Key Research Results On The Mechanism Of Tatacept in Treating IgA Nephropathy Released

IgA nephropathy (IgAN) is one of the most common primary glomerular diseases in China and one of the important causes of end-stage renal disease (ESRD) [1]. The glomerular disease management guidelines released by KDIGO in 2021 pointed out that there is currently a lack of specific therapeutic drugs for IgAN, and existing hormones and traditional immunosuppressants have not fully met the needs for treatment [2]. In view of this, based on the pathogenesis of IgAN, it is particularly important to develop targeted therapeutic drugs to effectively control this disease.

Click to Cistanche for kidney disease

Studies have found that the main pathological feature of IgAN is the deposition of IgA in the mesangial area, in which the level of core galactose-deficient IgA1 (Gd-IgA1) is proportional to the severity of pathological damage [3]. Among them, two key cytokines in the process of B cell proliferation and differentiation - B lymphocyte stimulating factor (BLyS) and proliferation-inducing ligand (APRIL), can participate in the proliferation and differentiation of abnormal B cells, promote Gd-IgA1 and its Antibody production[4,5]. As a dual-target biological agent, Tatacept can simultaneously target APRIL and BLyS, inhibit the proliferation and development of B cells, and reduce the production of Gd-IgA1 [6]. Previous phase II studies have shown that Tatacept can reduce the production of Gd-IgA1 and immune complexes, effectively reduce proteinuria in IgAN patients, and reduce the risk of disease progression [7].

In order to further reveal the mechanism of action of Tatacept in treating IgAN, Professor Zhang Hong and his team from the Department of Nephrology, Peking University First Hospital conducted further research. The research results were published in "Kidney International Reports" (IF=6.0) in January 2024 [8]. This article aims to describe this study in detail and interpret its conclusions.

Research background and research design

The Phase II study of tatasercept in the treatment of IgAN was a randomized, double-blind, placebo-controlled clinical trial. Even though the recruited subjects received optimized supportive care for 3 months, their 24-hour urine protein level was still ≥0.75g/d. According to the ratio of 1:1:1, subjects who met the criteria were randomly assigned to the placebo group, the tatascept 160 mg group, and the tatascept 240 mg group. The primary endpoint of the study is to assess the change in 24-hour urinary protein levels from baseline after 24 weeks of medication.

This study analyzed plasma samples from 24 subjects (8 patients in the placebo group, 9 patients in the tatasercept 160 mg group, and 7 patients in the tatasercept 240 mg group). We measured Gd-IgA1, IgA immune complexes, C3a, C5a, and sC5b-9 before treatment (baseline) and at weeks 4, 12, and 24 after treatment using an enzyme-linked immunosorbent assay (ELISA). s level. In addition, this study also explored the association between changes in these markers and proteinuria reduction to reveal the mechanism of action and therapeutic effect of tatasercept.

Research result

In this study, the proportion of women in the tatasercept 160 mg group was 71.4%, the average age was 38.1 years, and the median urine protein value was 1.71 (1.15-1.96) g/d. The proportion of women in the Tatacept 240 mg group was 66.7%, the average age was 40.0 years old, and the median urine protein was 1.26 (1.05-1.53) g/d. The proportion of women in the placebo group was 37.5%, the average age was 35.8 years old, and the median urine protein was 1.78 (1.37-1.97) g/d.

Tatacept

Significantly improve IgAN biomarker levels and inhibit the occurrence and development of the disease from the source

Gd-IgA1 levels

After 24 weeks of tatasercept treatment, Gd-IgA1 levels in the 240 mg group decreased by 50.4% from baseline, while the decrease in the 160 mg group was 43.9%.

PolyIgA immune complex levels

At 24 weeks of treatment with Tatacept, polyIgA immune complex levels decreased by 67.2% in the 240 mg group and by 41.3% in the 160 mg group.

As a specific molecular marker of IgAN in serum, the detection of polyIgA immune complexes is used to evaluate the immune activity of IgAN, provide early warning, assist in diagnosis, and manage the entire life cycle of patients. Monitoring this indicator can help to gain a deeper understanding of the pathological mechanism of IgAN and provide more precise treatment for patients [9].

IgG-IgA immune complex levels

At 24 weeks of treatment with Tatacept, IgG-IgA immune complex levels decreased by 42.7% in the 240 mg group and by 31.7% in the 160 mg group.

Gd-IgA1/IgA levels

During 24 weeks of tatasercept treatment, Gd-IgA1/IgA levels remained stable, indicating that tatasercept has an inhibitory effect on various types of IgA.

complement level

Circulating levels of complement C3a, C5a, and sC5b-9 did not change significantly during treatment.

Tatacept

It can effectively delay disease progression and is significantly related to changes in serum biomarkers and urinary protein levels.

Decreases in patient plasma levels of IgA, Gd-IgA1, polyIgA, and IgG-IgA immune complexes from the beginning of the study to each follow-up visit were significantly associated with changes in proteinuria throughout the follow-up period. It is worth noting that in the high-dose group of tatasercept, the reduction of polyIgA and IgG-IgA immune complexes was particularly significant and consistent with the decreasing trend of proteinuria, while the levels of total IgA and Gd-IgA1 were not. showing the same downward trend.

This phenomenon indicates that tatacept has a significant effect in reducing polyIgA and IgG-IgA immune complexes. In contrast, total IgA and Gd-IgA1 levels may be less responsive to disease progression, or their decline may only be apparent later in the disease process. This means that by paying close attention to polyIgA and IgG-IgA levels, clinicians can more accurately assess the efficacy of tetacept and adjust treatment plans in a timely manner to maximize patient outcomes.

Research conclusions and discussion

This study investigated changes in circulating biomarker levels during treatment with tatasercept. The results showed that tatasercept could reduce the levels of Gd-IgA1, IgG-IgA, and polyIgA immune complexes in patients with IgAN, and the reduction was more prominent in the high-dose group. Notably, the reduction of these biomarkers was closely related to the reduction of proteinuria in IgAN patients, especially the reduction of IgG-IgA and polyIgA immune complexes. These findings highlight the potential value of using these biomarkers to predict clinical response.

However, this study also has limitations. First, it is only an exploratory study in a phase II clinical trial with a small sample size. As blood samples were not successfully obtained from some patients, failure to include all randomly selected patients may have introduced selection bias. Therefore, larger studies are needed to validate these preliminary findings. Second, the short 24-week follow-up period limits the assessment of the association of these biomarkers with long-term kidney health outcomes.

Despite these challenges, this study demonstrates that tetacept displays significant biomarker modulation in the treatment of IgAN. It is reported that the Phase III clinical study of Tatasercept for the treatment of IgAN is actively being promoted in China and the United States. It is expected that the drug will be officially approved in the future, providing new possibilities for the treatment of IgAN.

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.

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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.