IgA nephropathy: Emerging therapies and updated KDIGO guidance

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Reference: September-October 2026 | Issue 5 | Vol 19 | Page 22

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Immunoglobulin A nephropathy (IgAN), also known as Berger’s disease, remains the most common primary glomerulonephritis worldwide and is a leading cause of chronic kidney disease (CKD) and kidney failure among young and middle-aged adults.

Despite decades of research, treatment options were historically limited to supportive care and non-specific immunosuppression. However, the past five years have witnessed a remarkable transformation in the management of IgAN, driven by advances in understanding disease pathogenesis and the development of targeted therapies.¹

The publication of the KDIGO (Kidney Disease Improving Global Outcomes) clinical practice guideline for the management of IgAN and IgA vasculitis in 2025 represents the most substantial advance in guidance since the KDIGO glomerular diseases guideline published in 2021.

Building on the 2024 public review draft and incorporating evidence available up to August 2024, the guideline reflects a fundamental shift from a predominantly supportive-care approach towards risk-stratified, mechanism-based management.¹

Rather than focusing solely on the consequences of glomerular injury, clinicians are now encouraged to address both the underlying disease-specific mechanisms and the downstream pathways leading to nephron loss simultaneously.¹

This approach is particularly relevant, as several novel therapies targeting different pathogenic mechanisms have entered clinical practice. The emergence of targeted-release budesonide, endothelin receptor antagonists, complement inhibitors, and therapies directed against B-cell activating pathways has transformed expectations regarding disease modification and long-term renal preservation.¹

Epidemiology and disease burden

IgAN occurs across all ethnic groups but shows marked geographic variation in reported incidence and prevalence. The highest rates are observed in East Asian populations, where routine population-based urine screening programmes enable earlier detection, including of asymptomatic disease. Reported prevalence in Europe is lower, although IgAN still accounts for approximately 20-30 per cent of biopsy-confirmed primary glomerulonephritides and remains a significant cause of CKD and progression to end-stage kidney disease.²

The disease most commonly presents between the second and fourth decades of life, although diagnosis may occur at any age. Men are affected more frequently than women, particularly in European populations. Clinical presentations vary considerably, ranging from asymptomatic microscopic haematuria to rapidly progressive glomerulonephritis. Macroscopic haematuria following upper respiratory tract infections remains a classic presentation, although many patients are identified incidentally during investigation of persistent proteinuria or declining renal function.²

Long-term outcome studies consistently demonstrate that IgAN is not a benign condition, with a substantial proportion of patients progressing to advanced kidney disease over time. Approximately 30-40 per cent of individuals develop kidney failure within 20 years of diagnosis. Disease progression is strongly associated with persistent proteinuria, hypertension, reduced estimated glomerular filtration rate (eGFR), and adverse histopathological features, all of which are recognised as key predictors of renal decline.³

Pathogenesis

Understanding of the pathogenesis of IgAN has advanced considerably over the past decade. The current disease model is based on the multi-hit hypothesis, which describes a stepwise process involving aberrant IgA1 production, formation of pathogenic immune complexes, and subsequent glomerular deposition. This framework provides the mechanistic basis for the development of emerging targeted therapies aimed at interrupting specific stages of disease progression.⁴

The initial pathogenic step in IgAN is increased production of galactose-deficient IgA1 (Gd-IgA1), primarily originating from mucosal-associated lymphoid tissue. This abnormal form of IgA1 is immunogenic, and triggers an autoimmune response, leading to the generation of anti-glycan antibodies. These antibodies bind to Gd-IgA1, forming circulating immune complexes that are deposited in the glomerular mesangium, where they initiate inflammation and mesangial injury.⁴

Mesangial deposition of immune complexes triggers a downstream cascade of inflammatory and injurious processes within the glomerulus. This includes activation of the complement system, release of pro-inflammatory cytokines, mesangial cell proliferation, podocyte injury, and progressive extracellular matrix expansion leading to fibrosis. Increasing evidence indicates that activation of the alternative and lectin complement pathways plays a central role in driving ongoing renal injury and disease progression.

