Exploring The Role Of APRIL in The Pathogenesis Of IgA Nephropathy

With a heavy disease burden and limited treatment options, IgA nephropathy urgently needs a solution.

To begin with, Professor Lu Jicheng first elaborated on the disease burden and treatment status of IgA nephropathy from the current status of the disease. He mentioned that IgA nephropathy is the most common primary glomerular disease in the world, with IgA deposition in the glomerular mesangial area as its pathological feature [1-4]. Although IgA nephropathy is often clinically asymptomatic, approximately 25-30% of patients slowly progress to renal failure within 20-25 years [5]. In my country, there are about 4.59 million adult IgA nephropathy patients, of which about 570,000 have been diagnosed. The disease mostly occurs in young adults, with about 80% of patients aged 20 to 59 years old. The average age at first diagnosis is between 30.5 and 40 years old. , there is no significant difference in gender ratio [6,7].

Click to Cistanche for kidney disease

In terms of treatment, there is currently no treatment for IgA nephropathy and supportive measures are mainly used in clinical practice. Based on the results of the TESTING study, the risk of renal failure in patients with IgA nephropathy who receive supportive care increases by 7.8% per year, and nearly 80% of patients may develop renal failure within 10 years. Hormone therapy can reduce the risk of renal failure by 40%, but 50% of patients may still develop end-stage kidney disease (ESKD) within 10 years [8]. In addition, Professor Lu Jicheng emphasized that proteinuria level is a key factor affecting the prognosis of the disease. For every 20% increase in proteinuria level, the risk of renal failure or death increases by 26%, and for every 40% increase, the risk increases by 58% [9]. Compared with patients with proteinuria levels below 0.3g/d, patients with proteinuria levels above 2.0g/d have a 38-fold higher risk of renal composite endpoint events [10].

Pay equal attention to theory and research to explore the role of APRIL in the pathogenesis of IgA nephropathy

In recent years, research on the pathogenesis of IgA nephropathy has continued to make new progress. Currently, the most internationally recognized pathogenesis of IgA nephropathy is the "four hits" theory. This view summarizes the occurrence factors, development process, deterioration factors, prognosis process, and prognosis of this disease, and effectively guides clinical practice and practice.

Professor Lu Jicheng provided a detailed interpretation of this theory [11]. The first of the "four strikes" is the circulation of high levels of Gd-IgA1 in the patient's body, which is the initiating factor in the course of the disease. The second blow involves Gd-IgA1 as an autoantigen, prompting the production of autoantibodies in the body. The third blow is that the formed anti-sugar antibodies and galactose-deficient IgA1 form circulating immune complexes and are deposited in the kidneys. The fourth blow is that these pathogenic immune complexes pass through the glomerular endothelial cell windows and deposit in the glomerular mesangium, thereby activating the complement pathway and causing glomerular damage [11].

In 1998, scientists identified APRIL as the 13th member of the tumor necrosis factor (TNF) superfamily, and its encoding gene is TNFSF13 [12]. Subsequently, in a genome-wide association study (GWAS) analysis, TNFSF13 was found to be a key candidate locus associated with glomerular lesions in patients with IgA nephropathy [13]. In addition, from the perspective of "four strikes", APRIL mainly plays a key role in the first stage, that is, it affects the entire disease process upstream. Specifically, APRIL significantly increases Gd-IgA1 production in the body by promoting B cell activation. Gd-IgA1 is the main autoantigen in IgA nephropathy, and its excessive production and abnormal aggregation are the initiating factors that trigger subsequent immune complex formation and kidney damage [14].

In addition to theoretical support, relevant studies also support the important role of APRIL in the pathogenesis of IgA nephropathy. A study conducted by Peking University First Hospital collected samples from 166 IgA nephropathy patients and 77 healthy controls between January and August 2014. The level of APRIL in their plasma was detected by ELISA technology, and the mRNA expression of APRIL and its receptor was detected using relative quantitative PCR method. Research results show that APRIL levels in patients with IgA nephropathy are significantly higher than healthy people, and their levels are positively correlated with the Gd-IgA1/IgA1 ratio. Furthermore, data analysis showed that patients with higher APRIL levels often showed higher urinary protein levels and lower eGFR, suggesting that they may be in more advanced stages of chronic kidney disease (stage 4-5 CKD) [15]. These findings highlight the potential of APRIL as a new therapeutic target, and its inhibition may open new pathways to prevent the progression of IgA nephropathy.

The results of the research on drugs targeting APRIL are released, showing impressive efficacy

Based on the "four strikes" theory, the treatment field of IgA nephropathy has ushered in a new breakthrough. Professor Lu Jicheng introduced at the conference that targeted drugs for intestinal mucosal immunity, BAFF/APRIL inhibitors and treatments targeting the terminal complement pathway have become current research hotspots. Currently, four drugs targeting APRIL have been developed to treat IgA nephropathy, among which Sibeprenlimab (VIS-649) is particularly eye-catching.

Sibeprenlimab is a humanized IgG2 monoclonal antibody that blocks the production of pathogenic IgA1 by binding to and neutralizing APRIL activity, providing a new therapeutic option for the treatment of IgA nephropathy. In animal experiments, 16 6-week-old female IgA nephropathy mice were divided into two groups. One group received Sibeprenlimab treatment, and the other group received isotype control antibody treatment, which was injected intravenously once a week for a total of 4 weeks. The results showed that Sibeprenlimab can significantly reduce serum IgA levels and reduce renal immune deposits [16].

In the clinical study, the Sibeprenlimab clinical phase 2b study randomly divided 155 IgA nephropathy patients into 4 groups. Three groups received Sibeprenlimab treatment at doses of 2 mg/kg (38 people), 4 mg/kg (41 people), and 8 mg/kg (38 people), and the last group of 38 people received placebo, administered once a month via intravenous infusion for 12 months, and the follow-up time was 16 months.

