The IgA nephropathy was first described by French scholar Jean Berger in 1968, marking the beginning of scientific exploration in this field. Today, after more than half a century of arduous exploration, significant progress has been made in understanding both the pathogenesis and treatment methods of IgA nephropathy. Recently, a review article published in the Medicina journal provided a comprehensive explanation of various treatment methods for IgA nephropathy. Among them, the intestinal mucosal B-cell immunomodulator - Budesonide enteric capsules (Nefecon) are considered a new type of etiological treatment drug, which is completely different from traditional systemic hormonal therapy, and its prominent position in the treatment of IgA nephropathy may lead to major changes in the treatment pattern of this field.
Key Discoveries in Understanding the Pathogenesis of IgA Nephropathy
IgA nephropathy is the most common primary glomerular disease in clinical practice, characterized by IgA deposition in the mesangial area of the glomerulus. Within 10 to 20 years after diagnosis, about 20% to 40% of patients with IgA nephropathy will progress to end-stage renal disease (ESRD), requiring dialysis or kidney transplantation. Although it has been 55 years since IgA nephropathy was described and named by the medical community, the pathogenesis is not yet fully understood. In the past 20 years, with the discovery of specific mucosal immune regulation abnormalities, galactose-deficient IgA1 molecules (Gd-IgA1) and Gd-IgA1 immune complexes in patients with IgA nephropathy, there has been a leap in understanding the pathogenesis of IgA nephropathy. The "Four-hit" hypothesis has been developed and is now internationally recognized as the pathogenesis of IgA nephropathy.
Gd-IgA1 and the Multi-Hit Hypothesis
Simply put, the multi-hit hypothesis believes that the production of Gd-IgA1 is the source of IgA nephropathy, that is, Hit 1. Gd-IgA1 is produced by the intestinal and tonsil mucosa and enters the bloodstream. The mucosal B cells in parts of the small intestine, including Peyer's patches in the terminal ileum, are the main sites of Gd-IgA1 molecule production. Subsequently, the body produces IgG autoantibodies that recognize Gd-IgA1 (Hit 2), which form circulating immune complexes with Gd-IgA1 (Hit 3). These immune complexes ultimately deposit in the kidneys, inducing local inflammation and immune responses, causing glomerular damage (Hit 4). Clinically, this can present as hematuria, proteinuria, and decreased kidney function.
Fig 1. The putative pathogenesis of IgAN, based on the four-hit hypothesis.1
Understanding the autoimmune pathogenesis of IgA nephropathy has paved the way for the development of drugs that target different points, including immune responses, mucosal immunity, renal inflammation, and complement activation. It is for this reason that several promising new treatment drugs have been developed in recent years, which are in various stages of clinical research and development, including preclinical and clinical trials. Some new drugs have been approved for the market and are benefiting patients, such as Budesonide enteric capsules.
Current Treatment Options for IgAN
Given the complexity of the pathogenesis of IgA nephropathy and the involvement of multiple factors and mechanisms, treatment options are varied. The review compiled treatment-related literature published as of July 13, 2023, and introduced several currently available clinical treatment methods and their evidence-based medical evidence. The currently available treatments include renin–angiotensin–aldosterone system inhibitors (RAAS-Is), tonsillectomies, sodium glucose co-transporter 2 (SGLT2) inhibitors, and glucocorticoids.
Focusing on Budesonide Enteric Capsules
Clinical Advantages in Treating IgA Nephropathy are Prominent, and Application Prospects are Broad. It needs to be emphasized that although the ingredient of Budesonide enteric capsules is a glucocorticoid, its unique formulation and target action point make it completely different from systemic hormones. As an intestinal mucosal B cell immunomodulator, Budesonide enteric capsules are a novel therapy for IgA nephropathy, which acts on the "four-hit" source, predominantly at the first hit, has clear clinical efficacy, and is safe. In contrast, systemic hormones mainly exert kidney protection through local renal anti-inflammatory effects, acting on the downstream stages of the "four-hit," and while they can reduce proteinuria to a certain extent, there is controversy over their efficacy in slowing down the decline in renal function. Also, safety is a major clinical concern, as they may cause serious adverse reactions such as upper respiratory tract infection, femoral head necrosis, gastrointestinal bleeding, and others.
Conclusion
In conclusion, though the pathogenesis of IgA nephropathy is not yet fully understood, treatment methods have been constantly improving towards better efficacy and fewer side effects over the more than half a century since the disease was discovered by the medical community. Budesonide represent an important breakthrough in this regard. This treatment approach could potentially drive significant shifts in the pattern of care for patients with IgA nephropathy, offering a more effective and safer treatment alternative. In addition,the upcoming therapeutic options for IgAN also provides more options and hope for the treatment of this disease.
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Reference
- Shimizu, Yoshio, Yasuhiko Tomino, and Yusuke Suzuki. "IgA Nephropathy: Beyond the Half-Century." Medicina 60.1 (2023): 54.
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