1. Introduction
IgA nephropathy (IgAN) is the most common primary glomerulonephritis globally [ 1 ]. Approximately 30–40% of patients with IgAN progress to end-stage kidney disease (ESKD) within 20 years of the estimated time of disease onset [ 2 , 3 ]. Furthermore, the development of IgAN can reduce life expectancy by approximately 10 years [ 2 ]. Disease-specific treatments for IgAN are yet to be established. One reason is that the pathogenesis of IgAN remains unclear. Interactions between genetic predisposition and environmental factors determine susceptibility to IgAN [ 4 ]. Another reason is that the clinical and pathological manifestations of IgAN exhibit considerable heterogeneity among individuals and ethnicities [ 5 ]. Consequently, treatment modalities may vary among geographical regions. A tonsillectomy is considered an option in some regions, particularly in Japan, based on recent clinical studies. Some studies have reported that a tonsillectomy, either alone or in combination with steroid therapy, decreased hematuria and proteinuria while attenuating the progression of renal dysfunction [ 6 , 7 ]. Current guidelines recommend non-specific conservative management, including salt reduction, smoking cessation, blood pressure control, and the maximum tolerated dose of renin–angiotensin–aldosterone system inhibitors [ 8 ], which potentially worsen kidney function. Despite these interventions, there remains a notable residual risk of disease progression. The safety and efficacy of systemic corticosteroids for IgAN have been previously investigated multiple times [ 9 , 10 ]. However, there is currently insufficient evidence to support the recommendation of corticosteroids, owing to the persistent uncertainty about their benefits and risks. Therefore, optimal therapeutic strategies targeting the pathogenic mechanisms underlying IgAN to halt disease progression have been developed in recent years.
Our understanding of the underlying complex autoimmune mechanisms has advanced in recent years. Aberrant O–glycosylated IgA1 (commonly termed galactose-deficient [Gd]-IgA1) and immune complexes formed by glycan-specific autoantibodies are crucial for the development of IgAN ( Figure 1 ) [ 4 , 11 ]. Most human IgA is produced by plasma cells residing in mucosal-associated lymphoid tissues (MALTs). Two major regions are involved in IgAN, including gut-associated lymphoid tissues (GALTs) and nasopharynx-associated lymphoid tissue (NALT). Mucosae and lymphoid organs are regarded as sites of Gd-IgA1 production. Antigen-experienced IgA+ B cells leave MALTs and migrate to effector sites through the lymphatic system and circulation ( Figure 1 ). It has been hypothesized that the dysregulated expression of homing receptors may redirect certain mucosa-derived B cells/plasma cells to the bone marrow instead of their intended mucosal destination in patients with IgAN [ 12 , 13 ] ( Figure 1 ). Plasma cells with sustained production of IgA antibodies, derived from the mucosa or bone marrow, may produce and release Gd-IgA1 into circulation. Gd-IgA1-containing immune complexes are considered nephritogenic. Their deposition of immune complexes on mesangial cells stimulates the production of proinflammatory cytokines, resulting in the infiltration of inflammatory cells into the glomeruli, the proliferation of mesangial cells, and an uncontrolled inflammatory cascade via the activation of the complement pathway. Complement component 3 (C3) co-localizes with IgA in more than 90% of biopsies with IgAN, indicating complement activation. Complement activation may occur predominantly through the alternative and/or lectin pathways and serves as a central mediator of glomerular inflammation and damage [ 14 ]. These responses contribute to inflammation and scarring. Therefore, it has been hypothesized that Gd-IgA1 and Gd-IgA1-containing immune complexes are potential therapeutic targets. A reduction in the levels of these key molecules can potentially attenuate disease activity and improve kidney prognosis.
The tumor necrosis factor (TNF) family proliferation-inducing ligand (APRIL, also known as TNFSF13) plays a crucial role in regulating B cell activation, survival of long-lived plasma cells, and immunoglobulin isotype class switching [ 15 , 16 , 17 ]. This regulation is essential for maintaining effective immune responses and ensuring proper functioning of the immune system. B-cell activating factor of the TNF family (BAFF), which is closely associated with APRIL, acts as a pivotal survival factor for transitional and mature B cells. APRIL plays a pivotal role in the pathogenesis of IgAN, other autoimmune diseases such as lupus erythematosus and Sjögren’s syndrome [ 18 ], and some mature B cell neoplasms such as chronic lymphocytic leukemia and non-Hodgkin lymphoma [ 19 , 20 ]. BAFF is also thought to be involved in the pathogenesis of IgAN. As discussed in Section 3 on the role of APRIL in IgAN, emerging evidence indicates that APRIL is involved in the production of Gd-IgA1. Given the involvement of APRIL in the pathogenesis of IgAN, it is hypothesized that blocking the binding of APRIL to its receptors would potentially be a promising treatment option for IgAN that prevents downstream events such as the production of Gd-IgA1 and the subsequently formed Gd-IgA1 containing immune complexes, ultimately leading to the prevention of kidney damage and loss of function. Recent clinical trials have demonstrated the efficacy and safety of anti-APRIL and dual APRIL/BAFF treatments in patients with IgAN. Here, we review the physiological function of APRIL, the current knowledge on the role of APRIL in the pathogenesis of IgAN, and therapeutic strategies focusing on APRIL-targeting agents for IgAN.
2. Biology and Physiological Functions of APRIL
APRIL, which belongs to the TNF superfamily of ligands, is a type two transmembrane protein involved in late-stage B cell differentiation, generation and maintenance of antibody-secreting plasma cells, and IgA class switching [ 18 ]. Myeloid cells, including macrophages, dendritic cells, and blood monocytes, as well as polymorphonuclear cells, such as neutrophils, eosinophils, and mucosal epithelial cells, are responsible for APRIL production [ 21 , 22 , 23 , 24 ].
