IgA nephropathy (IgAN) is a disease that quietly damages the kidneys over years, often decades, before many patients are even aware something is wrong. It is the most common form of primary glomerulonephritis in the world, affecting millions of people across all continents and representing a leading cause of chronic kidney disease (CKD) progressing to end-stage renal disease (ESRD). Despite its global prevalence, IgAN has historically been under-recognized and undertreated, partly because its mechanisms were poorly understood and effective targeted therapies were lacking.
That picture is now changing rapidly. Over the past decade, fundamental advances in immunology, genomics, and clinical trial science have transformed the way the nephrology community understands and approaches IgAN. The International Society of Nephrology has been central to this transformation — facilitating scientific collaboration, developing clinical guidelines, and supporting the research infrastructure bringing new therapies from the laboratory to patients worldwide.
What Is IgA Nephropathy and Why Does It Matter?
To understand IgAN, it helps to understand the role of immunoglobulin A (IgA) in the body. IgA is an antibody produced in large quantities by the immune system, particularly at mucosal surfaces such as the lining of the gut and respiratory tract. Its primary function is to defend these surfaces from infection. In most people, IgA circulates harmlessly and is cleared efficiently from the body.
In people with IgAN, however, a structural abnormality in certain IgA1 molecules — specifically, a deficiency of galactose sugar on specific attachment sites — leads to what scientists call galactose-deficient IgA1, or Gd-IgA1. This abnormal form of the antibody is poorly recognized and cleared by the body’s usual mechanisms. Instead, it accumulates in the bloodstream and becomes a trigger for an immune response that ultimately damages the kidneys.
The clinical consequences are serious. Many patients with IgAN develop progressive proteinuria (excess protein in the urine), hematuria (blood in the urine), and a gradual decline in kidney filtration capacity measured by the estimated glomerular filtration rate (eGFR). Without effective intervention, approximately 20–40% of patients with IgAN will reach ESRD within 20 years of diagnosis, requiring dialysis or a kidney transplant to survive.
The Four-Hit Model: A Framework for Understanding Disease Progression
The scientific understanding of how IgAN develops has been organized into what is now widely known as the four-hit pathogenesis model, consolidated by Wyatt and Julian in a landmark review published in the New England Journal of Medicine in 2013. This model describes the disease as a sequential process involving four interconnected events:
- Hit 1 — Overproduction of Gd-IgA1: Mucosal plasma cells, particularly those in the gut, produce excessive quantities of galactose-deficient IgA1. This abnormal antibody is thought to be driven in part by dysregulated mucosal immune signaling.
- Hit 2 — Autoantibody formation: The aberrant Gd-IgA1 is recognized as “foreign” by the immune system, which responds by generating autoantibodies — antibodies directed against the body’s own molecules — that specifically target these abnormal IgA1 molecules.
- Hit 3 — Immune complex deposition: The Gd-IgA1 molecules and their corresponding autoantibodies bind together to form immune complexes, which circulate in the bloodstream and deposit in the mesangium — the central supporting tissue of the kidney’s filtering units, known as glomeruli.
- Hit 4 — Glomerular inflammation: The deposited immune complexes trigger local inflammation in the mesangium, activating the complement system and other inflammatory pathways, causing glomerular injury and progressive kidney damage.
This four-hit model has proven invaluable not only for explaining disease biology but also for identifying potential therapeutic targets at each stage of the pathological cascade.
The Genetic Landscape of IgAN
A major advance in understanding IgAN came from large-scale genomic research. A landmark genome-wide association study (GWAS) by Kiryluk and colleagues, published in Nature Genetics in 2014, identified 15 susceptibility loci associated with IgAN risk. These genetic variants span several important biological pathways, including:
- Complement system genes, which regulate immune complex clearance and inflammatory activation
- Cytokine signaling networks, including pathways governing mucosal immune responses
- HLA (human leukocyte antigen) regions, which orchestrate the body’s adaptive immune recognition
These findings confirmed that IgAN emerges from a complex interplay between innate and adaptive immunity, and revealed substantial genetic diversity across ethnic populations — helping explain why IgAN prevalence is notably higher in East Asian populations than in individuals of African descent. The ISN (International Society of Nephrology) has actively supported the integration of genomic data into clinical research, recognizing that genetic susceptibility is essential context for developing precision medicine approaches to IgAN.
