IgA nephropathy (IgAN)

About IgA nephropathy

Immunoglobulin A nephropathy (IgAN) is the most common form of glomerulonephritis worldwide^1,2 and a leading cause of kidney failure³. IgAN is an autoimmune kidney disease caused by deposition of galactose-deficient IgA1-containing immune complexes in the glomerular mesangium, leading to inflammation and kidney injury^3-5.

IgAN is a highly heterogenous disease, with variation across geographic regions and populations in^2,3,6,7:

• incidence, prevalence and sex distribution
• clinical presentation and progression
• pathogenic initiating factors
• treatment response

Without effective treatment, IgAN can lead to irreversible worsening of kidney function⁷, and is associated with high morbidity and mortality^3,7.

Incidence, prevalence and burden of IgA nephropathy

The incidence of IgAN is at least 2.5 per 100,000 per population per year¹, with peak incidence at 10–30 years of age^3,8.

The prevalence of IgAN shows marked variation across geographic regions and ethnic groups⁶, and is much higher in people from East Asia, compared with those in North America and Europe^2,3. Of primary glomerulonephritis cases, IgAN accounts for approximately⁷:

• 10–20% in the United States
• 20–30% in some European countries
• 40–50% in developed Asian countries

However, prevalence data for IgAN does not encompass subclinical IgAN³, and is complicated by the need for biopsy-based diagnosis⁹. Geographical variability in prevalence may be influenced by different health screening policies and biopsy practices between regions, and genetic susceptibility³.

Although its clinical course is highly variable³, IgAN is associated with an increased risk of mortality, and a 6–10 year reduction in life expectancy from progression to kidney failure^3,7.

Approximately 20–40% of people with IgAN will have reached kidney failure within 20 years after diagnosis³

As IgAN is a major cause of kidney failure in young adults, the worsening renal impairment from this disease has been associated with loss of labour force participation and a significant social burden⁷.

Signs and symptoms of IgA nephropathy

The clinical presentation of IgAN is variable, ranging from asymptomatic microscopic haematuria to sustained proteinuria and rapidly declining kidney function⁶.

The hallmark clinical feature of IgAN is episodic, visible (macroscopic) haematuria, due to red blood cells passing through the glomeruli into the urinary space³. In children and young adults, this is often accompanied by febrile illness³. In adults, microscopic haematuria is often observed, with or without proteinuria³.

IgAN should be suspected in young people with a history of macroscopic haematuria, especially if accompanied by febrile illness, and in cases of asymptomatic haematuria and/or proteinuria³

Evidence suggests the clinical presentation of IgAN can vary by geographical region⁶. In particular, people with IgAN from Asia have been reported to:

• present with more severe clinical signs and symptoms, and a higher risk of disease progression, compared with people with IgAN from Europe⁶
• have a more rapid rate of kidney function decline, compared with other regions of the world⁶

Pathophysiology of IgA nephropathy

The pathogenesis of IgAN involves dysregulated IgA production¹, resulting in deposition of galactose-deficient IgA1-containing immune complexes in the glomerular mesangium^9,10.

Although the precise mechanism through which IgA becomes dysregulated remains unclear¹, the pathogenesis of IgAN is widely accepted to follow the four-hit process (Figure 1) that starts with abnormal production of galactose-deficient IgA1^5,7,11. Ultimately, this results in accumulation of immune complexes in the glomerular mesangium, and leads to inflammation, progressive scarring and impairment of kidney function³.

Figure 1. The four-hit hypothesis for IgAN pathogenesis^11-15 (Adapted¹⁴ under Creative Commons License CC-BY-4.0). High blood levels of Gd-IgA1 (Hit 1) and production of autoantibodies specific for Gd-IgA1 (Hit 2) lead to formation of pathogenic circulating immune complexes (Hit 3)^3,11, which accumulate in glomeruli and induce kidney injury (Hit 4)^3,11,15.

Through an evolving understanding of IgAN, it is now recognised that its pathophysiology also involves the immune response, complement activation, mucosal immunity, kidney inflammation and autophagy⁷.

Genetic factors may also influence susceptibility to IgAN, which may account for some of the geographic and ethnic variation in prevalence of the disease⁷.