A related cytokine, B cell-activating factor from the TNF family (BAFF, also known as BLyS or TNFSF13B), has been identified as a crucial survival factor for B cells and is essential for their maturation. BAFF supports the survival of both transitional and mature B cells, plays a critical role in their maturation into immunoglobulin-producing cells, and contributes to their longevity. It has also been extensively studied, particularly in the field of autoimmunity. BAFF shares 48% homology with APRIL. APRIL and BAFF are produced as type II transmembrane proteins and are cleaved at the furin protease site, resulting in their secretion in a soluble form [ 25 ]. A recent study reported the expression of APRIL-δ isoforms lacking the consensus motif for the furin convertase, which remains membrane-bound on leukemia cell precursors [ 26 ]. BAFF exists in a membrane-bound state; however, its processed soluble form is essential for maintaining B cell homeostasis [ 27 ]. The homology between APRIL and BAFF also results in the sharing of these two receptors; however, BAFF possesses a unique receptor known as the BAFF receptor (BAFF-R; also known as TNFRSF13C) ( Figure 2 ). APRIL and BAFF have two common receptors: the transmembrane activator and CAML interactor (TACI; also referred to as TNFRSF13B) and the B cell maturation antigen (BCMA; also known as TNFRSF17). APRIL exhibits a robust binding affinity to BCMA and moderate affinity to TACI, whereas BAFF exhibits a weak binding to BCMA and strong affinity to TACI [ 28 ]. Furthermore, BAFF has a high binding affinity for BAFF-R [ 28 ]. The three primary receptors, BAFF-R, TACI, and BCMA, exhibit unique expression patterns during the various stages of B cell development, reflecting their distinct functions. It has been hypothesized that APRIL and BAFF engage with their respective receptors through distinct mechanisms characterized by varying affinities [ 29 ]. Because of these subtle differences, targeting APRIL, BAFF, or both may be a therapeutic approach for other diseases caused by immune dysregulation. APRIL plays a pivotal role in mediating class switch recombination to IgA in T-cell-independent responses, primarily through its interaction with TACI ( Table 1 ) [ 30 ]. In vitro experiments have demonstrated that recombinant APRIL can also enhance the T-cell-dependent switch [ 31 ]. There are two well-defined antibody-producing cells that represent the late differentiation stages of B lymphocytes: plasmablasts, generated within secondary lymphoid organs, and fully differentiated plasma cells, originating from plasmablasts. In a steady state, plasma cells migrate and become established in the bone marrow. Similar to autoimmune responses, this response can also be elicited in the presence of inflammation. In contrast to plasmablasts, plasma cells are characterized by their significant longevity. Myeloid-derived APRIL further supports plasma cell survival by promoting the formation of survival niches within the bone marrow and mucosal compartments, thereby establishing reservoirs for long-lived antibody-secreting cells. Plasma cell survival is primarily mediated by BCMA and TACI. While all plasma cells express BCMA, BCMA on these cells does not respond to BAFF stimulation [ 32 ]. BAFF-R exhibits an expression pattern closely resembling that of CD20, including the complete loss of expression during the plasma cell differentiation stage. BAFF-R is not expressed on B cell precursors within the bone marrow. However, it is expressed on immature B cells following the acquisition of a functional B cell receptor (BCR) [ 33 ]. BAFF-R is indispensable for the survival and maturation of immature B cells [ 34 ]. BAFF-R is also present in human mesangial cells and tubular epithelial cells (TECs) [ 35 , 36 ]. BAFF induces increased expression of BAFF-R in human tubular epithelial cells (TECs), possibly resulting in an autocrine loop [ 37 ]. TACI interacts with APRIL and heparan sulfate proteoglycans (HSPG) to exert its physiological effects [ 38 ]. BCMA expression is limited to plasmablasts and plasma cells [ 39 ], where it supports the survival of long-lived plasma cells.
3. The Role of APRIL in IgAN
Basic research, including biochemical, genetic, and physiological investigations, has suggested a potential role for APRIL in pathogenesis of IgAN. Genome-wide association studies (GWASs) identified a risk allele at the 17p23 TNFSF13 locus, which encodes APRIL [ 40 ]. Furthermore, a recent GWAS revealed that TACI, located on chromosome 17p11, is a novel susceptibility locus in addition to TNFSF13 [ 41 ]. A high serum level of APRIL was noted, which correlated with the urine protein/creatinine ratio (UPCR) and was observed to affect the prognosis of kidney function in patients with IgAN [ 42 , 43 ]. However, the organ and cellular origins of APRIL, the mechanisms underlying its overexpression, and its role in the pathogenesis of IgAN remain unknown. We have previously demonstrated that APRIL is overexpressed in tonsils, especially in germinal center (GC) B cells [ 44 ]. We also found that these GC B cells express not only the common cleavable APRILα mRNA but also the membrane-bound APRIL-δ/ζ mRNAs, which are less frequently expressed and not cleavable due to the lack of furin cleavage sites. APRIL-δ has also been identified as a novel APRIL isoform in patients with B cell precursor acute lymphoblastic leukemia [ 26 , 43 ]. Studies have demonstrated that mature B cell neoplasms, including chronic lymphocytic leukemia and follicular lymphoma, and B cells from patients with autoimmune diseases, such as systemic lupus erythematosus, generate APRIL [ 45 , 46 , 47 ]. This uncleavable membrane-bound variant of APRIL may persist on the B cell membrane for an extended period and enhance the synthesis of Gd IgA1, which is further accelerated by an excess of the soluble form of APRIL. Moreover, aberrant APRIL expression in tonsillar GC was correlated with clinical severity, and the patients exhibiting an APRIL overexpression in their tonsillar GC responded favorably to a tonsillectomy, which was accompanied by concurrent reductions in their serum levels of Gd-IgA1. We have also demonstrated that the TLR9 ligands CpG-oligonucleotides (CpG-ODN) increase gene expression and serum levels of APRIL in grouped ddY mice, which spontaneously develop IgAN, and that serum levels of APRIL are associated with those of Gd-IgA1 in these mice [ 48 ]. Moreover, in vitro experiments using human IgA1-secreting cell lines have shown that the knockdown of APRIL siRNA completely inhibits the overproduction of Gd-IgA1 [ 48 ]. The treatment of grouped ddY mice with an anti-APRIL antibody led to a reduction in IgA, aberrantly galactosylated IgA, and immune complexes in the serum, in addition to a reduction in proteinuria and markedly reduced kidney deposits of IgA, IgG, and C3, highlighting the potential therapeutic benefits of anti-APRIL agents for the treatment of IgAN [ 49 ]. However, to the best of our knowledge, no study has elucidated the role of APRIL in the direct modulation of IgA glycosylation. RNA sequencing and quantitative polymerase chain reaction (PCR) both showed that recombinant human TNFSF13 did not modulate the expression of glycosyltransferase enzymes in vitro using human B cells [ 50 ]. However, excess APRIL expression may contribute to a relative increase in the secretion of Gd-IgA1 by prolonging B cell survival [ 50 ].
Recently, the role of BAFF in IgAN has been discussed. Some studies reported elevated serum BAFF levels in patients with IgAN [ 42 , 43 , 51 ]. The serum levels of BAFF correlate with the severity of clinical data, such as the estimated glomerular filtration rate, serum creatinine levels, and histopathological findings of kidney biopsy, including the severity of tubular atrophy/interstitial fibrosis [ 51 ]. Furthermore, the stimulation of tonsillar mononuclear cells with CpG-ODNs resulted in the markedly higher production of IgA and BAFF in the patients with IgAN than in those without IgAN [ 52 ]. Transgenic mice overexpressing BAFF exhibited increased levels of polymeric IgA and mesangial IgA deposits, although extreme elevations in serum IgA levels were observed in these mice [ 42 ]. This condition depends on commensal flora and involves the disruption of the normal barrier between the mucosal and peripheral compartments [ 42 ]. An imbalance in the interactions between the immune system and commensal organisms contributes to the development of autoimmune disorders such as inflammatory bowel disease [ 53 ]. However, the treatment of grouped ddY mice with anti-BAFF agents failed to improve IgA and C3 deposition, urinary albumin excretion, serum levels of IgA-IgG immune complexes, and serum levels of Gd-IgA1 [ 54 ].
Preclinical studies in nonhuman primates have shown that treatment with sibeprenlimab (VIS649), a humanized IgG2 monoclonal antibody directed against APRIL, results in a dose-dependent decrease in serum IgA levels by up to 70%, highlighting the critical role of APRIL in regulating IgA production [ 49 ]. Treatment with belimumab, a monoclonal antibody targeting soluble BAFF, resulted in a modest 16% reduction in serum IgA levels, implying a restricted impact of BAFF on IgA production [ 55 ].
