Evolving therapeutic landscape of immunoglobulin A nephropathy: targeted immune pathways and novel therapies

Abstract

Recent advances in the understanding of immunoglobulin A nephropathy (IgAN) pathogenesis have led to a rapidly expanding therapeutic landscape for the condition. Treatments have historically relied on optimized supportive care aimed at controlling blood pressure and reducing proteinuria through blockading of the renin-angiotensin system and inhibition of the sodium glucose cotransporter 2. Growing insights into immune dysregulation, mucosal immunity, complement activation, and maladaptive hemodynamic responses have facilitated the development of multiple disease-targeting therapies for IgAN. These include agents that modulate mucosal immune responses, inhibit APRIL (a proliferation-inducing ligand) and BAFF (B-cell activating factor) signaling, block complement activation, or target endothelin-mediated pathways. Several of these therapies have shown promising antiproteinuric and kidney-protective effects in clinical trials. This review summarizes recent advances in the treatment of IgAN, with a particular focus on therapies targeting disease-specific pathogenic drivers and their implications for future therapeutic strategies.

Introduction

Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide and remains the leading cause of chronic kidney disease (CKD) and end-stage kidney disease, particularly in East Asian populations. Despite its heterogeneous clinical course, up to 30%–40% of patients with IgAN progress to kidney failure within 2–3 decades, underscoring the substantial long-term disease burden [1–4]. Historically, the treatment of IgAN has relied on optimized supportive care targeting the downstream consequences of nephron loss, rather than disease-specific mechanisms. This approach centers on blood pressure control and the reduction of proteinuria, with renin-angiotensin system (RAS) blockade and sodium-glucose cotransporter-2 (SGLT2) inhibitors represent as the cornerstones of optimized supportive therapy, alongside lifestyle modification [5–7].

Recent advances in the understanding of IgAN pathogenesis have highlighted the four-hit hypothesis, in which the disease’s development involves the overproduction of galactose-deficient IgA1 (Gd-IgA1; Hit 1), formation of autoantibodies (Hit 2), generation of circulating immune complexes (Hit 3), and mesangial deposition with complement-mediated injury (Hit 4). These insights underscore the need for therapies that target IgAN-specific pathogenic drivers, including mucosal immune dysregulation and complement activation, in addition to optimized supportive care [8].

Immunosuppressive therapy, particularly with systemic corticosteroids, has historically been used in selected high-risk patients with persistent proteinuria, despite optimized supportive care. However, their role remains controversial because of their inconsistent efficacy and substantial treatment-related toxicity. Recent evidence from the Therapeutic Evaluation of Steroids in IgA Nephropathy (TESTING) trial suggests that reduced-dose systemic glucocorticoids may provide a more favorable balance between efficacy and safety in carefully selected patients [9].

More recently, mechanism-based therapies targeting the upstream pathogenic pathways have emerged for patients with IgAN. These include targeted-release budesonide and agents directed at a proliferation-inducing ligand (APRIL)/B-cell activating factor (BAFF) signaling [10], complement activation [11], and endothelin pathways [12]. Reflecting on these advances, the 2025 KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline incorporates a mechanism-based, risk-stratified treatment approach for IgAN [5].

In this review, we summarize recent advances in the treatment of IgAN with a particular focus on mechanism-based therapies targeting disease-specific drivers such as APRIL/BAFF inhibitors, complement pathway inhibitors, and endothelin receptor antagonists (ERAs), along with a brief discussion of targeted-release budesonide and reduced-dose glucocorticoids.

Optimized supportive care: the foundation of immunoglobulin A nephropathy management

Optimized supportive care remains the cornerstone of IgAN management and should be implemented in all patients, regardless of disease severity. These interventions primarily target the generic responses to nephron loss, including glomerular hypertension, hyperfiltration, and proteinuria, which are major drivers of progressive kidney injury. Intensive blood pressure control and reduction of proteinuria are the central therapeutic goals of this therapy. Current clinical practice guidelines recommend the use of RAS blockade as a first-line pharmacological therapy [5]. RAS blockade reduces intraglomerular pressure and proteinuria, and has been consistently associated with slower declines in kidney function in patients with IgAN [13].

