Precision Treatment of IgA Nephropathy Based on a New Framework: Angiorenal Protection, Immunity Inhibition, B-Cell/Plasma-Cell Modulation, and Complement Inhibition

Given the strong association between BP, proteinuria, and disease progression, controlling proteinuria is a central goal in IgAN management [1]. To control BP to a target of ≤120/70 mm Hg, renin-angiotensin system inhibitors (RASis), including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, have been the standard approach. Recent advancements add the use of endothelin receptor antagonists (ERAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) [2], as well as mineralocorticoid receptor antagonists (MRAs). The dual endothelin angiotensin receptor antagonist, sparsentan [3], exemplifies a promising agent. The PROTECT trial demonstrated that sparsentan significantly reduced proteinuria and preserved kidney function over 2 years in IgAN patients, gaining FDA approval [3].

For optimal anti-proteinuria control, a strategy integrating these agents might involve starting from maximally tolerated RASi and subsequently adding an ERA (or switching to dual endothelin angiotensin receptor antagonist), an SGLT2i, and/or an MRA, depending on patient tolerability. This combined approach aims to prevent nephron loss early in the disease course and stabilize the glomerular function.

Targeting immunity within the kidneys is crucial in managing IgAN, particularly in patients with high-risk progressive IgAN. Among the agents advancing immunity control, modified-release budesonide (Nefecon) has shown efficacy in selectively suppressing IgA production targeted gut-associated lymphoid tissues, a key contributor to IgAN pathogenesis. Nefecon’s phase 3 NefIgArd trial reported reductions in both urinary protein-to-creatinine ratio and eGFR decline, highlighting its potential in managing IgAN’s inflammatory component with minor adverse systemic effects of traditional glucocorticoids [4].

Clinical trials such as STOP-IgAN and TESTING have investigated systemic glucocorticoids in managing IgAN. In the STOP-IgAN trial, high-risk Caucasian IgAN patients were randomized to receive supportive care with or without immunosuppressive therapy [5]. Although more patients in the intervention group achieved remission than those on supportive care alone (17% vs. 5%; p = 0.01), there was no significant long-term benefit in kidney function preservation over a 10-year follow-up, and adverse events (AEs) were notable, with increased risk for infections and impaired glucose tolerance. The TESTING trial [6], primarily involving Southeast Asian patients, revealed that methylprednisolone significantly reduced proteinuria and the risk of kidney function decline, kidney failure, or kidney-related death compared to placebo. However, serious AEs, including infection-related deaths, led to the trial suspension. When resumed with a lower dose and antimicrobial prophylaxis, the reduced regimen preserved proteinuria and renal function benefits while minimizing AEs. This comparison highlights that while systemic glucocorticoids can reduce proteinuria short term, the long-term kidney outcomes and AEs remain controversial.

Other immunosuppressive agents, including mycophenolate mofetil, calcineurin inhibitors, azathioprine, cyclophosphamide, and leflunomide, have been explored. However, studies emphasize cautious use due to inadequate evidence and potential AEs. KDIGO guideline recommends careful patient selection for these therapies, particularly in those who remain at high risk for progression after maximal supportive care. Together, these findings underscore the importance of immunity control in IgAN but emphasize the need for targeted, lower dose regimens to balance efficacy and safety.

Given the immunological basis of IgAN, modulating B-cell activity is an essential aspect of modern IgAN therapy, particularly for patients with inadequate response to conventional treatments, frequent relapses, steroid dependence, or those with rapidly progressive glomerulonephritis. B-cell activating factor and a proliferation-inducing ligand (APRIL) have emerged as critical cytokines in IgAN pathogenesis. These molecules support the maturation, survival, and IgA class-switch recombination of B cells. APRIL-specific inhibitors like sibeprenlimab [7] have demonstrated reductions in galactose-deficient IgA1 (Gd-IgA1) and proteinuria and a slowing of kidney function decline. Furthermore, inhibitors targeting B-cell activating factor and APRIL, such as atacicept, povetacicept, and telitacicept have shown encouraging results. atacicept significantly lowered serum Gd-IgA1 and proteinuria in the phase 2b ORIGIN study, with sustained results through a 60-week extension [8]. Povetacicept has shown the most potent efficacy by reducing UPCR by 64.1% at 36 weeks and significantly lowering Gd-IgA1 levels with a 78.6% reduction at 20 weeks. Moreover, CD20-directed therapies have been investigated. Although rituximab (RTX) has shown no significant effects on Gd-IgA1 levels or proteinuria in IgAN patients, other, more potent CD20-targeting agents, such as obinutuzumab, still require further evaluation for potential efficacy in this context. CD38-directed therapies are also under investigation, with agents like felzartamab and mezagitamab showing potential in depleting plasma cells. These agents may offer advantages by specifically targeting pathogenic IgA production in IgAN, potentially reducing proteinuria and preserving kidney function.

Complement activation is increasingly recognized as a key driver of immunity in IgAN, especially through the alternative and lectin pathways. Therapeutic strategies targeting complement pathways are promising additions to IgAN management. For instance, the factor B inhibitor iptacopan demonstrated a significant reduction in proteinuria in the phase 3 APPLAUSE-IgA trial [9], supporting its role in controlling immunity mediated by the alternative pathway. Similarly, ravulizumab [10], a C5 inhibitor, reduced proteinuria by 41.9% over 26 weeks in patients with persistent IgAN proteinuria, demonstrating a protective effect on renal function. Complement-targeted therapies are most beneficial in patients with evidence of complement activation, emphasizing the need for biomarkers to tailor therapy. Multiple ongoing clinical trials are assessing the therapeutic potential of novel inhibitors targeting key components of the complement system. These include Ionis-FB-LRX for factor B, pegcetacoplan for C3, vemircopan and pelecopan for factor D, cemdisiran for C5, and avacopan for C5a receptor 1.

