IgA nephropathy: Entering an era of disease-modifying treatment

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Reference: 2026 | Issue 7 | Vol 12 | Page 18

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IgA nephropathy (IgAN) was first described in 1968 by Jean Berger, a French pathologist who applied the then novel technique of immunofluorescence microscopy to renal biopsies, reporting a cohort of patients with the hallmark finding of IgA-dominant immune complex deposition within the glomerulus. Formerly known as Berger’s disease, IgAN is the most prevalent primary glomerulonephritis worldwide with an estimated global incidence of 2.5 per 100,000 individuals per year. The reported incidence varies substantially worldwide, likely reflecting a combination of underlying genetic susceptibility within distinct populations and ethnicities; differences in socioeconomic status, healthcare access, and screening; and variation in kidney biopsy practices worldwide. IgAN is most prevalent in individuals with Asian ancestry, has a lower prevalence in European and American populations, and is least common in individuals of African ancestry. For many years, IgAN was regarded as an indolent and slowly progressive disease; however, recent studies have shown that the lifetime risk of end-stage kidney disease (ESKD) is significantly higher than previously appreciated, with more than 50 per cent of patients progressing to ESKD within 20 years of diagnosis and few patients able to escape renal failure in their expected lifetime.

Pathogenesis of IgAN

Our knowledge of the pathogenesis of IgAN is framed around the widely accepted four hit hypothesis, which describes a sequential series of four immunopathological processes that culminate in progressive renal injury.

• First hit: Aberrant production of galactose-deficient IgA: Galactose-deficient immunoglobulin A1 (Gd-IgA1), characterised by defective O-glycosylation of the hinge region, is produced by B-cells leading to elevated levels in the circulation. Aberrant IgA glycosylation can occur in those with underlying genetic susceptibility and may be precipitated by respiratory or gastrointestinal infection.
• Second hit: Formation of autoantibodies against Gd-IgA1: Circulating Gd-IgA1 is recognised as a neoantigen, triggering the formation of IgG and IgA autoantibodies directed against Gd-IgA1.
• Third hit: Pathogenic immune complex formation: The autoantibodies bind with Gd-IgA1 to form circulating immune complexes.
• Fourth hit: Glomerular deposition of Gd-IgA1-containing immune complexes: Immune complexes are deposited within the mesangium of the glomerulus, resulting in mesangial cell activation and proliferation, excessive extracellular matrix deposition, complement activation, and the release of pro-inflammatory cytokines and pro-fibrotic growth factors. These events propagate glomerular and tubulointerstitial inflammation, ultimately leading to progressive fibrosis, nephron loss, and declining renal function.

Additional risk factors for the development of IgAN have been identified which expand and modulate the above framework.

• Mucosa-associated lymphoid tissue (MALT) plays a pivotal role in coordinating the immune response to antigens encountered at mucosal surfaces. There is significant evidence of dysregulated mucosal IgA production in IgAN. Clinical presentations often arise with concurrent or preceding/chronic respiratory or gastrointestinal infection. The cytokines B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) promote B-cell survival, maturation, and differentiation. They regulate differentiation of mucosal B-cells into IgA-producing plasma cells and are heavily implicated in IgAN pathogenesis by animal models and genetic studies.
• Complement activation is implicated in the pathogenesis of IgAN by mesangial deposition of complement cascade components in biopsy tissue. Gd-IgA1 can activate the alternative complement pathway, and activation of the mannose-binding-lectin pathway is also observed in a subset of individuals with IgAN.
• Genome-wide association studies have identified over 30 susceptibility loci for IgAN, involving genes encoding members of the human leukocyte antigen region region, complement pathway, APRIL/BAFF, and members of the tumour necrosis factor superfamily.
• IgAN may occur in association with other systemic disorders and has been termed ‘secondary’ IgAN in that context, though a consensus definition is lacking. The systemic diseases reported to exhibit a strong association with secondary IgAN are listed in Table 1.