SGLT2 inhibitors have also emerged as an important component of supportive therapy for proteinuric CKD, including IgAN. In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, an IgAN subgroup analysis demonstrated significant reductions in albuminuria and the risk of kidney disease progression among patients who were receiving dapagliflozin in addition to standard care, supporting the use of SGLT2 inhibitors as a component of optimized supportive therapy [6]. Lifestyle interventions are also recommended to reduce glomerular hyperfiltration and cardiovascular risks. These include dietary sodium restriction, weight control, smoking cessation, and regular physical activity, all of which contribute to improved blood pressure and proteinuria control [7].

Targeting the endothelin pathway has emerged as a complementary strategy to further reduce proteinuria and glomerular injury. Endothelin-1, which acts primarily through the endothelin type A (ETA) receptor, promotes vasoconstriction, mesangial cell proliferation, podocyte injury, and extracellular matrix accumulation, thereby contributing to glomerular hypertension and progressive kidney damage [14,15]. Within the multi-hit model of IgAN, endothelin signaling is thought to amplify downstream kidney injury following immune complex deposition and complement activation. Consequently, ERAs have been investigated as adjunctive therapies to reduce proteinuria beyond what is achievable through conventional supportive care. In the phase 3 atrasentan in patients with IgAN trial, the selective ETA receptor antagonist atrasentan significantly reduced proteinuria [16]. Dual endothelin-angiotensin receptor antagonists have recently been developed as well. Sparsentan, which simultaneously blocks ETA receptors and angiotensin II receptors, demonstrated superior proteinuria reduction compared to irbesartan in the PROTECT trial, and has been approved for the treatment of IgAN in several regions [17]. These findings suggest that endothelin pathway inhibition may further enhance the antiproteinuric effects of optimized supportive care. Although ERAs are discussed here within the context of optimized supportive care due to their primary effects on downstream hemodynamic and injury pathways, they may also be considered a class of non-immunological targeted therapies in the evolving treatment landscape of IgAN. Thus, ERAs can be viewed as bridging conventional supportive care and mechanism-based targeted therapy.

Despite optimal supportive care, a substantial proportion of patients with IgAN continue to exhibit persistent proteinuria and progressive declines in kidney function. This observation underscores the limitations of strategies that primarily address downstream injury pathways, and highlights the need for therapies targeting the disease-specific immunological drivers of IgAN.

Targeting immunoglobulin A nephropathy-specific drivers: established therapies

Targeted-release budesonide (Nefecon)

Targeted-release budesonide, Nefecon (Calliditas Therapeutics), represents the first therapy specifically designed to modulate the mucosal immune response implicated in IgAN pathogenesis. The drug was formulated to deliver budesonide to the distal ileum, where gut-associated lymphoid tissue, including Peyer’s patches, plays a key role in the production of Gd-IgA1, corresponding to the first hit in the multi-hit model of IgAN (Fig. 1) [18,19].

Figure 1. The four-hit hypothesis of IgAN and therapeutic targets.

The pathogenesis of IgAN is commonly explained by the four-hit hypothesis. Hit 1 involves the overproduction of galactose-deficient IgA1 (Gd-IgA1) by mucosal B-cells. Therapies targeting mucosal immune responses, including the targeted release of budesonide and a proliferation-inducing ligand (APRIL) or B-cell activating factor (BAFF) inhibitors, aim to reduce pathogenic IgA production at this stage. Hit 2 refers to the generation of autoantibodies (IgG or IgA) directed against Gd-IgA1. Conventional immunosuppressive therapies such as corticosteroids and mycophenolate mofetil (MMF) may modulate this immune response. Hit 3 involves the formation of circulating immune complexes (ICs) comprising Gd-IgA1 and autoantibodies. In Hit 4, these ICs are deposited in the glomerular mesangium, leading to complement activation, inflammation, and kidney injury. Complement pathway inhibitors that target components such as complement component 3 (C3) or C5 aim to interrupt downstream inflammatory amplification at this stage.