The Role of Mucosal Immunity: APRIL, BAFF, and the Gut-Kidney Axis
One of the most important emerging areas in IgAN research concerns the relationship between mucosal immunity and kidney disease — often described informally as the gut-kidney axis. Research has identified two cytokines, APRIL (a proliferation-inducing ligand) and BAFF (B-cell activating factor), as key drivers of the overproduction of aberrantly glycosylated IgA1 by mucosal plasma cells in the gut lining.
These cytokines promote the survival and activity of plasma cells — antibody-secreting immune cells — particularly at mucosal surfaces. When their signaling is dysregulated in susceptible individuals with IgAN, the result is an excess of abnormal Gd-IgA1 entering the circulation and reaching the kidneys.
This mechanistic insight provided the scientific rationale for a novel therapeutic approach: delivering an anti-inflammatory drug directly to the mucosal immune cells responsible for producing excess Gd-IgA1. Targeted-release budesonide (Nefecon) was designed with exactly this purpose — to release the corticosteroid budesonide specifically in the distal ileum, where the highest density of IgA-producing mucosal plasma cells is located, minimizing systemic steroid exposure while suppressing local mucosal immune activity.
The NefIgArd phase 3 clinical trial, published by Barratt and colleagues in the New England Journal of Medicine in 2023, demonstrated that targeted-release budesonide significantly reduced proteinuria and slowed eGFR decline over two years in patients with IgAN. This represented a major milestone — the first regulatory-approved therapy specifically targeting an immunological mechanism in IgAN.
Complement Inhibition: A Central Therapeutic Strategy
Alongside mucosal immune targeting, inhibition of the complement system has emerged as one of the most promising therapeutic directions in IgAN. The complement system is a network of proteins that amplifies immune responses and promotes inflammation. In IgAN, complement activation — particularly through the alternative and lectin pathways — plays a critical role in amplifying glomerular injury triggered by immune complex deposition.
Iptacopan, a small-molecule inhibitor of complement Factor B — a key component of the alternative complement pathway — has been evaluated in the APPLAUSE-IgAN clinical trial. By blocking Factor B, iptacopan interrupts the amplification loop of the alternative pathway, thereby reducing downstream complement-mediated inflammation in the glomeruli.
The potential of complement-directed therapy in IgAN reflects a broader trend in nephrology: moving from generalized immunosuppression toward pathway-specific interventions that target the precise mechanisms driving kidney damage in individual patients.
Sparsentan and the Dual-Receptor Approach
Beyond immunological targets, another innovative strategy in IgAN management has been simultaneous blockade of two receptors involved in kidney injury: the endothelin receptor and the angiotensin receptor. Sparsentan, a dual endothelin and angiotensin receptor antagonist, was evaluated in the PROTECT trial, published by Rovin and colleagues in The Lancet in 2023.
The trial demonstrated that sparsentan achieved significantly greater reductions in proteinuria compared to irbesartan — a standard angiotensin receptor blocker — at 36 weeks of follow-up. Proteinuria is not only a marker of kidney injury in IgAN but also a direct driver of progressive damage; reducing it is therefore a meaningful clinical goal in its own right.
The development of sparsentan illustrates how therapeutic innovation in IgAN is occurring across multiple fronts simultaneously — targeting immunological mechanisms, hemodynamic factors, and inflammatory pathways in parallel, with the goal of offering combination therapies that address the disease from several angles at once.
The Oxford MEST-C Classification: Standardizing Biopsy Reporting
Accurate diagnosis and disease stratification are essential prerequisites for effective treatment. In IgAN, the kidney biopsy remains the gold standard for diagnosis and provides critical information about the degree and type of kidney damage present. The Oxford MEST-C classification system, originally described by Roberts and colleagues in Kidney International in 2009 and updated in 2017, provides a standardized framework for biopsy reporting in IgAN.