4. Current and Perspective Therapeutic Strategies Focusing on APRIL-Targeted Therapy
4.1. Systemic Corticosteroid Therapy and Targeting Gut-Associated Lymphoid Tissues (GALTs)
Clinical trials on the use of systemic corticosteroids for IgAN have been conducted over the years; however, their efficacy and safety remain controversial. However, the exact mechanism of action of corticosteroids in IgAN is not fully understood. Systemic corticosteroids have been thought to suppress the production of Gd-IgA1 and Gd-IgA1-containing immune complexes. However, the absence of a reduction in Gd-IgA1-positive plasmablasts/plasma cells in patients with IgAN treated with prednisone indicates that systemic corticosteroids may not effectively suppress Gd-IgA1 production. The efficacy and safety of systemic corticosteroids for the treatment of IgAN have shown variable results in multiple randomized controlled trials (RCTs). Two RCTs, Supportive Versus Immunosuppressive Therapy of Progressive IgA Nephropathy (STOP-IgAN) and Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING), which included a run-in period to optimize supportive care, did not demonstrate efficacy with complete safety [ 56 , 57 ]. The STOP-IgAN study did not show a significant improvement in the rate of estimated glomerular filtration rate (eGFR) decline with systemic corticosteroid administration in patients with IgAN, proteinuria above 0.75 g/day, and an eGFR greater than 60 mL/min/1.73 m 2 [ 56 ]. In the TESTING trial, oral methylprednisolone was compared with placebo in patients with IgAN at a high risk of progression to renal failure, with a urinary protein >1 g/day and an eGFR of 20 to 120 mL/min. This study was terminated early because of a high incidence of adverse events such as serious infections in the corticosteroid group, although the corticosteroid group demonstrated a reduction in the composite endpoint, which include a reduction of over 40% in eGFR and the incidence of end-stage renal failure [ 57 ]. Although the TESTING II study found that tapering methylprednisolone (0.4 mg/kg/day over six months) slowed the decline of kidney function in patients with IgAN, this treatment also led to more adverse events [ 9 ]. In contrast, a survey involving a Japanese cohort confirmed that the incidence of adverse events such as severe infections and hyperglycemia due to corticosteroid use was low [ 58 ]. The corticosteroid doses commonly used in Japan are lower than those used in clinical trials.
The local immunosuppressive effect of the targeted-release formulation (TRF) budesonide (Nefecon; Calliditas Therapeutics AB) on the intestinal mucosa may be a promising novel therapeutic candidate for IgAN. Macroscopic hematuria due to upper respiratory tract infections, such as tonsillitis or intestinal tract infections, highlights the involvement of mucosal–kidney connections in the pathogenesis of IgAN [ 5 ]. The interaction between the dysregulated immune system in the GALT and IgAN has been a topic of discussion for decades [ 59 , 60 ]. Recent GWASs have identified common risk alleles for IgAN and inflammatory bowel disease (IBD) that are linked to the integrity of the intestinal mucosal barrier [ 61 , 62 ]. Population-based cohort studies have shown that patients with IgAN have an increased risk of developing IBD [ 63 , 64 ]. The gut–kidney axis hypothesis highlights the pivotal role of the imbalance between the immune system and microbiota in the development and progression of IgAN. In patients with IgAN, there is an increase in the serum levels of IgA1, which lacks galactose in its hinge region. This deficiency exposes the N-acetylgalactosamine (GalNAc) residues that are recognized by anti-glycan autoantibodies. The gut microbiota can induce B cell activation via BAFF, and this enhanced stimulation promotes a significant transition from IgA2 to IgA1 production [ 65 ]. Notably, high serum levels of gut-homing IgA + B lymphocytes indicates the involvement of intestinal mucosal immune dysregulation in the pathogenesis of IgAN [ 43 ]. Budesonide, a novel oral glucocorticoid TRF, was specifically designed to be deployed in the ileum and to deliver glucocorticoids locally to the ileal gut-associated lymphoid system with limited systemic exposure. The global phase 3 NefIgArd trial demonstrated that treatment with Nefecon at 16 mg/day significantly reduced the decline in eGFR and proteinuria in patients with IgAN who were already on an optimized RAS blockade, implying a disease-modifying effect of Nefecon in these patients [ 66 ]. Budesonide is recognized for its favorable safety profile compared to systemic corticosteroids, primarily because of its significant hepatic first-pass metabolism, resulting in less than 10% of the drug entering the systemic circulation [ 67 ]. Importantly, this study demonstrated a reduction in the serum levels of Gd-IgA1 and IgA/IgG immune complexes. Reduction in the serum levels of APRIL, BAFF, and soluble BCMA were observed following treatment with Nefecon, indicating an impact on disease activity through the direct modulation of APRIL and BAFF [ 68 ]. This study highlights the changes in chemokines related to lymphocyte migration to the intestinal mucosa, suggesting that Nefecon impacts immune cells residing in or migrating to gut-associated lymphoid tissues (GALTs). Nefecon received an accelerated approval from the United States Food and Drug Administration (FDA) in December 2021 for the treatment of IgAN. In December 2023, the FDA granted a full approval to Nefecon, making it the first fully approved treatment for IgAN.
4.2. B-Cell and Plasma Cell-Targeted Treatment
Targeting B cells, which are responsible for the production of Gd-IgA1, has recently emerged as a promising strategy for IgAN treatment. Rituximab, a monoclonal anti-CD20 antibody, does not significantly affect urinary protein levels, eGFR, or Gd-IgA1 levels, despite the effective depletion of peripheral B cells [ 69 ]. Plasmablasts are rapidly produced as short-lived effector cells that home to either the bone marrow or the mucosa, where they secrete antibodies as terminally differentiated plasma cells. CD20 is highly expressed in mature naïve B cells but is gradually lost during B cell differentiation. As B cells differentiate into plasma cells, plasmablasts and plasma cells lose their CD20 expression [ 70 ]. Notably, IgA plasmablasts have been identified in the mucosa following rituximab treatment [ 71 ]. Therefore, anti-CD20 treatment may not reduce the number of plasmablasts or plasma cells responsible for the production of Gd-IgA1, thereby perpetuating Gd-IgA1 synthesis even after rituximab treatment in patients with IgAN. An alternative depletion approach currently under evaluation for IgAN and adapted for the treatment of multiple myeloma is CD38 depletion ( Table 2 ). In contrast to B cells, plasma cells exhibit high CD38 expression and low CD20 expression [ 72 ]. BAFF has been demonstrated to selectively augment the survival and differentiation of CD38 + plasmablasts derived from activated human memory B cells. Strategies targeting CD38 + plasma cells, such as felzartamab, a human IgG1 monoclonal antibody, are being explored in phase 2 RCTs for their potential to target the cells responsible for the production of Gd-IgA1 ( NCT05065970 ). Mezagitamab, another anti-CD38 human IgG1 monoclonal antibody, is currently being evaluated in phase 1 studies in IgAN ( NCT05174221 ). The proteasome inhibitor bortezomib, a plasma cell-depleting agent, has been used to treat multiple myeloma by inhibiting the transcriptional factor nuclear facto-kappa B (NF-κB) and inducing the apoptosis of myeloma cells through a misfolded protein response. An open pilot study involving eight patients with IgAN was conducted to evaluate the effects of bortezomib [ 73 ]. The results showed that three of the eight patients achieved complete remission after four doses of bortezomib at 1 year of follow-up, suggesting that plasma cell depletion could potentially improve outcomes in IgAN. Therefore, larger trials are needed to confirm the efficacy and safety of these drugs.