IgA, immunoglobulin A; IgAN, IgA nephropathy; IgG, immunoglobulin G.

In the phase 3 NefIgArd trial, treatment with targeted-release budesonide (Nefecon 16 mg/day for 9 months) significantly reduced proteinuria by approximately 27% and slowed declines in estimated glomerular filtration rate (eGFR) vs. a placebo, in patients with persistent proteinuria despite optimized supportive therapy. Over 2 years of follow-up, the mean eGFR decline was –2.47 mL/min/1.73 m² in the budesonide group versus –7.52 mL/min/1.73 m² in the placebo group [20]. The treatment was generally well tolerated, with a lower incidence of systemic glucocorticoid-related adverse events vs. conventional steroid therapy, reflecting its predominantly local intestinal activity.

Based on these findings, targeted-release budesonide received accelerated approval from the U.S. Food and Drug Administration in December 2021, followed by full approval in December 2023. This therapy has subsequently been approved in multiple regions, including Europe and South Korea, by the Ministry of Food and Drug Safety for the treatment of adults with IgAN at risk of disease progression.

Reduced-dose systemic glucocorticoids

Systemic glucocorticoids have long been used to suppress immune-mediated glomerular injury in IgAN, particularly in patients who exhibit persistent proteinuria despite receiving optimized supportive care. However, their clinical use remains controversial because previous studies have demonstrated inconsistent efficacy and substantial toxicity, including serious infections and metabolic complications [21,22].

The TESTING trial provided important new insights into the risk–benefit profile of systemic glucocorticoid therapy [9]. Following safety concerns over the initial high-dose regimen, that trial was modified to evaluate a reduced-dose methylprednisolone protocol combined with infection prophylaxis [9,23]. The final results demonstrated that reduced-dose systemic glucocorticoids significantly lowered the risk of major kidney outcomes, including kidney failure and substantial eGFR decline, while improving proteinuria control, vs. a placebo. Nevertheless, the incidence of treatment-related adverse events was higher in the steroid-treated group, highlighting the importance of careful patient selection and monitoring.

Agents directed at a proliferation-inducing ligand and B-cell activating factor pathway inhibition

Increasing evidence indicates that dysregulated mucosal immunity plays a central role in the pathogenesis of IgAN. A key component of this process is the overproduction of Gd-IgA1 by the mucosal plasma cells, which subsequently leads to the formation of circulating immune complexes and mesangial deposition [24]. Among the cytokines that regulate B-cell activation and IgA production, APRIL and BAFF have emerged as critical mediators of pathogenic IgA production [25]. Dysregulation of the APRIL/BAFF axis is believed to drive the upstream step of the multi-hit model (Hit 1) by promoting class-switch recombination toward IgA production and supporting the survival of IgA-secreting plasma cells (Fig. 1).

APRIL signaling promotes the differentiation and survival of IgA-producing plasma cells through interactions with receptors such as transmembrane activator and CAML interactor (TACI) and B-cell maturation antigen (BCMA) [26]. Elevated circulating levels of APRIL have been reported in patients with IgAN, and have been associated with increased Gd-IgA1 production and disease activity [27]. These observations have led to the development of therapeutic agents targeting the APRIL/BAFF axis, as a strategy to reduce pathogenic IgA production upstream in the disease cascade.

Several agents targeting this pathway are currently under clinical investigation (Table 1). Among the APRIL-targeting agents, sibeprenlimab has demonstrated promising results in clinical trials. In a phase 2 study, treatment with sibeprenlimab led to significant reductions in proteinuria and decreased circulating Gd-IgA1 levels, suggesting effective modulation of the pathogenic IgA pathway [28]. The ongoing phase 3 VISIONARY trial is evaluating its long-term efficacy and safety in patients with IgAN who are at risk of disease progression [29]. Another APRIL-targeting monoclonal antibody, zigakibart (formerly BION-1301), has been shown to reduce proteinuria and circulating pathogenic IgA levels in early-phase clinical studies [30].

Table 1.