Combining agents within the AIBC framework requires careful monitoring to minimize risks. For angiorenal protection, RAS inhibitors and MRAs can increase the risk of hyperkalemia and kidney injury, necessitating frequent monitoring of potassium and renal function. Immunosuppressants like glucocorticoids may interact with CNI, affecting glucose control. B-cell/plasma-cell modulators and complement inhibitors could increase infection risks when used with immunosuppressants, requiring infection prophylaxis and monitoring. A phased or sequential introduction of therapies and personalized monitoring are essential to ensure safety and efficacy.

Individualized therapy is essential due to IgAN’s heterogeneity, with specific considerations for ethnic variations in disease presentation and response to treatment. Genome-wide association studies have highlighted differences in genetic risk factors for IgAN, with East Asian populations showing a higher prevalence of risk loci, such as variations in HLA-DQ and CFH genes, which influence complement activation and immune responses. Ethnic variations in IgAN presentation and treatment response highlight the need to tailor the AIBC framework. For East Asian populations, where genetic predispositions and complement activation are more prominent, complement inhibitors like iptacopan may be prioritized. Caucasian patients may benefit from lower dose glucocorticoids or gut-targeted therapies like Nefecon, while African and Hispanic populations often require a focus on addressing comorbidities and lifestyle modifications in addition to pharmacological treatments. A personalized approach accounting for genetic, clinical, and socioeconomic factors is essential to optimize outcomes across diverse populations.

One critical area for improvement in IgAN management is the development of validated biomarkers to guide treatment, monitor response, and detect toxicity. While promising omics-based research is underway to identify potential biomarkers through genomics, transcriptomics, and proteomics, clinically validated biomarkers are still lacking. Reliable serum and urine biomarkers together with histological markers are essential to implement a genuinely personalized approach, making biomarker research a priority for advancing IgAN care. Future treatment approaches aim to halt nephron loss by integrating multi-targeted therapies early, potentially combining supportive therapies such as RASis with novel agents targeting immunity, pathogenic IgA production, and complement activation. This approach not only seeks to stabilize kidney function but also represents a shift from monotherapy to a synergistic, sequential, multi-targeted model of care.

The treatment landscape for IgAN is shifting from monotherapy to a multi-targeted approach that concurrently addresses BP, proteinuria, immunity, B-/plasma-cell modulation, and complement activation. The AIBC framework offers a comprehensive strategy to mitigate disease progression and reduce the risk of kidney failure in IgAN patients (online suppl. supplement 1; for all online suppl. material, see https://doi.org/10.1159/000544998 AIBC Decision Tree). Notably, cyclical consolidation therapy should be considered, as several agents have shown benefits on proteinuria and renal function might disappear 2–3 years after drug discontinuation, suggesting the importance of maintenance or consolidation therapy in potential progressive IgAN. Cyclical consolidation therapy aims to sustain treatment benefits by alternating or reintroducing therapies based on disease course, activity, potential harm, and patient response. Initially, combination therapy (e.g., RAS inhibitors, SGLT2 inhibitors, and immunomodulators) is used to achieve proteinuria control (<0.5 g/d) and stabilize eGFR. For patients unable to achieve therapeutic goals, with reversible histological damage, rapidly progressing disease, or refractory lesions, systemic or targeted immunosuppressive therapy, B-/plasma-cell modulation, and complement inhibition should be promptly administered to achieve effective disease control and remission, with a course duration of no less than 9 months. Once treatment goals are achieved, therapy transitions to a lower dose angiorenal protective combination to minimize long-term toxicity. During disease recurrence or progression, therapies such as immunomodulators, B-/plasma-cell modulation, or complement inhibitors are reintroduced cyclically, guided by histological and biomarker trends.

Low-toxicity drugs can be used for long-term maintenance therapy. When the disease progresses to an irreversible stage of kidney failure, only supportive therapy is required. This dynamic strategy ensures effective management while minimizing adverse effects and addressing the patient’s evolving needs. A “treat-to-target” approach, aiming to maintain proteinuria at <0.3 g/d or slow eGFR decline to <1 mL/min/1.73 m² annually, achieving a trajectory comparable to the age-related physiological decline in adults is recommended.

As we enter this new era of IgAN management, clinical trials and real-world studies will refine these strategies, optimize therapy combinations, and pave the way for personalized treatment approaches. By properly balancing the benefits and risks of therapies, IgAN patients will be able to achieve improved long-term outcomes and truly benefit from numerous milestone clinical trials.

Shengqiang Yu was a member of the journal’s Editorial Board at the time of submission.

This work was supported by National Natural Science Foundation of China (81970640, 82370735), Shanghai Science and Technology Innovation Action Plan of Scientific Instruments and Chemical Reagents Project (24142201800), and China Scholarship Council (202408310237).

B.D., S.Y., and L.Y. conceived and performed the study, reviewed the data, and contributed to the writing of the manuscript. C.X., W.G., and Y.X. contributed to the writing of the manuscript. B.D. revised the manuscript. All authors reviewed the manuscript.

Cheng Xue, Shengqiang Yu, and Wei Gou contributed equally to this work.