Progress in the Treatment of Membranous Neuropathy with Integrated Traditional Chinese and Western Medicine

Introduction

MN is one of the main causes of adult nephrotic syndrome. About 20% of the patients are Secondary Membranous Nephropathy (SMN), which is mostly related to drug treatment, such as non-steroidal anti-inflammatory drugs, or diseases secondary to malignant tumors, systemic lupus erythematosus, hepatitis B, hepatitis C, and other diseases. The other patients, with unknown etiology, are Idiopathic Membranous Nephropathy (IMN) [1-3]. About one-third of patients with this disease can experience spontaneous remission without treatment, while the remaining patients will maintain proteinuria symptoms and retain renal function for a long time after treatment. But still one-third of patients will progress to end-stage renal disease, and even die.

Research on the Pathogenesis

The main feature of MN is the deposition of immune complexes formed by target antigens and antibodies on the basement membrane, leading to thickening of the glomerular capillary wall. Immuno deposition includes immunoglobulin G, related antigens, and complement components.

Complement Components

Research has shown that the pathogenesis of IMN is the combination of Immunoglobulin G (IgG) antibodies and intrinsic antigens on the basal membrane of podocytes to form a membrane attack complex, leading to podocyte damage. The main type of immune complex in IMN is IgG4, so the key to its pathogenesis lies in the pathway and/or Mannose Binding Lectin (MBL) pathway. In recent years, continuous research has shown that MBL can activate the MBL pathway by binding to IgG4 anti PLA2R antibodies with galactose deficient side chains [4]. In IMN patients with complete MBL deficiency, the complement system can be activated through a bypass pathway [5].

Antigen and Antibody Components

Target Antigen: ① Neutral Endopeptidase (NEP). According to a foreign case of allogeneic prenatal membranous nephropathy, if the mother lacks NEP in her body, anti NEP antigen antibodies may be produced during early miscarriage or after miscarriage, and then an immune response can be produced through the combination of the placenta and fetal foot cell antigens to cause the disease. The severity of neonatal kidney disease also depends on the severity of the reaction [6] M-type Phospholipase A2 Receptor (PLA2R1). PLA2R is distributed on the glomerular podocyte membrane, and IMN patients contain IgG antibodies that react with PLA2R protein and may lead to podocyte damage and proteinuria [7] Thrombospondin type-1 domain containing 7A (THSD7A). Experiments have shown that 2.5-5% of IMN patients have anti THSD7A antibodies distributed within glomerular podocytes, and the pathogenesis is related to the formation of immune complexes with THSD7A antigen [8]. The antibody titer level is also correlated with the prognosis of MN [9] Exotoxin 1/Exotoxin 2. Research has found that EXT1/EXT2 can be target antigens for SMN, and renal biopsy shows that about 85% of patients have SMN features related to autoimmune diseases, especially lupus disease, and the majority of patients are young women [10] Neuro epidermal growth factor like 1 protein (NELL-1). Sethi, et al. found that MN associated with NELL1 has a unique feature, that is, IgG capillary ring staining is segmental or incomplete under immunofluorescence detection [11].

Compared with other antigen related MNs, MNs associated with NELL1 are more significantly associated with malignant tumors [12] Semaphorin 3B (SEMA3B). Immunohistochemistry of the glomeruli of MN patients showed that Sema3B is a novel target antigen for MN, and among the 11 cases of SEMA3B related MN, 8 were children. From this, it can be seen that MN associated with SEMA3B is a unique type, and the affected population is mostly children [13] Neural Cell Adhesion Molecule 1 (NCAM1). Research has found that MCAM1 can be detected and localized in the deposition of glomerular immune complexes, and its reactivity to NCAM1 recombinant protein is also shown in the serum of MN patients associated with NCAM1. Therefore, it can be determined that NCAM1 is a target autoantigen for patients with membranous lupus nephritis [14] Protocadherin 7 (PCDH7). Research has found that PCDH7 and circulating anti PCDH7 autoantibodies are present in PLA2R⑧ Protocadherin 7 (PCDH7). Research has found that PCDH7 and circulating anti PCDH7 autoantibodies are novel antigens in PLA2R negative MN patients [15] Serine protease 1 (HTRA1). HTRA1 has been confirmed to be a unique foot cell antigen of some IMNs, and antibody levels are associated with disease activity [16].

