Advances in Diagnosis And Treatment Of C3 Glomerulopathy

On June 30, Professor Chen Wei, director of the Nephrology Department of the First Affiliated Hospital of Sun Yat-sen University, focused on the topic of "Diagnosis and Treatment Progress of C3 Glomerulopathy" at the 2023 Academic Annual Meeting of the Nephrology Branch of Zhejiang Medical Association, and gave a speech on C3 glomerulopathy. The overview, diagnosis, treatment status, and prospect of glomerulopathy (C3G) are introduced.

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Overview of C3G

Professor Chen Wei introduced that in recent years, we have gained an important understanding of the relationship between complement, kidney disease, and systemic diseases, and made breakthroughs. There are three pathways for complement activation, including the classical pathway, the lectin pathway, and the alternative pathway. The three pathways have a common end, which is the formation of the membrane attack complex, which ultimately leads to cytolytic effects.

More and more studies have shown that complement is a "double-edged sword". On the one hand, complement participates in the inflammatory response and immune response of the human body, and plays a role in the normal defense function of the body. On the other hand, complement is involved in the occurrence and development of many diseases. When the three pathways of complement are abnormally activated, it is easy to cause a series of organ damage. The kidney is one of the organs that is easily affected when complement is abnormally activated, and abnormal complement activation can be seen in various kidney diseases.

C3G is defined as the obvious deposition of complement C3 under immunofluorescence of renal pathology, with little or no deposition of immunoglobulin (the intensity of C3 deposition is equal to or more than 2 grades higher than other immune reactants), and it is a type of complement pathway Complex, chronic, rare kidney diseases caused by dysregulation have not yet entered the list of rare diseases. Kidney biopsy only complements C3 deposition or mainly C3 deposition. According to the distribution and morphology of electron-dense matter under the electron microscope, it can be divided into two subtypes: dense deposit deposition disease (DDD) and C3 glomerulonephritis (C3GN).

Under a DDD electron microscope, it can be manifested as homogeneous, streamer-like/ribbon-like electron-dense deposits in the glomerular basement membrane compact layer, which can be seen in 33% of C3G patients; under C3GN electron microscope, the manifestations are: glomerular mesangium, inner Subcutaneous, subepithelial, and/or intranasal membrane deposits at multiple sites were seen in 66% of C3G patients. In terms of pathological features, C3GN may have more obvious vascular lesions and chronic lesions (including glomerulosclerosis and interstitial fibrosis); DDD is more likely to have crescentic glomerulonephritis. C3G has various morphological patterns under the light microscope, among which mesangial proliferative glomerulonephritis and membranoproliferative glomerulonephritis are more common.

The prognosis of C3G is poor. 50% of patients will develop end-stage renal disease within 10 years after diagnosis, of which, 70% of children will develop end-stage renal disease within 10 years after diagnosis, and 30% to 50% of adult patients will develop end-stage renal disease within 10 years after diagnosis kidney disease. Patients with DDD who present more acutely (with crescentic glomerulonephritis) at a younger age are more likely to develop end-stage renal disease. In addition, if the etiology is not identified and symptomatic treatment is not given, abnormal activation of the bypass pathway in C3G patients after renal transplantation may lead to C3G recurrence. Post-transplant recurrence and allograft loss are common in C3G patients (50% for DDD and 75% for C3GN).

The pathogenesis of C3G is abnormal activation of the alternative complement pathway leading to C3 deposition. Factors driving complement dysregulation include: gene mutations and/or autoantibody formation, 25% of C3G patients carry complement gene mutations, and 30% of C3G patients are abnormally positive for complement genes. Dysregulation of the alternative complement pathway is a major driver in the pathogenesis of C3G, and its etiology includes acquired factors (autoantibodies) and genetic factors (genetic variation).

(1) Autoantibodies: The main autoantibodies related to C3G are the C3 nephritis factor and C5 nephritis factor, which can stabilize C3 and C5 converting enzymes and prolong their half-life. In addition, anti-H factor, anti-B factor, and anti-C3b autoantibodies are also included.

(2) Genetic variation: Genetic abnormalities in complement genes may drive overactivation of the alternative pathway, including mutations in C3, CFB, CFH, CFI, and CFHR genes; genetic polymorphisms in CFH, C3, CFB, and MCP genes; CFH-CFHR Genomic rearrangements of loci result in mutant proteins. In addition, monoclonal globulin can activate the alternative complement pathway, leading to C3G.

The clinical features of C3G are as follows:

(1) Kidney disease: patients have various clinical manifestations, which may manifest as asymptomatic hematuria and/or proteinuria, or acute nephritic syndrome, nephrotic syndrome, rapidly progressive nephritic syndrome, etc.

(2) Existence of autoantibodies: such as serum C3, C4, and C5 nephritis factors, or H factor, B factor autoantibodies.

(3) Complement deficiency: about 2/3 of C3G patients have low levels of complement C3.

(4) Extrarenal manifestations and complications, such as local lipodystrophy, eye complications (drusen), etc.

Current status of diagnosis and treatment of C3G

The diagnosis of C3G relies on clinical history, renal biopsy (light microscopy, immunofluorescence microscopy, electron microscopy), laboratory tests, and genetic testing. The "2021 KDIGO Guidelines for Glomerulonephritis" pointed out: (1) Before the diagnosis of C3G, exclude infection-related glomerulonephritis or post-infection glomerulonephritis. (2) For patients diagnosed with C3G for the first time and aged ≥ 50 years, evaluate whether there is a monoclonal protein. In addition, C3G requires a differential diagnosis from other forms of glomerulonephritis.

In terms of treatment, there is currently no recognized optimal treatment strategy for C3G and optimal supportive care is usually recommended:

(1) Blood pressure management: Systolic blood pressure <120 mmHg (1 mmHg=0.133 kPa).

(2) The maximum tolerated dose of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers.

(3) Assess cardiovascular risk and intervene appropriately as needed. For C3G patients who have undergone renal transplantation, the immunosuppressive regimen is usually adjusted after renal transplantation, and anti-C5 inhibitor therapy is initiated.

In this session, Professor Chen Wei introduced the treatment research of C3G.

(1) A retrospective cohort study showed that mycophenolate mofetil was superior to other existing treatment options in the treatment of C3G, but more prospective studies are still needed to confirm.

(2) A retrospective study of the anti-C5 inhibitor eculizumab in the treatment of C3G showed that 53% of patients had no remission, and the benefit of eculizumab in C3G patients was limited.

(3) The alternative complement pathway is the main driving factor for the pathogenesis of C3G, and there is currently no approved therapy for this target. However, more clinical research in this field is underway. Among them, Iptacopan, which has a high degree of attention, can inhibit complement factor B, thereby inhibiting the complement alternative pathway. Studies have shown that Iptacopan reduces C3G and C3 deposition and stabilizes renal function in renal transplant patients.

Summary

At the end of the report, Professor Chen Wei concluded that complement is a double-edged sword, normal can regulate the immune response, and abnormal can participate in the occurrence of diseases. C3G is a rare kidney disease caused by the abnormality of the alternative pathway of complement. There are still great challenges in diagnosis in clinical practice. It is necessary to improve clinicians' understanding of this disease and establish a standardized diagnosis and treatment process for C3G. Special attention should be paid to the differential diagnosis of C3G, including post-infectious nephritis, monoclonal globulin-related diseases, and immune complex-related nephritis. Currently, targeted anti-complement therapy provides a new treatment option for C3G.

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.