Based on multiple studies, strategies for APRIL inhibition are currently being explored as potential therapies for IgAN ( Table 2 ). Several novel agents targeting APRIL, including sibeprenlimab, atacicept, telitacicept, povetacicept, and zigakibart are currently being investigated for the treatment of IgAN ( Figure 2 ). These novel treatments exert their therapeutic effects by reducing the production of Gd-IgA1 and the subsequently formed Gd-IgA1-containing immune complexes ( Figure 1 ). Preliminary results suggest that these agents are well-tolerated and reduce Gd-IgA1 levels, leading to an improvement in proteinuria. A phase 2 multicenter double-blind RCT assessed the efficacy of 12 monthly intravenous infusions of sibeprenlimab at doses of 2, 4, or 8 mg/kg body weight versus placebo in patients with IgAN who exhibited a high susceptibility to disease progression [ 74 ]. At the end of the 12-month period, the sibeprenlimab cohort showed significantly greater reductions in the 24-h UPCR from the baseline, in a dose-dependent manner, compared to the placebo group. A significant reduction in the rate of eGFR decline was observed in the two higher-dose groups. Importantly, these effects were accompanied by a decrease in the serum levels of APRIL and Gd-IgA1 in the treatment group, although there was no evidence of clinically significant immunosuppression. The decreased UPCR observed in the sibeprenlimab group continued for five months after the treatment was discontinued. However, the APRIL and Gd-IgA1 levels tended to increase, suggesting the need for ongoing therapeutic interventions. Phase 3 trials and open-label extension studies are currently underway ( NCT05248646 and NCT05248659 ).
Blisibimod, a monoclonal antibody against both soluble and membrane-bound BAFF, was one of the first agents approved for the treatment of systemic lupus erythematosus (SLE). Clinical studies have demonstrated benefits, such as steroid reduction, decreased proteinuria, and improvements in serological markers in patients with SLE [ 75 ]. Blisibimod has been evaluated for its efficacy and safety in patients with IgAN. The phase 2/3 BRIGHT-SC study ( NCT02062684 ) demonstrated that blisibimod-mediated BAFF inhibition significantly reduced peripheral B cells, immunoglobulins, and UPCR in patients with IgAN compared to a placebo [ 76 ]. The long-term efficacy and safety of targeting BAFF alone in IgAN remains uncertain because comprehensive results from relevant studies have not yet been published.
Atacicept is a novel immunomodulatory agent composed of a fully humanized recombinant fusion protein that includes the Fc region of human IgG1 and the TACI-binding domain [ 77 , 78 ]. Atacicept acts by binding soluble BAFF and APRIL and membrane-bound BAFF, thereby interfering with the cellular interactions of these cytokines and their receptors, TACI, BCMA, and BAFF-R. In a phase 2 study, atacicept dose-dependently reduced proteinuria and Gd-IgA1 antibody levels [ 78 ]. The phase 2B ORIGIN clinical trial of atacicept, involving 116 patients with IgAN, also showed promising results. The trial met its primary endpoint with the 150-mg-dose group achieving a 33% mean reduction in proteinuria from the baseline at 24 weeks [ 79 ]. Notably, atacicept treatment resulted in significant dose-dependent reductions in IgA, IgG, IgM, and Gd-IgA1 levels by week 24, which were sustained until week 72. The safety profile of atacicept was similar to that of the placebo. Additionally, the 72-week data indicated a consistent and sustained reduction in proteinuria and a stabilization of eGFR, further supporting the potential of atacicept as a disease-modifying treatment for IgAN. A phase 3 ORIGIN study is currently evaluating the efficacy and safety of a 150 mg dose of atacicept compared to a placebo in terms of urinary findings, kidney function, and immunomodulatory effects in patients with IgAN ( NCT04716231 ).
Telitacicept, a recombinant fusion protein consisting of TACI and the Fc portion of human IgG, inhibits both APRIL and BAFF. Based on prior efficacy and safety data, telitacicept received approval in China for the management of patients with active SLE [ 80 , 81 ]. A phase 2 RCT showed that 240 mg of telitacicept reduced the mean 24-h proteinuria by 49%, and stabilized the mean eGFR at 24 weeks in 44 Chinese patients with IgAN [ 82 ]. In addition, treatment with 160 or 240 mg of telitacicept decreased circulatory Gd-IgA1 and IgA-containing immune complexes at week 24 [ 83 ]. These findings suggest that telitacicept reduces the risk of disease progression. A phase 3 trial is currently in progress ( NCT05799287 ).
Povetacicept, a human TACI–Fc fusion protein engineered for dual APRIL/BAFF inhibition, has been studied in patients with IgAN, primary membranous nephropathy (MN), and lupus nephritis. A phase 1B/2A study ( NCT05732402 ) recruited patients with autoimmune glomerulonephritis, including IgAN. Preliminary data presented in 2024 at the World Congress of Nephrology (WCN) indicate that treatment with povetacicept every 4 weeks is associated with a significant reduction in proteinuria, stable kidney function, and significant reductions in circulating Gd-IgA1 levels in patients with IgAN [ 84 ].
Zigakibart (BION-1301) is a humanized IgG4 monoclonal antibody that blocks APRIL. The interim results from a phase 1/2 trial of zigakibart in patients with IgAN ( NCT03945318 ) demonstrated clinically meaningful and sustained reductions in proteinuria, accompanied by rapid and sustained decreases in serum levels of IgA and Gd-IgA1 [ 85 , 86 , 87 ]. Zigakibart was well-tolerated, with no severe adverse effects reported. The BEYOND study, a phase 3, randomized, double-blind, placebo-controlled trial to explore the safety and efficacy of zigakibart in patients with IgAN who are at risk of progressing renal dysfunction is currently in progress ( NCT05852938 ).
Although APRIL/BAFF inhibition has shown promising results with no notable adverse events, the effects of suppressing one on the expression of the other are not fully understood. Some studies have suggested that targeting one of these cytokines may not necessarily lead to the overexpression of the other [ 88 , 89 ]. However, further research is required to clarify this interaction and its implications in immune regulation and potential therapies.
5. Conclusions and Future Perspectives
Our recent understanding of the pathogenesis of IgAN including immune dysregulation has evolved, and various strategies that focus on inhibiting signaling pathways including APRIL/BAFF, depleting plasma cells, modulating mucosal immunity, blocking complement cascades, and other downstream pathways that are activated following IgA deposition to treat different aspects of the pathogenesis of IgAN and the progression, have shown safety and efficacy. However, the appropriate indication or optimal treatment duration with each modulator, including APRIL/BAFF inhibitors, remains unclear. The optimal choice between exclusive APRIL antagonists and combined APRIL/BAFF inhibitors, in terms of safety and efficacy, remains uncertain. Moreover, we may need to consider the nephritogenic mucosal site of each patient based on their clinical characteristics or ethnicity, depending on the treatment options. Further validation studies are required to resolve these issues.
Acknowledgments
We express our gratitude to all staff members in our department for their contributions to the description of the current manuscript.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Author Contributions
M.M. participated in drafting the manuscript, and H.S. and Y.S. revised the manuscript. All authors have read and agreed to the published version of the manuscript.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflicts of interest.
