent of suppressing pathogenic antibody production.

SAFETY AND RISK MITIGATION IN CKD

B cell–directed therapies require careful safety assessment, particularly in patients with CKD, where immune modulation may impact immunoglobulin levels, infection risk and vaccine responses.

APRIL and dual BAFF/APRIL inhibitors (e.g. sibeprenlimab, zigakibart, atacicept, telitacicept, povetacicept) are associated with a class-wide effect of serum IgG reduction (≈15–30%), however, most patients maintain IgG levels above the lower limit of normal. No opportunistic infections or vaccine failures have been reported to date in IgAN trials, although proteinuria rebound has occurred following treatment discontinuation in both the sibeprenlimab and atacicept phase 2 studies, suggesting a need for sustained therapy, and longer-term safety remains unclear [ 59 ].

This profile is consistent with broader experience from belimumab, a BAFF inhibitor used in SLE, which shows mild reductions in IgG and preserved vaccine responses to pneumococcal and influenza vaccines, suggesting that BAFF blockade modulates rather than fully suppresses humoral immunity.

CD38-targeting agents such as felzartamab and mezagitamab deplete long-lived plasma cells. In the two IgAN trials to date, no serious infections have been reported, however, the theoretical risk of hypogammaglobulinaemia and reduced vaccine responsiveness remains, especially with repeated or high-dose regimens. In multiple myeloma, daratumumab has been associated with diminished vaccine responsiveness, and in tuberculosis (TB)-endemic regions, latent TB and viral reactivation (e.g. HBV, CMV) are additional concerns. While dosing is lower in IgAN and no cases of TB or viral reactivation have been reported, long-term monitoring remains prudent.

We are entering a new era of therapeutic manipulation of B cells and plasma cells in nephrology and at the moment a cautious approach is warranted as these drugs enter clinical practice. There are minimal long-term data and therefore we must base any recommendations on the criteria used in the respective clinical trials. Therefore none of these B cell–directed therapies should be used in pregnancy or during lactation, and women of child-bearing potential should be advised to use contraception and not attempt to conceive while on these therapies. In terms of vaccinations, all patients should be advised to be up to date with their nationally recommended vaccinations prior to commencing a B cell–directed agent. Consistent with the entry criteria for the respective current trials, patients should be screened for hepatitis B and C and latent TB prior to starting treatment and specific treatment should be instituted a minimum of 6 weeks prior to commencing a B cell–directed therapy. In light of the potential for immunoglobulin suppression, all patients should have immunoglobulin levels checked prior to starting treatment and if total IgG levels are <3 g/l, B cell– and plasma cell–directed therapies should be avoided.

In terms of on-treatment monitoring, little is known about the optimal process. However, as a minimum, immunoglobin levels should be monitored every 3 months, as in the clinical trials, and treatment stopped if the IgG level falls below 3 g/l.

As more information emerges from the clinical trials it will become clearer what the minimal requirements will be in terms of pre-dosing evaluation and monitoring requirements when on a B cell– or plasma cell–directed therapy.

SPECIAL POPULATIONS AND COMPLEX CLINICAL SCENARIOS

Application of B cell–targeted therapies in IgAN must account for population-specific challenges that influence both efficacy and safety. Growth, immune responsiveness, comorbid therapies and reproductive status all shape the risk–benefit calculus across a patient’s lifetime. Given the likelihood that these agents will require long-term or even lifelong administration, their cumulative safety burden must be considered at each life stage.

In children, the impact of early immunomodulatory intervention must be weighed against concerns such as linear growth, pubertal development and vaccine responsiveness. A phase 1b study of the APRIL-targeting monoclonal antibody zigakibart (BION-1301) is under way in adolescents ages 12–17 years to assess safety, pharmacokinetics and optimal dosing in this age group [ 60 ]. Furthermore, the PIONEER trial ( NCT06983028 ), evaluating atacicept’s safety and efficacy in multiple autoimmune glomerular diseases, is recruiting IgAN patients ≥10 years of age, potentially paving the way for such therapies to be utilised in paediatric cohorts [ 61 ].