The role of complement in IgA nephropathy

A combination of histological, genetic and clinical data indicate that activation of the alternative and lectin pathways of the complement cascade are involved in the pathophysiology of IgAN³. This complement activation and subsequent deposition of complement components in the kidney (Figure 2) are thought to initiate and/or amplify glomerular inflammation and kidney injury¹⁴.

Figure 2. Local activation of the alternative and lectin complement pathways and renal deposition of complement components in IgAN^3,5,14,16-18 (Adapted¹⁴ under Creative Commons License CC BY 4.0). Gd-IgA1, galactose-deficient IgA1; IgAN, IgA nephropathy; MBL, mannose-binding lectin; MASP, MBL-associated serine protease.

The most frequently observed complement component deposits in IgAN biopsies are C3 (colocalised with IgA in >90% of IgAN biopsies^3,6), Factor H (69–85%) and C5b9 (75%)³.

It is thought that glomerular deposition of galactose-deficient IgA1 immune complexes can trigger complement activation via the alternative pathway, leading to renal deposition of complement components¹⁹

Evidence suggests a possible association between renal complement deposition in IgAN and disease severity and/or prognosis. For example, mannose-binding lectin (MBL) or C4d deposition have been associated with worse prognosis⁵, while C5a deposition has been correlated with proteinuria and pathological grade in IgAN¹⁶.

Particular complement components appear to be associated with IgAN severity in specific geographic locations and ethnic groups⁶. For example, serum MBL levels have been associated with IgAN severity in Chinese, but not non-Chinese populations⁶. The authors considered this may suggest that differences in complement dysregulation could contribute to the more severe clinical patterns and pathology observed in people with IgAN from Asia⁶.

Genetic variants in complement genes have also been associated with outcomes in IgAN¹⁴. Risk variants in the MBL2 gene have been associated with an increased risk of IgAN progression²⁰, while a common deletion within the Factor H gene locus may be protective against IgAN¹⁴. This deletion results in loss of the FHR1 and FHR3 genes, while leaving the gene for Factor H intact; each copy of the deletion was reported to reduce the risk of IgAN by almost 40% ^14,21,22. It is thought that this protective effect may arise from reduced competition of Factor H-related proteins with Factor H, which may promote inhibition rather than activation, possibly reducing inflammation¹⁴.

While complement activation, deposition and genetic changes have been associated with various aspects of IgAN, the precise mechanisms through which the lectin pathway and alternative pathway are acivated in IgAN remain to be elucidated⁵. Further research will help to better characterise the mechanisms of complement activation in IgAN, and shed more light on their contribution to disease pathophysiology¹⁷.

Challenges in IgAN management

Effective and well-tolerated disease-modifying agents that target the underlying pathophysiology of IgAN are greatly needed^3,7,23, as management of IgAN has been largely limited to supportive measures^7,24. These supportive measures include the use of antihypertensive agents to control blood pressure and reduce proteinuria, and immunosuppressants^7,24. However, treatment response is variable, and up to 40% of patients with IgAN still progress to kidney failure within 20 years of diagnosis^3,5,7.

A targeted-release form of the corticosteroid budesonide was granted accelerated approval by the US Food and Drug Administration (FDA) in 2021^25,26 and by the European Medicines Agency (EMA) in 2022²⁷, for treatment of IgAN. This formulation delivers a delayed release of budesonide to the distal ileum, suppressing local immune cell activity, including Gd-IgA1-producing cells that cause immune complex formation in IgAN²³. Results of clinical trials have demonstrated a reduction in proteinuria and stablisation of kidney function in patients with IgAN who were treated with this formulation^23,28. The approval of this medicine has strengthened interest in targeting the underlying pathogenesis of IgAN²³.

As our understanding of the IgAN pathogenesis evolves, further new treatment approaches are being investigated in clinical trials, including those that target the complement cascade and other immunological pathways that contribute to the disease³.

Are you interested in more information on diagnosis, risk prediction, treatment, unmet needs and investigational treatments for IgAN? More content is coming soon to this learning zone. Stay tuned for further updates

Learn about complement-mediated kidney diseases, their burden and impact