References
1. McGrogan A. Franssen C.F.M. de Vries C.S. The incidence of primary glomerulonephritis worldwide: A systematic review of the literature Nephrol. Dial. Transplant. 2010 26 414 430 10.1093/ndt/gfq665 21068142
2. Hastings M.C. Bursac Z. Julian B.A. Baca E.V. Featherston J. Woodford S.Y. Bailey L. Wyatt R.J. Life Expectancy for Patients From the Southeastern United States With IgA Nephropathy Kidney Int. Rep. 2017 3 99 104 10.1016/j.ekir.2017.08.008 29340319 PMC5762959
3. Moriyama T. Tanaka K. Iwasaki C. Oshima Y. Ochi A. Kataoka H. Itabashi M. Takei T. Uchida K. Nitta K. Prognosis in IgA Nephropathy: 30-Year Analysis of 1,012 Patients at a Single Center in Japan PLoS ONE 2014 9 e91756 10.1371/journal.pone.0091756 24658533 PMC3962373
4. Suzuki H. Kiryluk K. Novak J. Moldoveanu Z. Herr A.B. Renfrow M.B. Wyatt R.J. Scolari F. Mestecky J. Gharavi A.G. The Pathophysiology of IgA Nephropathy J. Am. Soc. Nephrol. 2011 22 1795 1803 10.1681/ASN.2011050464 21949093 PMC3892742
5. Suzuki Y. Monteiro R.C. Coppo R. Suzuki H. The Phenotypic Difference of IgA Nephropathy and its Race/Gender-dependent Molecular Mechanisms Kidney360 2021 2 1339 1348 10.34067/KID.0002972021 35369654 PMC8676395
6. Hirano K. Matsuzaki K. Yasuda T. Nishikawa M. Yasuda Y. Koike K. Maruyama S. Yokoo T. Matsuo S. Kawamura T. Association Between Tonsillectomy and Outcomes in Patients With Immunoglobulin A Nephropathy JAMA Netw. Open 2019 2 e194772 10.1001/jamanetworkopen.2019.4772 31150076 PMC6547111
7. Koike K. Kawamura T. Hirano K. Nishikawa M. Shimizu A. Joh K. Katafuchi R. Hashiguchi A. Yano Y. Matsuzaki K. Clinicopathological prognostic stratification for proteinuria and kidney survival in IgA nephropathy: A Japanese prospective cohort study Clin. Kidney J. 2023 17 sfad294 10.1093/ckj/sfad294 38213485 PMC10783253
8. Rovin B.H. Adler S.G. Barratt J. Bridoux F. Burdge K.A. Chan T.M. Cook H.T. Fervenza F.C. Gibson K.L. Glassock R.J. KDIGO 2021 Clinical practice guideline for the management of glomerular diseases Kidney Int. 2021 100 S1 S276 34556256 10.1016/j.kint.2021.05.021
9. Lv J. Wong M.G. Hladunewich M.A. Jha V. Hooi L.S. Monaghan H. Zhao M. Barbour S. Jardine M.J. Reich H.N. Effect of oral methylprednisolone on decline in kidney function or kidney failure in patients with IgA nephropathy: The TESTING randomized clinical trial JAMA 2022 327 1888 1898 10.1001/jama.2022.5368 35579642 PMC9115617
10. Zhang Y.-M. Lv J.-C. Wong M.G. Zhang H. Perkovic V. Glucocorticoids for IgA nephropathy-pro Kidney Int. 2023 103 666 669 10.1016/j.kint.2023.01.018 36948768
11. Cheung C.K. Barratt J. Further Evidence for the Mucosal Origin of Pathogenic IgA in IgA Nephropathy J. Am. Soc. Nephrol. 2022 33 873 875 10.1681/ASN.2022020201 35393339 PMC9063891
12. Knoppova B. Reily C. Maillard N. Rizk D.V. Moldoveanu Z. Mestecky J. Raska M. Renfrow M.B. Julian B.A. Novak J. The Origin and Activities of IgA1-Containing Immune Complexes in IgA Nephropathy Front. Immunol. 2016 7 117 10.3389/fimmu.2016.00117 27148252 PMC4828451
13. Gesualdo L. Di Leo V. Coppo R. The mucosal immune system and IgA nephropathy Semin. Immunopathol. 2021 43 657 668 10.1007/s00281-021-00871-y 34642783 PMC8551125
14. Rajasekaran A. Julian B.A. Rizk D.V. IgA Nephropathy: An Interesting Autoimmune Kidney Disease Am. J. Med. Sci. 2020 361 176 194 10.1016/j.amjms.2020.10.003 33309134 PMC8577278
15. Sakurai D. Hase H. Kanno Y. Kojima H. Okumura K. Kobata T. TACI regulates IgA production by APRIL in collaboration with HSPG Blood 2006 109 2961 2967 10.1182/blood-2006-08-041772 17119122
16. He B. Santamaria R. Xu W. Cols M. Chen K. Puga I. Shan M. Xiong H. Bussel J.B. Chiu A. The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88 Nat. Immunol. 2010 11 836 845 10.1038/ni.1914 20676093 PMC3047500
17. Belnoue E. Pihlgren M. McGaha T.L. Tougne C. Rochat A.-F. Bossen C. Schneider P. Huard B. Lambert P.-H. Siegrist C.-A. APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early-life bone marrow stromal cells Blood 2008 111 2755 2764 10.1182/blood-2007-09-110858 18180376
18. Baert L. Manfroi B. Casez O. Sturm N. Huard B. The role of APRIL-A proliferation inducing ligand-In autoimmune diseases and expectations from its targeting J. Autoimmun. 2018 95 179 190 10.1016/j.jaut.2018.10.016 30385081
19. Kern C. Cornuel J.-F. Billard C. Tang R. Rouillard D. Stenou V. Defrance T. Ajchenbaum-Cymbalista F. Simonin P.-Y. Feldblum S. Involvement of BAFF and APRIL in the resistance to apoptosis of B-CLL through an autocrine pathway Blood 2004 103 679 688 10.1182/blood-2003-02-0540 14504101
20. Chiu A. Xu W. He B. Dillon S.R. Gross J.A. Sievers E. Qiao X. Santini P. Hyjek E. Lee J.-W. Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL Blood 2006 109 729 739 10.1182/blood-2006-04-015958 16960154 PMC1785096
21. Hardenberg G. Planelles L. Schwarte C.M. van Bostelen L. Le Huong T. Hahne M. Medema J.P. Specific TLR ligands regulate APRIL secretion by dendritic cells in a PKR-dependent manner Eur. J. Immunol. 2007 37 2900 2911 10.1002/eji.200737210 17899538
22. Chu V.T. Fröhlich A. Steinhauser G. Scheel T. Roch T. Fillatreau S. Lee J.J. Löhning M. Berek C. Eosinophils are required for the maintenance of plasma cells in the bone marrow Nat. Immunol. 2011 12 151 159 10.1038/ni.1981 21217761
23. Matthes T. Dunand-Sauthier I. Santiago-Raber M.-L. Krause K.-H. Donze O. Passweg J. McKee T. Huard B. Production of the plasma-cell survival factor a proliferation-inducing ligand (APRIL) peaks in myeloid precursor cells from human bone marrow Blood 2011 118 1838 1844 10.1182/blood-2011-01-332940 21642598
24. Puga I. Cols M. Barra C.M. He B. Cassis L. Gentile M. Comerma L. Chorny A. Shan M. Xu W. B cell–helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen Nat. Immunol. 2011 13 170 180 10.1038/ni.2194 22197976 PMC3262910