Histopathological studies consistently demonstrate glomerular deposition of complement components, including C3, properdin, factor H-related proteins, and mannose-binding lectin pathway-associated molecules, highlighting the importance of complement activation in the pathobiology of IgAN.⁵

Genetic studies have further reinforced the central role of mucosal immune dysregulation, complement pathway regulation, and adaptive immune responses in determining susceptibility to IgAN. These findings have significantly advanced understanding of disease biology and have enabled the development of more targeted therapeutic strategies that act on specific pathogenic pathways.⁵

Risk stratification and prognosis

The 2025 KDIGO guideline places strong emphasis on early risk stratification and a personalised approach to management. Rather than adopting a uniform treatment strategy for all patients, clinicians are encouraged to assess individual risk of disease progression and to tailor therapy accordingly. This approach supports more targeted use of emerging disease-specific treatments alongside optimised supportive care.¹

Proteinuria remains the most important modifiable predictor of renal outcome in IgAN. Persistent proteinuria above 0.5g/day is now recognised as a marker of increased risk of progression, while levels exceeding 1g/day are strongly associated with a more rapid decline in kidney function. As a result, reduction and sustained control of proteinuria has become the primary therapeutic target, supported by extensive evidence demonstrating a consistent association between proteinuria reduction and improved long-term renal outcomes.¹

The International IgAN prediction tool remains a cornerstone of contemporary risk stratification. This validated model integrates key clinical and pathological variables, including age, sex, blood pressure, eGFR, proteinuria, use of immunosuppressive therapy, and Oxford MEST-C histopathological features, to estimate the risk of a 50 per cent decline in kidney function or progression to kidney failure. By combining clinical and biopsy data, it provides a robust framework for individualised prognosis and supports more informed treatment decision-making.⁶

The 2025 KDIGO guideline also emphasises the importance of longitudinal assessment rather than reliance on single time-point measurements, recognising that disease activity, treatment response, and risk of progression in IgAN can change significantly over time. Continuous reassessment of clinical parameters such as proteinuria, blood pressure, and eGFR is essential to ensure timely adjustment of therapy and more accurate risk stratification.¹

KDIGO 2025: A paradigm shift in management

The 2025 KDIGO guideline represents the most significant revision of IgAN management recommendations since the original 2021 publication. Perhaps the most important conceptual shift is the recognition that effective management of IgAN must target both the underlying disease-specific mechanisms and the downstream pathways that drive progressive nephron loss.

Earlier therapeutic strategies focused largely on supportive care, particularly blood pressure control and reduction of proteinuria. While these interventions remain fundamental to management, they are now understood to represent only one component of a broader, more integrated treatment approach that also addresses the immunological and inflammatory processes driving disease progression.¹

The guideline proposes a dual-pathway framework. Disease-specific interventions target pathogenic IgA production, immune complex formation, complement activation, and glomerular inflammation. Concurrently, nephroprotective therapies address hyperfiltration injury, hypertension, proteinuria, and cardiovascular risk factors.¹

The ultimate therapeutic objective is to reduce annual eGFR decline to less than 1mL/min/1.73m² per year, thereby approximating physiological age-related kidney function loss.¹

Supportive care remains the foundation of treatment

Alongside the development of novel targeted therapies, optimised supportive care remains the cornerstone of IgAN management. All patients should receive comprehensive nephroprotective treatment as baseline standard of care, with disease-specific therapies introduced in those who continue to demonstrate a high risk of progression despite maximised supportive measures.¹

Renin-angiotensin system inhibition remains the first-line treatment for proteinuric disease. Both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers reduce intraglomerular pressure, decrease proteinuria, and slow progression of kidney dysfunction.¹

The KDIGO guideline advocates intensive blood pressure control, with a target systolic blood pressure below 120mmHg, where tolerated. Evidence from CKD populations consistently demonstrates that tighter blood pressure control reduces progression risk and cardiovascular complications.^1,7

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as a key component of supportive therapy in IgAN. Subgroup analyses from the DAPA-CKD and EMPA-KIDNEY trials demonstrated consistent renal benefit in patients with IgAN, including reductions in proteinuria and a slower rate of decline in eGFR, supporting their role as standard nephroprotective therapy in this population.^8,9 These benefits appear independent of diabetes status and have resulted in widespread incorporation of SGLT2i into routine IgAN management.

