Advances in Research, Diagnosis And Treatment Of Complement And Kidney Diseases
Jan 13, 2023
Complement is an important part of innate immunity. It is composed of more than 30 proteins. It participates in the immune response to inactivate pathogens together with humoral factors or immune cells. However, it also participates in the immune damage caused by destroying self-tissues or cells. Complement plays an important role in some kidney diseases. Targeting complement could improve the treatment and prognosis of related kidney diseases.
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On August 7, 2022, at the 2021 Academic Annual Meeting (CSN 2021) of the Nephrology Branch of the Chinese Medical Association, Professor Zhao Minghui, director of Peking University First Hospital and Peking University Institute of Nephrology, made a presentation on "Complement and Kidney-related Diseases " academic report, sharing the complement system, complement-related kidney disease, and treatment progress.
Introduction to the Complement System
The activation of complement is divided into the classical pathway, the mannolectin pathway (MBL), and the alternative pathway. The conversion of C3 to C3b is an important part of each pathway of complement. After C3 is transformed into C3b, it can also affect the process of C5 into C5b. Through this series of cascade reactions, the complement system can resist pathogenic microorganisms; remove immune complexes, apoptotic tissues, and cells; maintain internal environment stability. However, C3a, C5a, and C5b-9 in complement can all cause inflammation and damage. Therefore, when treating complement-related diseases, the above-mentioned complement factors should be targeted, rather than the entire complement system.
Two key factors cause complement activation damage, namely the area where the activation occurs and the damage mechanism. Regarding the area of activation, it is necessary to consider whether the activation of complement occurs in blood circulation or on the surface of tissue cells. Occurs in the circulation and patients can present with hypocomplementemia, deposition of lytic components of complement, and/or activation of receptors leading to renal damage, such as C3G. If complement activation occurs on the surface of endothelial cells, the patient does not necessarily have hypocomplementemia, and the end-stage product of complement activation, MAC, such as TMA, can be formed on the endothelial surface. In addition, the injury mechanism needs to be considered. The products of complement activation, C3a, and C5a, are chemokines, which can attract chemoattractants and activate neutrophils and monocytes to cause inflammatory reactions, while C5b-9 mainly damages endothelial cells.
Complement activation injury involves not only the kidney but multiple organs or systems. Therefore, in complement-associated nephropathy, some diseases are accompanied by systemic reactions or other systemic symptoms.
Complement-associated kidney disease
Complement-associated nephropathy can be divided into three categories: the first category, complement is the main cause of disease; the second category, complement is the main cause of disease but indirectly causes the disease; the third category, complement is involved in the pathogenesis.
1 Complement is the main cause of disease
Such diseases mainly include:
①C3 glomerular disease: C3 glomerular disease is a rare kidney disease with an incidence of about 1-2 per million people. The main factor affecting the correct diagnosis is renal pathology.
②Atypical hemolytic uremic syndrome (aHUS): It is a rare thrombotic microvascular disease, and its mechanism is damage to vascular endothelial cells caused by various reasons. Its incidence rate is 2 million people, slightly more in children, and there is a tendency for recurrence. 50% of adult patients progress to ESRD, and the mortality rate is about 25%. And TMA/aHUS is related to the abnormal activation of complement, the key to its pathogenesis is gene + inducement, and the inducement includes infection and pregnancy. In addition to kidney damage, the blood system, heart, and brain may all be damaged.
③ membrane proliferative glomerulonephritis (MPGN). It is worth noting that MPGN is a pathological pattern, not a disease.
2 Complement is the main cause of disease but indirectly causes disease
① Monoclonal gammopathy of renal significance (MGRS). Monoclonal immunoglobulins in these patients can indirectly affect complement activation, thereby indirectly causing C3G or TMA lesions. For example, monoclonal λ can form dimers, which are functionally similar to autoantibodies to the complement regulatory protein factor H, which eventually leads to abnormal activation of complement and triggers monoclonal gammopathy (MGRS). In such patients, the main treatment is chemotherapy in the department of hematology, rather than the treatment of nephritis in the department of nephrology. Therefore, the diagnosis of the disease is very important and may cause a large difference in prognosis.
②Neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is also related to compliment. Unlike immunoglobulin A (IgA) nephropathy, the kidneys of patients with ANCA-associated nephritis on routine renal biopsy have less deposition of immunoglobulin and complement C3. The detection of C3d and B factor on renal biopsy specimens are mostly positive, indicating that complement is activated through the bypass pathway in renal vasculitis lesions.
A study published in the "New England Journal of Medicine" in 2021 found that avacopan, a small molecule inhibitor of the complement C5a receptor, can effectively treat ANCA-related vasculitis and nephropathy, and the efficacy is significantly improved compared with hormone therapy. This also shows that the complement system is involved in ANCA nephropathy.
3 Complement is involved in the pathogenesis
Complement is involved in many common kidney diseases, such as membranous nephritis, lupus nephritis (LN), IgA nephropathy, focal segmental glomerulosclerosis (FSGS), and diabetic nephropathy (DN). In these diseases, complement is involved in different degrees, some are not the main cause, and some are only involved in the pathogenic mechanism at the end.
Taking LN as an example, if the patient's renal pathology has thrombotic microangiopathy (TMA)-like vascular lesions, it may be related to abnormal activation of complement. In a study of 148 patients with LN, 36 (24.3%) patients had renal TMA. In addition, 47.8% of LN patients diagnosed by renal biopsy had anti-C3b IgG autoantibodies, which indicated that at least some patients had autoimmunity against complement, which of course may lead to abnormal activation of complement and may also lead to TMA. Therefore, such patients should be treated with immunosuppression + complement suppression.
Treatment progress
A Phase III international multicenter clinical study of the novel crovalimab targeting C5 is also enrolling patients in China. The study aims to evaluate complement intervention drugs for the treatment of aHUS. Its main features are
①Completely humanized;
②Subcutaneous injection, once every 2-4 weeks;
③It is also effective for C5 gene mutation.
For severe aHUS patients, the drug can quickly stabilize the indicators of blood system involvement, and can also quickly reduce the patient's creatinine level, and even get rid of dialysis.
Professor Zhao Minghui concluded that complement activation is involved in the pathogenesis of various kidney diseases, but the degree of participation in each kidney disease is different. At present, it is unclear which renal diseases warrant complement inhibitory therapy, and more research is needed. In addition, the new century of complement-targeted therapy has arrived, and relevant research and intervention methods are emerging in an endless stream, and more explorations are expected in the future.
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