Clinical trials of APRIL/BAFF pathway inhibitors in IgA nephropathy

Drug	Target	Trial name/registration identifier	Phase	Key notes
Sibeprenlimab (VIS649)	APRIL monoclonal antibody	ENVISION (NCT04287985)	Phase II	• Serum IgA/Gd-IgA1 reduction
				• Dose-dependent proteinuria reduction
				• Randomized placebo-controlled proof-of-concept trial
		VISIONARY (NCT05248646)	Phase III	• Sustained IgA suppression
				• ~50% proteinuria reduction (interim)
				• Global pivotal trial (ongoing)
Zigakibart (BION-1301)	APRIL monoclonal antibody	ADU-CL-19 (NCT03945318)	Phase I/II	• Marked reduction in IgA and Gd-IgA1
				• Proteinuria reduction observed
				• Open-label proof-of-concept study
		BEYOND (NCT05852938)	Phase III	• Proteinuria reduction endpoint
				• Global pivotal trial (ongoing)
Atacicept	Dual BAFF/APRIL (TACI-Fc fusion protein)	ORIGIN (NCT04716231)	Phase IIb	• ~30%–35% reduction in UPCR
				• Suppression of circulating IgA
				• Randomized placebo-controlled trial
		ORIGIN 3 (NCT04716231)	Phase III	• Renal outcome endpoint
				• Long-term efficacy and safety evaluation
				• Global pivotal trial (ongoing)
Telitacicept (RC18)	Dual BAFF/APRIL (TACI-Fc fusion protein)	NCT04905212	Phase II	• Significant proteinuria reduction
				• Decrease in serum IgA
				• Randomized placebo-controlled proof-of-concept trial
		NCT05799287	Phase III	• Proteinuria reduction endpoint
				• Long-term renal protection assessment
				• Global pivotal trial (ongoing)
Povetacicept (ALPN-303)	Dual BAFF/APRIL engineered TACI-Fc	RUBY-3 (NCT05732402)	Phase I/II	• Immunoglobulin reduction
				• Proteinuria reduction observed
				• Early proof-of-concept trial
		RAINIER (NCT06564142)	Phase III	• Proteinuria reduction endpoint
				• Long-term renal outcome evaluation
				• Global pivotal trial (ongoing)

APRIL, a proliferation-inducing ligand; BAFF, B-cell activating factor; Fc, fragment crystallizable; Gd-IgA1, galactose-deficient IgA1; IgA, immunoglobulin A; TACI, transmembrane activator and CAML interactor; UPCR, urine protein-to-creatinine ratio.

An alternative therapeutic strategy involves the dual inhibition of APRIL and BAFF, which may provide broader suppression of B-cell activation and immunoglobulin production. Atacicept, a TACI-Fc fusion protein that neutralizes both cytokines, has shown promising results in clinical trials. In the phase 2 ORIGIN trial, atacicept significantly reduced circulating Gd-IgA1 levels and produced clinically meaningful reductions in proteinuria vs. a placebo [31]. Similarly, povetacicept, an engineered dual APRIL/BAFF inhibitor with enhanced binding affinity, is currently being evaluated in clinical studies and has demonstrated early signals of antiproteinuric activity [32]. Collectively, these findings highlight the central role of B-cell–mediated mucosal immunity in IgAN pathogenesis and support APRIL-BAFF signaling as a promising therapeutic target.

These agents have generally demonstrated favorable safety profiles in early-phase studies. However, given their immunomodulatory effects on B-cell function, potential risks such as increased susceptibility to infections and reductions in immunoglobulin levels warrant careful monitoring in clinical practice.

Complement pathway inhibition

Complement activation is a major downstream mediator of glomerular injury in IgAN. Following mesangial deposition of IgA-containing immune complexes, activation of the complement cascade contributes to inflammatory signaling, mesangial cell proliferation, and progressive kidney injury [33]. In the context of the multi-hit model of IgAN, complement activation is considered a central component of the final pathogenic step (Hit 4) that links immune complex deposition to glomerular inflammation and tissue damage (Fig. 1).