25. López-Fraga M. Fernández R. Albar J.P. Hahne M. Biologically active APRIL is secreted following intracellular processing in the Golgi apparatus by furin convertase Embo Rep. 2001 2 945 951 10.1093/embo-reports/kve198 11571266 PMC1084076
26. Maia S. Pelletier M. Ding J. Hsu Y.-M. Sallan S.E. Rao S.P. Nadler L.M. Cardoso A.A. Aberrant Expression of Functional BAFF-System Receptors by Malignant B-Cell Precursors Impacts Leukemia Cell Survival PLoS ONE 2011 6 e20787 10.1371/journal.pone.0020787 21687682 PMC3110793
27. Bossen C. Tardivel A. Willen L. Fletcher C.A. Perroud M. Beermann F. Rolink A.G. Scott M.L. Mackay F. Schneider P. Mutation of the BAFF furin cleavage site impairs B-cell homeostasis and antibody responses Eur. J. Immunol. 2010 41 787 797 10.1002/eji.201040591 21287546
28. Day E.S. Cachero T.G. Qian F. Sun Y. Wen D. Pelletier M. Hsu Y.-M. Whitty A. Selectivity of BAFF/BLyS and APRIL for Binding to the TNF Family Receptors BAFFR/BR3 and BCMA Biochemistry 2005 44 1919 1931 10.1021/bi048227k 15697217
29. Mackay F. Schneider P. Rennert P. Browning J. BAFF and APRIL: A Tutorial on B Cell Survival Annu. Rev. Immunol. 2003 21 231 264 10.1146/annurev.immunol.21.120601.141152 12427767
30. Castigli E. Wilson S.A. Scott S. Dedeoglu F. Xu S. Lam K.-P. Bram R.J. Jabara H. Geha R.S. TACI and BAFF-R mediate isotype switching in B cells J. Exp. Med. 2005 201 35 39 10.1084/jem.20032000 15630136 PMC2212754
31. Castigli E. Wilson S.A. Elkhal A. Ozcan E. Garibyan L. Geha R.S. Transmembrane activator and calcium modulator and cyclophilin ligand interactor enhances CD40-driven plasma cell differentiation J. Allergy Clin. Immunol. 2007 120 885 891 10.1016/j.jaci.2007.06.012 17689597 PMC2121612
32. Bossen C. Cachero T.G. Tardivel A. Ingold K. Willen L. Dobles M. Scott M.L. Maquelin A. Belnoue E. Siegrist C.-A. TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts Blood 2008 111 1004 1012 10.1182/blood-2007-09-110874 17942754
33. Mihalcik S.A. Huddleston P.M. 3rd Wu X. Jelinek D.F. The structure of the TNFRSF13C promoter enables differential expression of BAFF-R during B cell ontogeny and terminal differentiation J. Immunol. 2010 185 1045 1054 10.4049/jimmunol.1001120 20554963 PMC3780588
34. Ng L.G. Sutherland A.P.R. Newton R. Qian F. Cachero T.G. Scott M.L. Thompson J.S. Wheway J. Chtanova T. Groom J. B Cell-Activating Factor Belonging to the TNF Family (BAFF)-R Is the Principal BAFF Receptor Facilitating BAFF Costimulation of Circulating T and B Cells J. Immunol. 2004 173 807 817 10.4049/jimmunol.173.2.807 15240667
35. Cao Y. Lu G. Chen X. Chen X. Guo N. Li W. BAFF is involved in the pathogenesis of IgA nephropathy by activating the TRAF6/NF-κB signaling pathway in glomerular mesangial cells Mol. Med. Rep. 2020 21 795 805 10.3892/mmr.2019.10870 31974601 PMC6947818
36. Zheng N. Wang D. Ming H. Zhang H. Yu X. BAFF promotes proliferation of human mesangial cells through interaction with BAFF-R BMC Nephrol. 2015 16 72 10.1186/s12882-015-0064-y 25975951 PMC4432501
37. Schwarting A. Relle M. Meineck M. Föhr B. Triantafyllias K. Weinmann A. Roth W. Weinmann-Menke J. Renal tubular epithelial cell-derived BAFF expression mediates kidney damage and correlates with activity of proliferative lupus nephritis in mouse and men Lupus 2017 27 243 256 10.1177/0961203317717083 28659046
38. Moreaux J. Sprynski A. Dillon S.R. Mahtouk K. Jourdan M. Ythier A. Moine P. Robert N. Jourdan E. Rossi J.F. APRIL and TACI interact with syndecan-1 on the surface of multiple myeloma cells to form an essential survival loop Eur. J. Haematol. 2009 83 119 129 10.1111/j.1600-0609.2009.01262.x 19456850
39. Stadanlick J.E. Kaileh M. Karnell F.G. Scholz J.L. Miller J.P. Quinn W.J. 3rd Brezski R.J. Treml L.S. Jordan K.A. Monroe J.G. Tonic B cell antigen receptor signals supply an NF-kappaB substrate for prosurvival BLyS signaling Nat. Immunol. 2008 9 1379 1387 10.1038/ni.1666 18978795 PMC2744141
40. Yu X.-Q. Li M. Zhang H. Low H.-Q. Wei X. Wang J.-Q. Sun L.-D. Sim K.-S. Li Y. Foo J.-N. A genome-wide association study in Han Chinese identifies multiple susceptibility loci for IgA nephropathy Nat. Genet. 2011 44 178 182 10.1038/ng.1047 22197929
41. Kiryluk K. Sanchez-Rodriguez E. Zhou X.-J. Zanoni F. Liu L. Mladkova N. Khan A. Marasa M. Zhang J.Y. Balderes O. Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy Nat. Genet. 2023 55 1091 1105 10.1038/s41588-023-01422-x 37337107 PMC11824687
42. McCarthy D.D. Kujawa J. Wilson C. Papandile A. Poreci U. Porfilio E.A. Ward L. Lawson M.A. Macpherson A.J. McCoy K.D. Mice overexpressing BAFF develop a commensal flora-dependent, IgA-associated nephropathy J. Clin. Investig. 2011 121 3991 4002 10.1172/JCI45563 21881212 PMC3195458
43. Sallustio F. Curci C. Chaoul N. Fontò G. Lauriero G. Picerno A. Divella C. Di Leo V. De Angelis M. Ben Mkaddem S. High levels of gut-homing immunoglobulin A + B lymphocytes support the pathogenic role of intestinal mucosal hyperresponsiveness in immunoglobulin A nephropathy patients Nephrol. Dial. Transplant. 2021 36 452 464 10.1093/ndt/gfaa264 33200215 PMC7898021
44. Muto M. Manfroi B. Suzuki H. Joh K. Nagai M. Wakai S. Righini C. Maiguma M. Izui S. Tomino Y. Toll-Like Receptor 9 Stimulation Induces Aberrant Expression of a Proliferation-Inducing Ligand by Tonsillar Germinal Center B Cells in IgA Nephropathy J. Am. Soc. Nephrol. 2016 28 1227 1238 10.1681/ASN.2016050496 27920152 PMC5373453
45. He B. Chadburn A. Jou E. Schattner E.J. Knowles D.M. Cerutti A. Lymphoma B Cells Evade Apoptosis through the TNF Family Members BAFF/BLyS and APRIL J. Immunol. 2004 172 3268 3279 10.4049/jimmunol.172.5.3268 14978135