The classification evaluates five key pathological features:
| Feature | Abbreviation | What It Describes |
|---|---|---|
| Mesangial hypercellularity | M | Increased number of cells in the mesangium |
| Endocapillary hypercellularity | E | Cells within the capillary loops of the glomerulus |
| Segmental glomerulosclerosis | S | Scarring affecting part of individual glomeruli |
| Tubular atrophy / interstitial fibrosis | T | Scarring in kidney tubules and surrounding tissue |
| Crescents | C | Abnormal cellular accumulations indicating severe injury |
The International Society of Nephrology has strongly endorsed the Oxford MEST-C classification as the standard approach for biopsy reporting in IgAN, and its use has been incorporated into both KDIGO Clinical Practice Guidelines for Glomerulonephritis (2012 and the 2021 update) and eligibility criteria for major multinational clinical trials. Standardized biopsy reporting enables researchers and clinicians to compare findings across diverse patient populations and to enrich clinical trials with patients who share similar disease characteristics — a critical requirement for generating reliable evidence about new therapies.
The Role of ISN in Shaping the IgAN Research Landscape
The International Society of Nephrology has played an instrumental role at multiple levels of IgAN research and clinical practice development. Through its scientific working groups, the ISN has facilitated international dialogue on IgAN pathophysiology, bringing together leading researchers, clinicians, and patient advocates to synthesize emerging evidence and identify priority areas for investigation.
The ISN-supported IgAN registry — a multinational platform for collecting epidemiological, clinical, and biomarker data from patients with IgAN — has been a particularly important resource. Registries of this kind are essential for understanding the natural history of IgAN across different ethnic groups, geographic regions, and healthcare settings, and for identifying biomarkers that predict disease progression or response to specific treatments.
ISN has also supported the development and dissemination of KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guidelines for Glomerulonephritis. These guidelines synthesize the best available evidence on the management of IgAN and related conditions, providing clinicians worldwide with evidence-based recommendations on when and how to treat patients, which biomarkers to monitor, and how to integrate new therapies into clinical practice.
The International Society of Nephrology has also promoted equitable access to IgAN diagnosis and treatment globally — a critical mission given that IgAN disproportionately affects populations in lower-resource settings where advanced diagnostics and novel therapies may not yet be widely available.
Toward Individualized Treatment: The Future of IgAN Management
The rapid expansion of therapeutic options for IgAN raises an important question: how should clinicians decide which treatment — or combination of treatments — is most appropriate for an individual patient? The answer will increasingly depend on a combination of clinical, histological, and biomarker data that together paint a detailed picture of each patient’s disease profile.
Key factors likely to guide individualized treatment decisions include:
- Serum levels of Gd-IgA1 and related autoantibodies, which may reflect the activity of the mucosal immune axis
- Complement activation markers that indicate the degree of complement-driven inflammation
- Oxford MEST-C biopsy scores that characterize the type and severity of glomerular and tubulointerstitial damage
- Rate of proteinuria reduction in response to initial therapy, which can serve as an early indicator of longer-term renal outcomes
- Genetic susceptibility markers that may predict disease course or drug response
The ISN and its collaborative networks are actively working to validate biomarkers and develop decision-support tools that can translate this biological knowledge into practical clinical guidance for nephrologists treating patients with IgAN worldwide.
Conclusion
IgA nephropathy stands at a pivotal moment in its clinical history. What was once managed largely with supportive care and nonspecific immunosuppression is now the focus of a rich pipeline of mechanism-targeted therapies — from mucosal immune modulation and complement inhibition to dual-receptor antagonism. The scientific advances behind this transformation have been built on decades of collaborative research in immunology, genomics, and clinical science, coordinated and supported in significant part by the International Society of Nephrology.
The work is far from complete. Many patients with IgAN still face an uncertain prognosis, and access to the newest diagnostics and treatments remains uneven across the globe. But the trajectory is clear: a future in which IgAN is managed with individualized, targeted therapies that meaningfully slow or halt disease progression is now within reach. For the ISN and the broader nephrology community it represents, ensuring that this future reaches all patients — regardless of where they live — remains a central and enduring mission.