The results showed that in terms of efficacy, after 12 months of treatment, the 24-hour urine protein/creatinine ratios of the 2 mg/kg, 4 mg/kg, 8 mg/kg Sibeprenlimab groups, and the placebo group were on average compared with the baseline. It was reduced by 47.2±8.2%, 58.8±6.1%, 62.0±5.7%, and 20.0±12.6%, showing a dose-dependent relationship.

After 12 months of treatment, the average glomerular filtration rate decreased by 7.4ml/min/1.73㎡ compared with the placebo. However, the average glomerular filtration rate of patients in the Sibeprenlimab 4mg group not only did not drop rapidly, but even increased. The average glomerular filtration rate of the two groups differed by 7.6ml/min/1.73㎡.

In terms of pharmacodynamics, Sibeprenlimab almost completely and consistently suppressed serum APRIL levels in a dose-dependent manner in both the 4 mg and 8 mg Sibeprenlimab groups. After discontinuation of sibeprenlimab, mean APRIL levels returned to baseline with a dose-dependent pharmacokinetic profile. In terms of safety, Sibeprenlimab has a good safety profile, with a low incidence of serious adverse events and no increased risk of infection [17].

Professor Lu Jicheng pointed out that currently the treatment options for IgA nephropathy are limited. Therefore, the research progress of Sibeprenlimab may not only change the current treatment status but also provide the new scientific basis for future disease management strategies. Currently, phase III clinical trials of the drug are underway, aiming to comprehensively evaluate its safety and effectiveness in a wider patient population. This large-scale study plans to recruit a total of 470 IgA nephropathy patients, including Chinese patients, to ensure data diversity and representativeness. Professor Lu said he was very much looking forward to the final results of this research. He believes that these research results demonstrate the importance of medical research in improving patient outcomes and quality of life, and also inspire global research to continue to explore more unknown areas.

At the end of the meeting, Professor Liu Hong made a concluding speech. She pointed out that the strategic application of "source targets" is crucial for the treatment of many diseases. Especially in the treatment of IgA nephropathy, clinical studies of Sibeprenlimab have shown that it can intervene in the initial stages of disease development, thus achieving good clinical therapeutic effects. According to clinical research data, Sibeprenlimab not only reduces the 24-hour urine protein/creatinine ratio but also effectively delays the decline in glomerular filtration rate. At the same time, Sibeprenlimab's monthly dosing frequency and good safety profile provide convenience for clinical application. In summary, Sibeprenlimab has great potential in the treatment of IgA nephropathy, and it is foreseeable that precise treatment of IgA nephropathy will be further implemented in the future.

How Does Cistanche Treat Kidney Disease?

Cistanche is a traditional Chinese herbal medicine used for centuries to treat various health conditions, including kidney disease. It is derived from the dried stems of Cistanche deserticola, a plant native to the deserts of China and Mongolia. The main active components of cistanche are phenylethanoid glycosides, echinacoside, and acteoside, which have been found to have beneficial effects on kidney health.

Kidney disease, also known as renal disease, refers to a condition in which the kidneys are not functioning properly. This can result in a buildup of waste products and toxins in the body, leading to various symptoms and complications. Cistanche may help treat kidney disease ase through several mechanisms.

Firstly, cistanche has been found to have diuretic properties, meaning it can increase urine production and help eliminate waste products from the body. This can help relieve the burden on the kidneys and prevent the buildup of toxins. By promoting diuresis, cistanche may also help Reduce high blood pressure, a common complication of kidney disease.

Moreover, cistanche has been shown to have antioxidant effects. Oxidative stress, caused by an imbalance between the production of free radicals and the body's antioxidant defenses, plays a key role in the progression of kidney disease. ies help neutralize free radicals and reduce Oxidative stress, thereby protecting the kidneys from damage. The phenylethanoid glycosides found in cistanche have been particularly effective in scavenging free radicals and inhibiting lipid peroxidation.

Additionally, cistanche has been found to have anti-inflammatory effects. Inflammation is another key factor in the development and progression of kidney disease. Cistanche's anti-inflammatory properties help reduce the production of pro-inflammatory cytokines and inhibit the activation of inflammation mandatory pathways, thus alleviating inflammation in the kidneys.

Furthermore, cistanche has been shown to have immunomodulatory effects. In kidney disease, the immune system can be dysregulated, leading to excessive inflammation and tissue damage. Cistanche helps regulate the immune response by modulating the production and activity of immune cells, such as T cells and macrophages. This immune regulation helps reduce inflammation and prevent further damage to the kidneys.

Moreover, cistanche has been found to improve renal function by promoting the regeneration of renal tubes with cells. Renal tubular epithelial cells play a crucial role in the filtration and reabsorption of waste products and electrolytes. In kidney disease, these cells can be damaged, leading to damaged renal function. Cistanche's ability to promote the regeneration of these cells helps restore proper renal function and improve overall kidney health.

In addition to these direct effects on the kidneys, cistanche has been found to have beneficial effects on other organs and systems in the body. This holistic approach to health is particularly important in kidney disease, as the condition often affects multiple organs and systems. che has been shown to have protective effects on the liver, heart, and blood vessels, which are commonly affected by kidney disease. By promoting the health of these organs, cistanche helps improve overall kidney function and prevent further complications.

In conclusion, cistanche is a traditional Chinese herbal medicine used for centuries to treat kidney disease. Its active components have diuretic, antioxidant, anti-inflammatory, immunomodulatory, and regenerative effects, which help improve renal function and protect the kidneys from further damage. , cistanche has beneficial effects on other organs and systems, making it a holistic approach to treating kidney disease.