46. Gupta M. Dillon S.R. Ziesmer S.C. Feldman A.L. Witzig T.E. Ansell S.M. Cerhan J.R. Novak A.J. A proliferation-inducing ligand mediates follicular lymphoma B-cell proliferation and cyclin D1 expression through phosphatidylinositol 3-kinase–regulated mammalian target of rapamycin activation Blood 2009 113 5206 5216 10.1182/blood-2008-09-179762 19321861 PMC2686190
47. Chu V.T. Enghard P. Schürer S. Steinhauser G. Rudolph B. Riemekasten G. Berek C. Systemic activation of the immune system induces aberrant BAFF and APRIL expression in B cells in patients with systemic lupus erythematosus Arthritis Rheum. 2009 60 2083 2093 10.1002/art.24628 19565488
48. Makita Y. Suzuki H. Kano T. Takahata A. Julian B.A. Novak J. Suzuki Y. TLR9 activation induces aberrant IgA glycosylation via APRIL- and IL-6–mediated pathways in IgA nephropathy Kidney Int. 2019 97 340 349 10.1016/j.kint.2019.08.022 31748116 PMC7372907
49. Myette J.R. Kano T. Suzuki H. Sloan S.E. Szretter K.J. Ramakrishnan B. Adari H. Deotale K.D. Engler F. Shriver Z. A Proliferation Inducing Ligand (APRIL) targeted antibody is a safe and effective treatment of murine IgA nephropathy Kidney Int. 2019 96 104 116 10.1016/j.kint.2019.01.031 31027890
50. Han S.S. Yang S.H. Choi M. Kim H.-R. Kim K. Lee S. Moon K.C. Kim J.Y. Lee H. Lee J.P. The Role of TNF Superfamily Member 13 in the Progression of IgA Nephropathy J. Am. Soc. Nephrol. 2016 27 3430 3439 10.1681/ASN.2015060677 27068226 PMC5084881
51. Xin G. Shi W. Xu L.-X. Su Y. Yan L.-J. Li K.-S. Serum BAFF is elevated in patients with IgA nephropathy and associated with clinical and histopathological features J. Nephrol. 2012 26 683 690 10.5301/jn.5000218 23042433
52. Goto T. Bandoh N. Yoshizaki T. Nozawa H. Takahara M. Ueda S. Hayashi T. Harabuchi Y. Increase in B-cell-activation factor (BAFF) and IFN-gamma productions by tonsillar mononuclear cells stimulated with deoxycytidyl-deoxyguanosine oligodeoxynucleotides (CpG-ODN) in patients with IgA nephropathy Clin. Immunol. 2008 126 260 269 10.1016/j.clim.2007.11.003 18249037
53. Xavier R.J. Podolsky D.K. Unravelling the pathogenesis of inflammatory bowel disease Nature 2007 448 427 434 10.1038/nature06005 17653185
54. Kim J. Suzuki H. Kano T. Fukao Y. Nakayama M. Suzuki Y. POS-399 Anti-BAFF antibody is effective to inhibit the production of immunoglobulins, but not nephritogenic IgA in murine IgA nephropathy Kidney Int. Rep. 2022 7 S180 10.1016/j.ekir.2022.01.421
55. Navarra S.V. Guzmán R.M. E Gallacher A. Hall S. A Levy R. E Jimenez R. Li E.K.-M. Thomas M. Kim H.-Y. León M.G. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: A randomised, placebo-controlled, phase 3 trial Lancet 2011 377 721 731 10.1016/S0140-6736(10)61354-2 21296403
56. Rauen T. Eitner F. Fitzner C. Sommerer C. Zeier M. Otte B. Panzer U. Peters H. Benck U. Mertens P.R. Intensive Supportive Care plus Immunosuppression in IgA Nephropathy N. Engl. J. Med. 2015 373 2225 2236 10.1056/NEJMoa1415463 26630142
57. Lv J. Zhang H. Wong M.G. Jardine M.J. Hladunewich M. Jha V. Monaghan H. Zhao M. Barbour S. Reich H. Effect of oral methylprednisolone on clinical outcomes in patients with IgA nephropathy: The TESTING randomized clinical trial JAMA 2017 318 432 442 10.1001/jama.2017.9362 28763548 PMC5817603
58. Matsuzaki K. Suzuki H. Kikuchi M. Koike K. Komatsu H. Takahashi K. Narita I. Okada H. Committee of Clinical Practical Guideline for IgA Nephropathy 2020 Current treatment status of IgA nephropathy in Japan: A questionnaire survey Clin. Exp. Nephrol. 2023 27 1032 1041 10.1007/s10157-023-02396-0 37646957 PMC10654181
59. Barratt J. Rovin B.H. Cattran D. Floege J. Lafayette R. Tesar V. Trimarchi H. Zhang H. Why target the gut to treat IgA nephropathy? Kidney Int. Rep. 2020 5 1620 1624 10.1016/j.ekir.2020.08.009 33102954 PMC7569689
60. Coppo R. The Gut-Renal Connection in IgA Nephropathy Semin. Nephrol. 2018 38 504 512 10.1016/j.semnephrol.2018.05.020 30177022
61. Kiryluk K. Li Y. Scolari F. Sanna-Cherchi S. Choi M. Verbitsky M. Fasel D. Lata S. Prakash S. Shapiro S. Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens Nat. Genet. 2014 46 1187 1196 10.1038/ng.3118 25305756 PMC4213311
62. Shi D. Zhong Z. Wang M. Cai L. Fu D. Peng Y. Guo L. Mao H. Yu X. Li M. Identification of susceptibility locus shared by IgA nephropathy and inflammatory bowel disease in a Chinese Han population J. Hum. Genet. 2019 65 241 249 10.1038/s10038-019-0699-9 31857673
63. Rehnberg J. Symreng A. Ludvigsson J.F. Emilsson L. Inflammatory Bowel Disease Is More Common in Patients with IgA Nephropathy and Predicts Progression of ESKD: A Swedish Population-Based Cohort Study J. Am. Soc. Nephrol. 2021 32 411 423 10.1681/ASN.2020060848 33177116 PMC8054887
64. Nakayama T. Kaneko H. Okada A. Suzuki Y. Fujiu K. Takeda N. Morita H. Takeda N. Fukui A. Yokoo T. Association of inflammatory bowel disease with incident immunoglobulin A nephropathy Clin. J. Am. Soc. Nephrol. 2024 19 704 711 38600627 10.2215/CJN.0000000000000457 PMC11168824
65. Brandtzaeg P. Carlsen H.S. Halstensen T.S. The B-cell system in inflammatory bowel disease Adv. Exp. Med. Biol. 2006 579 149 167 16620017 10.1007/0-387-33778-4_10
66. Lafayette R. Kristensen J. Stone A. Floege J. Tesař V. Trimarchi H. Zhang H. Eren N. Paliege A. Reich H.N. 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 2023 402 859 870 10.1016/S0140-6736(23)01554-4 37591292
67. Edsbäcker S. Andersson T. Pharmacokinetics of Budesonide (Entocort TM EC) Capsules for Crohn’s Disease Clin. Pharmacokinet. 2004 43 803 821 10.2165/00003088-200443120-00003 15355126