Histopathological studies have consistently demonstrated mesangial deposition of complement components such as C3, properdin, and C5b-9, supporting the role of complement activation in disease progression [34]. Notably, IgAN is predominantly characterized by the activation of the alternative and lectin pathways, whereas involvement of the classical pathway appears relatively limited. The presence of complement split products, including C3 and C4d, in kidney biopsy specimens has also been associated with more aggressive disease and worse renal outcomes [35]. These observations have led to the development of therapeutic agents targeting the key components of the complement cascade, in a strategy designed to interrupt downstream inflammatory amplification in IgAN (Fig. 2). Several agents targeting distinct complement pathways are currently under clinical investigation (Table 2). Although these agents show promising efficacy, complement inhibition may increase susceptibility to infections, particularly those caused by encapsulated bacteria.

Figure 2. Complement activation pathways and therapeutic targets in IgAN.

Activation of the complement system contributes to glomerular inflammation and injury in patients with IgAN. The classical pathway is believed to play a limited role in IgAN, whereas the lectin and alternative pathways are considered the major drivers of complement activation. The lectin pathway is initiated by the MBL (mannan-binding lectin)–associated serine protease (MASP) complex, and can be inhibited by MASP-2 inhibitors such as narsoplimab. The alternative pathway amplifies complement activation via the formation of the complement component 3 (C3) convertase (C3bBb), which can be targeted by factor B inhibitors such as iptacopan. Inhibition at the level of C3 with agents such as pegcetacoplan can provide a broader suppression of complement activation. Activation of the terminal pathway leads to the cleavage of C5 and formation of the MAC (C5b-9), which mediates glomerular injury and can be inhibited by C5 inhibitors such as ravulizumab.

IgAN, immunoglobulin A nephropathy; MAC, membrane attack complex.

Table 2.

Key clinical trials of complement pathway inhibitors in IgAN

Complement pathway	Target	Drug	Trial name (registration identifier)	Phase	Key notes
Alternative pathway	Factor B	Iptacopan	APPLAUSE-IgAN (NCT04578834)	Phase III	• Oral selective factor B inhibitor
					• Significant proteinuria reduction
					• Randomized placebo-controlled pivotal trial
	Factor B synthesis	Sefaxersen	NCT05797610	Phase II/III	• Antisense oligonucleotide targeting FB mRNA
					• Alternative pathway suppression and proteinuria reduction
					• Randomized placebo-controlled trial (ongoing)
Lectin pathway	MASP-2	Narsoplimab	ARTEMIS-IgAN (NCT03608033)	Phase II/III	• MASP-2 monoclonal antibody
					• Proteinuria reduction
					• Phase II/III clinical trial (ongoing)
Central complement blockade	C3	Pegcetacoplan	NCT03453619	Phase II	• C3 inhibitor targeting central complement cascade
					• Reduction in complement activation markers
					• Randomized placebo-controlled proof-of-concept trial
Terminal pathway	C5	Ravulizumab	NCT04564339	Phase II	• Long-acting C5 monoclonal antibody
					• Inhibition of terminal complement activation
					• Early proof-of-concept trial (ongoing)
	C5 synthesis + C5 antibody	Cemdisiran + pozelimab	NCT04817618	Phase II	• Dual C5 inhibition (RNAi+monoclonal antibody)
					• Sustained suppression of terminal complement activity
					• Phase II proof-of-concept trial

C3, complement component 3; C5, complement component 5; FB, factor B; MASP-2, mannan-binding lectin-associated serine protease-2; mRNA, messenger RNA; RNAi, RNA interference.

Lectin pathway inhibition

The lectin pathway has emerged as an important therapeutic target in IgAN. Immune complexes containing Gd-IgA1 can activate the lectin complement pathway, leading to downstream complement amplification and glomerular injury. Activation of this pathway is mediated by mannan-binding lectin–associated serine protease-2 (MASP-2), a key enzyme responsible for the cleavage of complement components and initiation of the lectin pathway cascade [36].

Narsoplimab, a monoclonal antibody directed against MASP-2, inhibits activation of the lectin pathway, thereby limiting complement-mediated inflammatory injury. Early clinical studies evaluating narsoplimab in patients with IgAN have demonstrated reductions in proteinuria and stabilization of kidney function, supporting the potential role of lectin pathway inhibition as a therapeutic strategy [37]. However, larger randomized controlled trials are warranted to confirm its long-term efficacy and safety.