TABLE 1: Systemic diseases linked with IgAN

Clinical presentation

The spectrum of clinical presentation of IgA nephropathy is highly variable and ranges from the incidental detection of microscopic haematuria with preserved renal function to rapidly progressive glomerulonephritis leading to ESKD over a short time frame. Though IgAN can present at any age, most individuals present aged 40-45 years with components of the nephritic syndrome, namely microscopic haematuria, proteinuria, and hypertension, variably accompanied by impaired renal function. Childhood urinary screening, employed in many Asian countries with high incidence of IgAN, may lead to an earlier diagnosis with detectable microscopic haematuria and/or proteinuria. The ‘classic presentation’ of visible haematuria in association with an upper respiratory tract or gastrointestinal infection (synpharyngitic haematuria) arises in only 10-30 per cent of cases, tending to occur in young adults. Less frequent clinical presentations include rapidly progressive glomerulonephritis and, rarely, nephrotic syndrome.

Diagnosis

A renal biopsy is required to diagnose IgAN. The recently updated Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guideline on the management of IgAN has recommended that all adults with proteinuria >0.5g/day in whom IgAN is suspected should have a renal biopsy unless contraindicated. Characteristic features of IgAN on light microscopy include mesangial matrix expansion, mesangial and/or endocapillary hypercellularity, and cellular or fibrocellular crescent formation. Glomerulosclerosis, interstitial fibrosis, and tubular atrophy, if seen, are general markers of disease chronicity within the kidney. The hallmark finding is that of IgA dominant or co-dominant IgA mesangial staining on immunofluorescence, often accompanied by complement deposition. Electron microscopy demonstrates mesangial and, less frequently, sub-endothelial electron-dense immune deposits.

IgA-mediated kidney involvement may occur as part of IgA vasculitis (formerly Henoch–Schönlein purpura), a systemic small-vessel vasculitis characterised by IgA-dominant immune complex deposition, IgA-dominant infection-related glomerulonephritis, as well as secondary forms of IgAN. Consequently, primary IgAN is considered a diagnosis of exclusion after appropriate investigation for secondary causes.

Identification of patients at high risk of progression

There is a considerable variation in the presentation and clinical course of IgAN. However, recent work has redefined our understanding of the risk of progression to ESKD for individuals with IgAN, emphasising the importance of early identification of high-risk patients in our clinical cohorts.

Proteinuria is consistently associated with risk of disease progression and represents a key target for modification to reduce the likelihood of progression to ESKD. It is now recognised that levels of proteinuria previously characterised as low risk (<1g/day or 0.88g/day protein:creatinine ratio) are associated with high incidence of kidney failure within 10 years of diagnosis. Indeed, the probability of kidney survival reduced by almost half over the 15-year follow-up among patients with time-averaged proteinuria of between 0.44 to 0.88g/day.

In addition to establishing a diagnosis of IgAN, parameters reported in the renal biopsy provide valuable prognostic information and aid identification of patients at highest risk of disease progression.

The histopathological features of IgAN are evaluated using the Oxford Classification, a standardised scoring system based on kidney biopsy features independently associated with more rapid decline of renal function. Introduced in 2009, the original MEST scores are based on the presence and degree of mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T). In 2016, the classification was updated to MEST-C by incorporating a C (crescent) – denoting the presence and extent of cellular or fibrocellular crescents, reflecting their association with poorer outcomes.

The International IgAN Prediction Tool incorporates several clinical and histopathological parameters (including MEST-C scores) to estimate the risk of a 50 per cent decline in estimated glomerular filtration rate (eGFR) or progression to ESKD over the subsequent five years. A further refinement to the model can be used for risk stratification up to two years after the biopsy with updated clinical parameters, permitting reassessment of risk after a period of supportive care. While the updated KDIGO clinical practice guidelines for IgAN recommend use of MEST-C scoring and the International IgAN Prediction Tools to aid risk stratification, they reiterate that there are insufficient data to support the use of these prediction tools to inform specific treatment selection at present.