68. Wimbury D. Muto M. Bhachu J.S. Scionti K. Brown J. Molyneux K. Seikrit C. Maixnerová D. Pérez-Alós L. Garred P. Targeted-release budesonide modifies key pathogenic biomarkers in immunoglobulin A nephropathy: Insights from the NEFIGAN trial Kidney Int. 2024 105 381 388 10.1016/j.kint.2023.11.003 38008160
69. Lafayette R.A. Canetta P.A. Rovin B.H. Appel G.B. Novak J. Nath K.A. Sethi S. Tumlin J.A. Mehta K. Hogan M. A Randomized, Controlled Trial of Rituximab in IgA Nephropathy with Proteinuria and Renal Dysfunction J. Am. Soc. Nephrol. 2016 28 1306 1313 10.1681/ASN.2016060640 27821627 PMC5373458
70. Jourdan M. Caraux A. Caron G. Robert N. Fiol G. Rème T. Bolloré K. Vendrell J.-P. Le Gallou S. Mourcin F. Characterization of a Transitional Preplasmablast Population in the Process of Human B Cell to Plasma Cell Differentiation J. Immunol. 2011 187 3931 3941 10.4049/jimmunol.1101230 21918187
71. Mei H.E. Frölich D. Giesecke C. Loddenkemper C. Reiter K. Schmidt S. Feist E. Daridon C. Tony H.P. Radbruch A. Steady-state generation of mucosal IgA+ plasmablasts is not abrogated by B-cell depletion therapy with rituximab Blood 2010 116 5181 5190 10.1182/blood-2010-01-266536 20829370
72. Schrezenmeier E. Jayne D. Dörner T. Targeting B Cells and Plasma Cells in Glomerular Diseases: Translational Perspectives J. Am. Soc. Nephrol. 2018 29 741 758 10.1681/ASN.2017040367 29326157 PMC5827591
73. Hartono C. Chung M. Perlman A.S. Chevalier J.M. Serur D. Seshan S.V. Muthukumar T. Bortezomib for Reduction of Proteinuria in IgA Nephropathy Kidney Int. Rep. 2018 3 861 866 10.1016/j.ekir.2018.03.001 29988921 PMC6035125
74. Mathur M. Barratt J. Chacko B. Chan T.M. Kooienga L. Oh K.-H. Sahay M. Suzuki Y. Wong M.G. Yarbrough J. A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy N. Engl. J. Med. 2024 390 20 31 10.1056/NEJMoa2305635 37916620 PMC7615905
75. Merrill J.T. Shanahan W.R. Scheinberg M. Kalunian K.C. Wofsy D. Martin R.S. Phase III trial results with blisibimod, a selective inhibitor of B-cell activating factor, in subjects with systemic lupus erythematosus (SLE): Results from a randomised, double-blind, placebo-controlled trial Ann. Rheum. Dis. 2018 77 883 889 10.1136/annrheumdis-2018-213032 29563108
76. Barratt J. Hislop C. Pennington J. FR-PO1128 effects of blisibimod, a selective inhibitor of B-cell activating factor, in patients with IgA nephropathy J. Am. Soc. Nephrol. 2016 27 4B
77. Kaegi C. Steiner U.C. Wuest B. Crowley C. Boyman O. Systematic Review of Safety and Efficacy of Atacicept in Treating Immune-Mediated Disorders Front. Immunol. 2020 11 433 10.3389/fimmu.2020.00433 32265917 PMC7105675
78. Barratt J. Tumlin J. Suzuki Y. Kao A. Aydemir A. Pudota K. Jin H. Gühring H. Appel G. Randomized Phase II JANUS Study of Atacicept in Patients With IgA Nephropathy and Persistent Proteinuria Kidney Int. Rep. 2022 7 1831 1841 10.1016/j.ekir.2022.05.017 35967104 PMC9366370
79. Lafayette R. Barbour S. Israni R. Wei X. Eren N. Floege J. Jha V. Kim S.G. Maes B. Phoon R.K. A phase 2b, randomized, double-blind, placebo-controlled, clinical trial of atacicept for treatment of IgA nephropathy Kidney Int. 2024 105 1306 1315 10.1016/j.kint.2024.03.012 38552841
80. Dhillon S. Telitacicept: First Approval Drugs 2021 81 1671 1675 10.1007/s40265-021-01591-1 34463932
81. Yao X. Ren Y. Zhao Q. Chen X. Jiang J. Liu D. Hu P. Pharmacokinetics analysis based on target-mediated drug distribution for RC18, a novel BLyS/APRIL fusion protein to treat systemic lupus erythematosus and rheumatoid arthritis Eur. J. Pharm. Sci. 2021 159 105704 10.1016/j.ejps.2021.105704 33440243
82. Lv J. Liu L. Hao C. Li G. Fu P. Xing G. Zheng H. Chen N. Wang C. Luo P. Randomized Phase 2 Trial of Telitacicept in Patients With IgA Nephropathy With Persistent Proteinuria Kidney Int. Rep. 2022 8 499 506 10.1016/j.ekir.2022.12.014 36938094 PMC10014376
83. Zan J. Liu L. Li G. Zheng H. Chen N. Wang C. Xie D. Zuo L. Li R. Zhang P. Effect of telitacicept on circulating Gd-IgA1 and IgA-containing immune complexes in IgA nephropathy Kidney Int. Rep. 2024 9 1067 1071 10.1016/j.ekir.2024.01.003 38765591 PMC11101733
84. Madan A. Park I. Yalavarthy R. Mandayam S. Kulkarni H. Barratt J. Davies R. Enstrom A. Thomas H. Li J. #1342 Updated results from the RUBY-3 study of povetacicept, an enhanced dual BAFF/APRIL antagonist, in autoantibody-associated glomerulonephritis Nephrol. Dial. Transplant. 2024 39 gfae069-0431 10.1093/ndt/gfae069.431
85. Barratt J. Kooienga L. Hour B. Agha I. Schwartz B. Sorensen B. Lo J. King A. Sathaliya T. Iyer S. MO212: Updated interim results of a phase 1/2 study to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical activity of BION-1301 in patients with IgA nephropathy Nephrol. Dial. Transplant. 2022 37 i145 10.1093/ndt/gfac067.011
86. Barratt J. Kim S.G. Agha I. Kooienga L. Madan A. Ruiz-Ramon P. Thomas H. Workeneh B. Narayanan R. Sorensen B. WCN23-1175 updated interim results of a phase 1/2 study of BION-1301 in patients with IgA nephropathy Kidney Int. Rep. 2023 8 S280 S281 10.1016/j.ekir.2023.02.632
87. Kim S.G. Lee E.Y. Narayanan R. Sorensen B. Schwartz B.M. King A.J. Jones-Burton C. Barratt J. WCN23-1107 a phase 1/2 multicenter study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamis of BION-1301 in healthy volunteers and adults with iga nephropathy Kidney Int. Rep. 2023 8 S280 10.1016/j.ekir.2023.02.631
88. Carvalho-Santos A. Kuhnert L.R.B. Hahne M. Vasconcellos R. Carvalho-Pinto C.E. Villa-Verde D.M.S. Anti-inflammatory role of APRIL by modulating regulatory B cells in antigen-induced arthritis PLoS ONE 2024 19 e0292028 10.1371/journal.pone.0292028 38691538 PMC11062543
89. Thompson N. Isenberg D.A. Jury E.C. Ciurtin C. Exploring BAFF: Its expression, receptors and contribution to the immunopathogenesis of Sjögren’s syndrome Rheumatology 2016 55 1548 1555 10.1093/rheumatology/kev420 26790457