Exogenous antigen: Cationic Bovine Serum Albumin (BSA) is mainly derived from milk and is an exogenous food antigen. In 2011, Debiec and other scholars discovered that circulating BSA and anti BSA antibodies can be detected simultaneously in some children with MN. And the only way for these tested children to obtain this protein in their bodies is through milk, which suggests that exogenous food antigens induce immune responses [17]. Circulating antigens: human foot cell cytoplasmic antigen Aldose Reductase (AR), superoxide dismutase (Manganese superoxide dismutase, SOD2) α- Alpha enolase (ENO1) is located in the cytoplasm of podocytes. Bruschi, et al. have shown through research that ENO1 is present in the glomeruli of MN patients, and circulating ENO1 autoantibodies can also be detected in the serum of a large number of MN patients [18]. Prunotto, et al., found that AR and SOD2 are newly expressed proteins in the glomeruli of MN, which can be recognized by corresponding circulating antibodies and detected in subcutaneous immune deposition of the glomeruli [19], indicating that these antigens may be specific to MN.

Treatment Progress

Western Medicine Treatment

At present, the treatment of IMN mainly focuses on PLA2R related treatments. Initially, routine drug support is given based on the patient's complaint and complications, and then immunosuppressive agents are used for treatment. The treatment of SMN patients should be considered from the perspective of potential causes. For SMN patients who have not shown significant improvement after treatment, the treatment approach of IMN patients should be adopted. The treatment plan is as follows:

Symptomatic Treatment: All MN patients should receive symptomatic supportive treatment in the early stages of the disease. For edema symptoms, a low sodium diet should be recommended in daily care, and diuretics should be used in combination with serum electrolyte levels and adverse drug reactions during treatment [20]. After controlling sodium levels, blood pressure can be kept within the normal range. Angiotensin converting enzyme inhibitors and/or angiotensin II receptor antagonists can be used, while also reducing the patient's urine protein and promoting spontaneous symptom relief.

Immunosuppressive Therapy:

In 1998, Ponticelli, et al. found through a 10-year follow-up study that alternating the use of methylprednisolone and phenylbutyrate nitrogen mustard for 6 months resulted in a higher complete or partial remission rate of nephrotic syndrome and significantly prolonged end-stage renal survival. And therefore, a 6-month course of alternating use of methylprednisolone and phenylbutyrate nitrogen mustard immunosuppressive therapy ("Ponticelli regimen") was established as the standard for treating MN [21].

According to the KDIGO guidelines, CNIs+glucocorticoids are recommended for individuals who resist initial treatment regimens based on alkylating agents/hormones. Common CHI drugs include Tacrolimus (TAC) and Cyclosporin (CsA). Research has shown that TAC combined with corticosteroids can effectively alleviate the condition, reduce serum albumin levels, and accelerate disease recovery [22]. CsA can reduce proteinuria concentration in patients with progressive renal failure and delay the rate of renal failure [23].

Mycophenolate Mofetil (MMF) is a highly selective immunosuppressive agent that selectively inhibits the proliferation of T and B lymphocytes. Currently, it has been clinically used as a cytotoxic drug or alternative to CNIs for the treatment of IMN patients. Experimental analysis shows that the efficacy of MMF and CsA combined with low-dose corticosteroids in the treatment of IMN is similar [24].