Lifestyle interventions, including dietary sodium restriction, smoking cessation, weight management, and cardiovascular risk reduction, remain integral to long-term care.¹

Targeted-release budesonide: The first disease-specific therapy

The approval of targeted-release budesonide marked the beginning of a new therapeutic era in IgAN. Unlike conventional corticosteroids, this formulation delivers high concentrations of budesonide to Peyer’s patches within the distal ileum, a major site of pathogenic IgA production.¹⁰

The NefIgArd phase III trial demonstrated significant reductions in proteinuria accompanied by preservation of kidney function. Patients receiving targeted-release budesonide experienced substantially slower eGFR decline compared with placebo, and benefits were sustained beyond treatment completion.¹⁰

The targeted delivery system reduces systemic corticosteroid exposure and minimises adverse effects traditionally associated with glucocorticoid therapy. Although mild steroid-related effects still occur, rates of serious infection, diabetes, osteoporosis, and weight gain are substantially lower than those observed with conventional systemic corticosteroids.¹⁰

The KDIGO guideline now recommends targeted-release budesonide for patients with IgAN who continue to have persistent proteinuria despite optimised supportive care and who remain at increased risk of disease progression.¹

Endothelin receptor antagonism: Sparsentan and atrasentan

Endothelin-1 is a key mediator of glomerular haemodynamic stress and contributes to kidney injury through multiple mechanisms, including intraglomerular hypertension, podocyte damage, inflammation, and fibrosis. As a result, pharmacological inhibition of endothelin signalling has emerged as a promising therapeutic strategy aimed at reducing proteinuria and slowing progression of CKD.¹¹

Sparsentan is a dual-acting agent that combines endothelin type A receptor antagonism with angiotensin II type 1 receptor blockade in a single molecule. In the PROTECT trial, sparsentan achieved significantly greater reductions in proteinuria compared with irbesartan alone, supporting its efficacy as a highly potent antiproteinuric therapy and reinforcing its role as an important emerging treatment option in IgAN.¹²

Longer-term analyses suggest that sparsentan may contribute to meaningful preservation of kidney function, although continued follow-up is required to confirm effects on hard renal outcomes such as kidney failure. The degree of proteinuria reduction observed with sparsentan is greater than that typically achieved with conventional renin-angiotensin system blockade – and approaches levels previously seen only with more intensive immunosuppressive regimens.¹²

Atrasentan is a highly selective endothelin-A receptor antagonist that has progressed to regulatory approval following positive results from the ALIGN study. Treatment with atrasentan has been associated with clinically meaningful reductions in proteinuria, alongside an acceptable safety and tolerability profile. The emergence of two endothelin-targeting therapies represents a significant advance in nephroprotective treatment options for IgA nephropathy, expanding therapeutic choice for patients at higher risk of disease progression.¹³

Complement inhibition

Recognition of complement activation as a key mediator of glomerular injury in IgAN has generated substantial interest in the development of targeted complement-directed therapies aimed at interrupting this pathogenic pathway. Iptacopan is an oral factor B inhibitor that selectively targets the alternative complement pathway. Results from the APPLAUSE-IgAN trial demonstrated clinically meaningful reductions in proteinuria, together with a slower rate of decline in kidney function.