Alternative pathway inhibition

The amplification of complement activation through the alternative pathway represents a key driver of complement-mediated kidney injury in IgAN. Iptacopan, an oral selective inhibitor of complement factor B, blocks activation of the alternative pathway and prevents the amplification loop of complement activation and downstream inflammation. In the phase 3 APPLAUSE-IgAN trial, iptacopan significantly reduced proteinuria and slowed kidney function decline, vs. a placebo, in patients who were receiving optimized supportive care [38]. These findings suggest that inhibition of the alternative pathway may provide meaningful disease-modifying effects in IgAN.

Another approach to inhibition of the alternative pathway involves the suppression of factor B synthesis. Sefaxersen, an antisense oligonucleotide targeting the production of hepatic complement factor B, reduces circulating factor B levels, and thereby attenuates alternative pathway activation. Early clinical studies have demonstrated reductions in circulating factor B levels, complement activity, and proteinuria in patients with IgAN, and ongoing trials are evaluating its potential as a disease-modifying therapy [39].

Terminal complement inhibition

The terminal complement pathway represents the final effector of complement-mediated tissue injury. Ravulizumab, a long-acting monoclonal antibody targeting the C5 complement component, prevents cleavage of C5 and formation of the membrane attack complex (C5b–9), thereby limiting complement-mediated tissue injury. Clinical trials are currently evaluating its efficacy in IgAN, although experience with C5 inhibition in this disease remains limited compared to other complement-mediated disorders [40]. In particular, inhibition of C5 has been associated with an increased risk of meningococcal infection, and appropriate vaccination is recommended prior to treatment.

C3 pathway inhibition

The inhibition of complement activation at the level of C3 provides a strategy for broader suppression of the complement cascade. Because C3 lies upstream of the alternative, lectin, and terminal pathways, blockade at this level can broadly suppress complement activation and prevent downstream inflammatory amplification. Pegcetacoplan is a C3 inhibitor that prevents C3 cleavage, thereby inhibiting multiple complement effector pathways concurrently. In a phase 2 study that included patients with C3 glomerulopathy and other complement-mediated glomerular diseases, pegcetacoplan reduced complement activity and signals of antiproteinuric effects [41]. Additional clinical trials are currently underway to further evaluate the efficacy and safety of C3 inhibition in the context of IgAN (e.g., NCT03453619).

Future perspectives and therapeutic sequencing in immunoglobulin A nephropathy

The expanding therapeutic landscape of IgAN raises important questions regarding optimal treatment sequencing and patient selection. Current therapies target different stages of the disease process, ranging from the upstream modulation of pathogenic IgA production to the downstream inhibition of inflammatory and hemodynamic pathways. Given the diversity of therapeutic targets, future treatment strategies will likely move toward mechanism-based sequencing or combination therapy, in which agents acting on distinct pathogenic pathways are used in a complementary manner. In this context, therapies targeting the upstream immunological drivers of IgAN may be integrated with agents that inhibit downstream inflammatory amplification or glomerular injury to achieve more comprehensive disease control (Table 3).

Table 3.

