Immunomodulatory Therapies in IgA Nephropathy: The Next Step in Targeted Treatment

Lucas Scott^*
*Correspondence: Lucas Scott, Department of Analytical Chemistry, University of California, USA, Email:

Introduction

Immunoglobulin A Nephropathy (IgAN), also known as Berger's disease, is the most common primary glomerulonephritis worldwide. It is characterized by the deposition of IgA in the glomeruli, triggering an immune-mediated inflammatory response that leads to renal injury, glomerular inflammation, and ultimately progressive kidney disease. IgAN typically presents with haematuria (blood in the urine), proteinuria (protein in the urine), and can lead to chronic kidney disease (CKD) or even End-Stage Renal Disease (ESRD) in some cases. While the exact etiology of IgAN remains unclear, an abnormal immune response involving IgA, complement activation, and pro-inflammatory cytokines plays a central role in disease progression. [1] Current treatment strategies primarily focus on controlling blood pressure and proteinuria, with immunosuppressive therapies like corticosteroids used in more severe cases. However, these treatments have limited efficacy and are associated with significant side effects. Recent advances in understanding the pathogenesis of IgAN have led to the development of immunomodulatory therapies, which aim to specifically target the underlying immune dysfunction. This article explores the role of immunomodulatory therapies in IgA nephropathy, discussing current and emerging treatment options, their mechanisms of action, and the potential for targeted therapy in improving outcomes for IgAN patients. [2]

Description

Immunopathogenesis of IgA nephropathy

The pathogenesis of IgA nephropathy is largely driven by immune dysregulation, involving the deposition of IgA1 in the glomeruli. In IgAN, abnormal glycosylation of the IgA1 molecule leads to the formation of immune complexes that are poorly cleared by the immune system, causing them to deposit in the kidneys. Once deposited in the glomeruli, these IgA immune complexes activate the complement system—especially the alternative pathway—which amplifies inflammation and tissue damage. Inflammatory cells, such as T cells, macrophages, and neutrophils, are recruited to the site of injury, releasing cytokines such as TNF-α, IL-6, and IL-17 that further exacerbate glomerular inflammation and fibrosis. [4] Additionally, dysregulated B cell activity leads to the overproduction of abnormal IgA, contributing to the vicious cycle of inflammation and immune complex deposition. [3]

Current immunomodulatory therapies in IgA nephropathy

Several immunomodulatory strategies are currently being explored or used in the treatment of IgA nephropathy. These therapies aim to target key aspects of immune dysregulation, including IgA production, immune complex formation, complement activation, and inflammatory signalling.

Corticosteroids: In patients with progressive IgAN, corticosteroids are commonly used to reduce inflammation and proteinuria. However, their effectiveness is variable, and long-term use is often associated with significant side effects, including osteoporosis, hyperglycaemia, and weight gain. [5] As a result, corticosteroids are typically reserved for patients with more severe disease or those with rapid deterioration in kidney function.

Rituximab: Rituximab, a monoclonal antibody targeting CD20-positive B cells, has been investigated in IgAN due to its ability to reduce the production of abnormal IgA. By depleting B cells, rituximab aims to interrupt the cycle of autoantibody formation and immune complex deposition. Although some studies have shown promising results, the overall efficacy of rituximab in IgAN remains inconclusive, with some trials demonstrating a reduction in proteinuria but no significant improvement in long-term kidney function. [4]

Emerging therapies and future directions

As our understanding of IgAN pathogenesis continues to evolve, newer immunomodulatory therapies are being developed to target specific aspects of the immune system with greater precision and efficacy. One of the most exciting areas of research is gene editing and RNA-based therapies, which could potentially be used to correct the underlying defects in IgA production or glycosylation. For example, CRISPR/Cas9 technology is being explored to alter the genetic pathways responsible for IgA synthesis or to knock down pro-inflammatory cytokines that contribute to glomerular injury. Additionally, small molecule inhibitors of key inflammatory pathways, such as the Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway, are being investigated as a way to modulate immune responses and prevent kidney damage in IgAN. These therapies could offer a less invasive and potentially more effective alternative to biologics, with the advantage of oral administration and a more targeted effect on immune signaling.The development of biomarkers for disease activity and response to treatment is another critical area of research in IgAN. Non-invasive biomarkers such as serum IgA levels, complement activity, and urinary biomarkers of inflammation and fibrosis could allow for more accurate diagnosis, monitoring, and treatment of IgAN, enabling clinicians to identify patients who are most likely to benefit from immunomodulatory therapies. [5]

Conclusion

Immunomodulatory therapies represent an exciting and evolving frontier in the treatment of IgA nephropathy, offering the potential for more targeted, effective, and less toxic treatments compared to traditional immunosuppressive strategies. While corticosteroids and other immunosuppressants remains a cornerstone of treatment for severe disease, newer therapies such as rituximab, complement inhibitors, and Syk inhibitors are showing promise in modulating the immune response more specifically and safely. Gene editing, RNA-based therapies, and small molecule inhibitors may represent the next wave of treatment options, offering potential for even more personalized and precise interventions. However, despite these advances, significant challenges remain in determining the most effective treatment regimens, identifying optimal patient populations, and minimizing adverse effects. On-going research into the immunopathogenesis of IgAN, coupled with clinical trials of novel immunomodulatory agents, will be essential in improving the outcomes for patients with this challenging and often progressive kidney disease.

References

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