These findings support the concept that complement activation is not simply a biomarker of disease activity, but a key driver of disease progression in IgAN.¹⁴ By limiting complement-driven inflammation and subsequent structural damage within the kidney, these agents may slow disease progression while offering a more selective approach than conventional broad immunosuppressive therapy, with the potential for improved tolerability.¹⁴

Additional complement-targeting therapies are currently under investigation, including agents directed against factor D, MASP-2, C5, and other key components of the complement cascade. As understanding of disease heterogeneity and pathway-specific injury in IgAN continues to evolve, complement inhibition is expected to play an increasingly important role within future precision medicine approaches over the coming decade.²

BAFF and APRIL inhibition: Suppressing pathogenic IgA production

B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL) are important regulators of B-cell maturation and IgA production. Elevated levels of these cytokines are consistently observed in patients with IgAN and are associated with increased production of pathogenic Gd-IgA1.¹

Sibeprenlimab is a monoclonal antibody targeting APRIL. Clinical trials have demonstrated substantial reductions in proteinuria accompanied by decreases in circulating Gd-IgA1 concentrations. The observed effects support the concept that direct suppression of pathogenic IgA production may alter disease trajectory.¹⁵

Atacicept is a dual inhibitor of BAFF and APRIL signalling pathways, both of which play central roles in B-cell maturation and antibody production. Early clinical studies have demonstrated encouraging reductions in proteinuria alongside improvements in disease-associated biomarkers. This class of therapy is particularly promising because it targets upstream drivers of aberrant IgA production, rather than focusing solely on downstream inflammatory and fibrotic consequences of established disease.¹⁶

Long-term outcome data are still emerging; however, BAFF/APRIL inhibition has the potential to represent one of the most disease-specific therapeutic approaches in IgAN, given its direct effects on the pathways responsible for aberrant IgA production.

The role of corticosteroids

Historically, corticosteroids were the primary disease-modifying therapy available for patients with progressive IgAN. However, concerns regarding significant adverse effects and variable risk-benefit profiles have led to a reassessment of their role within contemporary treatment algorithms.

The TESTING trial confirmed that corticosteroids can reduce the risk of major renal outcomes in IgAN – however, this benefit was associated with a significant increase in serious adverse events, most notably infections. Although lower-dose regimens improved safety, they did not fully eliminate concerns, and the overall balance between efficacy and toxicity remains an important consideration in clinical decision-making.¹⁷

The 2025 KDIGO guideline continues to acknowledge systemic corticosteroids as a treatment option for carefully selected high-risk patients – however, it places growing emphasis on the use of more targeted therapies where these are available. The development of disease-specific agents, including targeted-release budesonide and other emerging therapies, is expected to progressively reduce dependence on conventional systemic glucocorticoid regimens in clinical practice.¹

Conclusion

The management of IgAN has undergone a profound shift over the past decade, fuelled by major advances in understanding disease pathogenesis and the identification of key therapeutic targets. This evolving knowledge has enabled the development of multiple disease-modifying therapies that intervene at distinct stages of the pathogenic cascade, moving management beyond supportive care alone. The 2025 KDIGO guideline reflects this paradigm shift and reinforces a comprehensive strategy that integrates optimised nephroprotective therapy with emerging disease-specific interventions.

Targeted-release budesonide, endothelin receptor antagonists such as sparsentan and atrasentan, complement inhibitors including iptacopan, and emerging BAFF/APRIL-directed therapies collectively represent a new generation of mechanism-based treatments. These agents not only reduce proteinuria but also have the potential to modify long-term disease trajectory by directly targeting key biological drivers of glomerular injury.

Despite these significant advances, important challenges remain. Key uncertainties persist regarding long-term safety, optimal sequencing and combination of therapies, equitable access, and cost-effectiveness across different healthcare systems. Full approval and reimbursement has yet to be granted for all of these therapies in Ireland. Nevertheless, the therapeutic landscape of IgAN has changed fundamentally.

For the first time, clinicians have access to an expanding portfolio of interventions that target the underlying immunological and inflammatory drivers of disease, rather than focusing solely on its downstream clinical consequences. As therapeutic innovation continues and precision medicine approaches become more refined, the prospect of substantially reducing progression to kidney failure in IgA nephropathy is becoming increasingly achievable.