Mechanism-based classification and therapeutic positioning in IgA nephropathy

Pathogenic stage/mechanism	Therapeutic target	Representative agents	Clinical development/key status
Upstream immune modulation (Hit 1)	APRIL	Sibeprenlimab, zigakibart	Phase II–III: ↓ Gd-IgA1, ↓ proteinuria
	APRIL/BAFF	Atacicept, telitacicept, povetacicept	Phase II–III: ↓ IgA production, ↓ proteinuria
Complement-mediated injury (Hit 4)	Factor B (alternative pathway)	Iptacopan, sefaxersen	Phase II–III: ↓ proteinuria, complement suppression
	MASP-2 (lectin pathway)	Narsoplimab	Phase II–III: ↓ proteinuria
	C3 (central complement)	Pegcetacoplan	Phase II: broad complement inhibition
	C5 (terminal pathway)	Ravulizumab, cemdisiran + pozelimab	Phase II: terminal pathway blockade
Downstream hemodynamic/injury pathway	Endothelin A (ETA) receptor	Atrasentan	Phase III: significant ↓ proteinuria
	Dual ETA + AT1 receptor	Sparsentan	Approved/phase III: superior ↓ proteinuria vs. irbesartan
Immune modulation (nonspecific)	Glucocorticoid receptor	Systemic glucocorticoids	Proven efficacy with safety concerns (TESTING trial)
	Gut-targeted steroid delivery	Targeted-release budesonide (Nefecon, Calliditas Therapeutics)	Approved: ↓ proteinuria, slower eGFR decline
Plasma cell-targeting (exploratory)	Proteasome inhibition	Bortezomib	Pilot/small studies: limited clinical evidence
Supportive therapy (foundation)	Hemodynamic modulation	RAS inhibitors, SGLT2 inhibitors	Standard of care: ↓ proteinuria, ↓ CKD progression

Foundation indicates standard-of-care therapies; exploratory denotes approaches with limited clinical evidence.

APRIL, a proliferation-inducing ligand; AT1, angiotensin II type 1; BAFF, B-cell activating factor; C3, complement component 3; C5, complement component 5; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ETA, endothelin A; Gd-IgA1, galactose-deficient IgA1; IgA, immunoglobulin A; MASP-2, mannan-binding lectin-associated serine protease-2; RAS, renin-angiotensin system; SGLT2, sodium-glucose cotransporter-2; TESTING, Therapeutic Evaluation of Steroids in IgA Nephropathy.

From a mechanistic perspective, combination strategies targeting complementary pathogenic pathways may offer synergistic therapeutic benefits. For example, combining optimized supportive therapies such as SGLT2 inhibitors and ERAs with targeted agents, including complement inhibitors or APRIL/BAFF pathway inhibitors, could simultaneously attenuate downstream hemodynamic stress and upstream immune dysregulation. Such multi-targeted approaches may provide more comprehensive disease control than single-agent therapy alone. Although clinical evidence remains limited, early-phase studies and ongoing trials are beginning to explore the feasibility of combination-based strategies in IgAN. Further clinical trials will be essential to determine the optimal combinations, sequencing, and safety profiles of these therapies.

Another key challenge is the identification of biomarkers that can facilitate personalized treatment selection. Biomarkers reflecting specific pathogenic mechanisms, such as circulating Gd-IgA1 levels, complement activation markers, or genetic risk profiles, may help identify which patients are most likely to benefit from targeted therapies. However, the clinical implementation of these biomarkers remains limited by several challenges, including restricted availability in routine practice, lack of assay standardization across laboratories, and cost considerations. In addition, their clinical utility in guiding treatment decisions has yet to be fully validated in prospective clinical settings. Advances in biomarker development and clinical trial design will therefore be essential for translating the expanding therapeutic armamentarium into more precise and personalized management strategies. Overall, the integration of mechanism-based therapies, biomarker-guided treatment selection, and optimized supportive care is expected to shape the future management paradigm for IgAN.

Despite the rapid global expansion of therapeutic options for IgAN, access to newly approved agents may vary substantially across regions because of differences in regulatory approval and reimbursement policies. Addressing these disparities will be important to ensuring that advances in IgAN therapeutics translate into meaningful improvements in clinical practice worldwide.

Conclusion

Recent advances in the understanding of IgAN pathogenesis, particularly the multi-hit model involving Gd-IgA1 production, immune complex formation, and complement-mediated injury, have led to the development of several mechanism-based therapies targeting key disease pathway. As the therapeutic landscape expands beyond traditional immunosuppression, future management of IgAN will likely move toward more personalized strategies, including mechanism-based sequencing, combination therapy, and biomarker-guided treatment selection. Continued translational research and well-designed clinical trials will be essential to refining these approaches and improving long-term kidney outcomes for patients. As the therapeutic landscape evolves, careful consideration of safety profiles alongside efficacy will be essential to optimize patient outcomes.