The PIONEER trial is also evaluating the safety and efficacy of atacicept in adult post-transplant IgAN recurrence, underscoring the broader exploration of B cell–targeted therapies across special populations. Additionally, CD38-targeting plasma cell–directed agents, such as daratumumab, have shown promise in the management of antibody-mediated rejection, supporting their potential safety and utility in recurrent IgAN [ 62 ].

During pregnancy, the transplacental transfer of IgG-based biologics (including BAFF/APRIL inhibitors) primarily occurs during the second and third trimesters. Although belimumab, a BAFF inhibitor used in SLE, has not shown teratogenicity in pregnancy registries, controlled data in IgAN are lacking. Kidney Disease: Improving Global Outcomes guidelines recommend, due to uncertain foetal safety, achieving stable disease control prior to conception and discontinuing immunomodulatory biologics during pregnancy and lactation [ 63 ].

FUTURE DIRECTIONS: DURABLE DISEASE REMISSION AND LIFELONG SUPPRESSION OF -DRIVEN NEPHRON LOSS

Several next-generation strategies are under investigation, aiming to noy only slow the rate of loss of kidney function in IgAN but to move closer to returning the loss of kidney function to the physiologic state. Among these strategies, B cell–directed therapies offer an exciting opportunity to achieve deeper and more sustained disease control [ 64 ]. There is also growing interest in time-limited induction regimens, spanning 6–12 months, combining B cell– and complement–directed approaches that might deliver rapid remission, followed by low-dose maintenance therapy with continued B cell–directed therapies [ 65 ].

An emerging but less-explored avenue involves the gut–microbiota–IgA axis, where modulation through prebiotics or mucosal-targeted vaccines may offer a novel adjunct to systemic immune therapies [ 66 , 67 ].

Looking further ahead, the field is beginning to consider more transformative approaches. Engineered strategies such as targeted B cell depletion, CAR-T cell therapies or genome-edited immune resetting hold the potential to reshape the disease course entirely, raising the possibility of curative outcomes for selected patients in the future [ 68 , 69 ].

Complement activation, particularly via the alternative and lectin pathways, is increasingly recognised as a central driver of glomerular injury in IgAN [ 70 ]. Histologic deposition of C3, C4d and mannose-binding lectin predicts faster progression and worse outcomes. Several agents targeting complement components (e.g. iptacopan, sefaxersen, ravulizumab) are now in late-phase trials and may offer complementary benefit alongside B cell therapies, with iptacopan now approved on the accelerated pathway in the USA for the treatment of IgAN at high risk of progression [ 71 , 72 ].

CONCLUSION

B cell–targeted therapies offer an immunologically grounded strategy for IgAN. With several agents demonstrating efficacy in reducing proteinuria and preserving kidney function, this therapeutic class is offering a new approach to the treatment landscape in IgAN. Future integration of biomarkers, multi-omic profiling and patient stratification may enable more personalised and durable disease control.

Contributor Information

Lydia Roberts, Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

Jonathan Barratt, Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

ACKNOWLEDGEMENTS

The topic of this review was also presented during the 62nd Congress of the European Renal Association, Vienna, Austria, 4–7 June 2025.

FUNDING

This paper is part of a Supplement that was financially supported by the ERA. The topic of this paper was also presented at the 62nd ERA Congress, Vienna & Virtual, June 4–7, 2025.

DATA AVAILABILITY STATEMENT

No new data were generated or analysed.

CONFLICT OF INTEREST STATEMENT

L.R. reports no conflicts of interest. J.B. reports consultancies with Otsuka, Novartis, Vera Therapeutics, Vertex, Takeda, Biogen, Calliditas, Alexion, Roche and research funding from Novartis, Otsuka, Calliditas, Alexion, Vertex, Vera Therapeutics.

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Associated Data

Data Availability Statement

No new data were generated or analysed.