A paradigm shift: Disease modification in IgAN

The recent insights into the natural progression and prognosis of IgAN have underscored the need for timely initiation of disease modifying treatment. Many individuals with IgAN have a prolonged subclinical course and are estimated to have suffered 50 per cent loss of nephron mass at the time of presentation to a nephrologist, with an eGFR between 50-60ml/min at the time of biopsy. This early phase represents a window for disease modification, where timely diagnosis and targeted intervention could attenuate the lifetime risk of kidney failure. Specific disease modifying therapies for IgAN were lacking for many years. Important insights into the underlying pathophysiology uncovered a number of potential therapeutic targets resulting in multiple clinical trials and a transformation of the therapeutic landscape, leading some to describe this as a ‘golden age’ in IgAN.

At early timepoints of IgAN, nephron loss is driven by an inflammatory glomerular injury in response to IgA immune complex deposition in the mesangium (as outlined in the four hit hypothesis). Emerging targeted treatments focus on reducing the production of pathogenic IgA (Targets: Gut associated lymphoid tissue (GALT), APRIL, APRIL/BAFF inhibitors, and CD38/plasma cells) and reducing the inflammatory response to glomerular immune complex deposition (targeting various components of the complement cascade as well as broad immunosuppression with corticosteroids and mycophenolate mofetil), reviewed by Cheung and Suzuki (2026), and Yau and Reich (2026).

Current treatment guidelines

The KDIGO 2025 guidelines reflect the new paradigm of treating IgA-specific pathways in addition to the more general management of IgA-driven accumulating nephron loss. The guidelines recommend that these measures are considered in parallel. They also provide clear cut management goals that help to monitor treatment effectiveness. Patients with proteinuria >0.5g/day are considered at high risk of progressive loss of renal function. The treatment goal for all patients is to reduce eGFR decline to the normal physiological state of <1mL/min/1.73m2 per year. The proteinuria goal is <0.5g/day either on or off treatment, or ideally, <0.3g/day.

(i) Management of IgAN-specific drivers of nephron loss: Here, the goal is to reduce or prevent the production of pathogenic IgA1 (Gd-IgA1), immune complex formation, and immune complex driven glomerular injury. A nine-month course of targeted-release budesonide is recommended (where available) in patients at risk of progressive loss of kidney function (proteinuria >0.5g/d). Where budesonide is unavailable, a treatment course with systemic glucocorticoids (combined with Pneumocystis jirovecii pneumonia prophylaxis) is recommended.

(ii) Treatment targeting IgAN-mediated nephron loss: The specific treatment goals are to reduce glomerular hyperfiltration, proteinuria, and progressive tubulointerstitial injury, and to control blood pressure to ≤120/70mmHg. Several non-pharmacological measures play an important role here, including lifestyle modifications, dietary salt restriction (<2g/d), smoking and vaping cessation, weight management, and regular exercise. The guidelines recommend maximally tolerated renin-angiotensin system blockade, or alternatively, dual endothelin angiotensin receptor antagonist (sparsentan). Sodium-glucose co-transporter 2 inhibitors (SGLT2i) should also be considered If patients are still unable to achieve proteinuria of less than 0.5g/d.

Conclusion

The lifetime risk of ESKD in IgAN is significantly higher than previously appreciated, and it is no longer considered an indolent form of glomerular disease. It is imperative that patients at high risk of progressive decline in renal function are identified and actively managed. An eGFR decline of <1ml/min per 1.73m2 should be targeted if patients are to avoid ESKD.

Advances in the understanding of IgAN pathophysiology have enabled the development of effective disease-modifying treatments with further clinical trials ongoing. It is likely that the treatment paradigm for IgAN will be modified frequently over coming years as the optimal strategies for integrating, sequencing, or combining these treatments are elucidated, enabling a personalised medicine approach reflecting individual risk profiles.

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