In 2002, Remuzzi, et al., first applied Rituximab (RTX) to the treatment of IMN patients with monoclonal antibodies against CD20. The therapeutic effect was significant, significantly reducing proteinuria levels and thus alleviating the condition [25]. Its therapeutic effect and short-term adverse reactions in IMN patients are superior to traditional immunosuppressive drugs. Anti CD20 antibodies, especially RTX, have gradually become the first-line treatment plan in clinical practice [26]. Rituximab is a human IgG1 type anti-CD20 monoclonal antibody drug. A study reported that a patient with refractory PLA2R related MN in a foreign country was resistant to RTX treatment and had severe adverse reactions. After receiving Rituximab treatment, the condition was effectively relieved, and only mild adverse reactions were observed. The adverse reactions can also quickly disappear after interruption of infusion and/or steroid administration [27] . Obinuzumab is a humanized and glycoengineered monoclonal antibody drug against CD20. Compared with RTX, it has stronger in vitro B cell toxicity, targeting different epitopes on CD20 and causing greater B cell apoptosis [28]. In a follow-up study of 10 MN patients by Sethi, et al., it was found that after 6 months of Obinutuzumab treatment, 4 patients achieved complete remission, 5 patients achieved partial remission, and 1 patient, although not relieved, had a nearly 50% decrease in urinary protein levels. After 12 months of treatment, all patients achieved complete or partial remission and remained in remission until 24 months [29].

Obinutuzumab is undoubtedly a very attractive alternative therapy for RTX resistant or sensitized patients, but we still need to conduct extensive prospective studies to confirm it. Ocrelizumab is a humanized anti-CD20 monoclonal antibody that has been approved for the treatment of Multiple Sclerosis (MS) [30]. A male patient from a foreign country was first diagnosed with MS, followed by clinical manifestations such as edema, massive proteinuria, and hypoalbuminemia, and was diagnosed with PLA2R related MN. Therefore, Ocrelizumab was chosen clinically to avoid double suppression of the immune system and can treat both MS and MN simultaneously. After 12 months of treatment, partial relief was achieved. After 20 months, PLA2R antibodies completely disappeared from circulation, and urine protein concentration decreased to a low level. After 2 years of treatment, the patient's MS and MN did not recur, PLA2R antibodies remained negative, and no significant adverse reactions occurred [31].

Traditional Chinese Medicine Treatment

In traditional Chinese medicine, MN, especially IMN, mainly belongs to the categories of "edema", "turbid urine", "lower back pain", "deficiency and fatigue", etc. Based on a data analysis, MN is mostly a syndrome of deficiency and excess, with spleen and kidney deficiency as the basis and wind, dampness, heat, and blood stasis as the criteria. Among them, stasis and internal obstruction are the most common [32-37]. Therefore, the treatment principle should mainly focus on supporting the right and eliminating evil and treat according to syndrome differentiation.

Diagnosis and Treatment Based on Syndrome Differentiation: Professor Huang Wenzheng, et al., believes that the treatment for spleen and kidney qi deficiency is to strengthen the spleen and benefit the kidneys, and the formula is modified with Shen Qi Di Huang Tang; The treatment for spleen kidney yang deficiency is to warm the kidney and strengthen the spleen, and the formula is modified with Jin Kui Shen Qi Wan; The treatment of liver and kidney yin deficiency syndrome is to nourish the liver and kidney, clear heat and nourish yin, and use Zhibai Dihuang Tang combined with Zishui Qinggan Yin with modifications; The treatment of water dampness syndrome involves warming yang and transforming qi, promoting diuresis and reducing swelling. The formula is modified with Fangji Huangqi Tang and Linggui Zhugan Tang; The treatment of blood stasis syndrome is to nourish blood and promote blood circulation, break through blood and remove stasis. The formula is modified with Siwu Tang combined with Dahuang Buchong Wan; The syndrome belongs to spleen and kidney deficiency, with a combination of water dampness and blood stasis. The treatment is to strengthen the spleen and kidney, dispel wind and dampness, promote blood circulation and remove blood stasis. The formula is modified with Cicada Silkworm Kidney Wind Decoction.

Professor Zhan Yongli, et al., believes that for patients with lung qi deficiency and blood stasis and water stagnation syndrome, the treatment should be beneficial to the lungs, consolidate the surface, promote blood circulation and diuresis, and choose Fangji Huangqi Tang combined with Danggui Shaoyao San for treatment; If the syndrome belongs to deficiency of spleen yang and cessation of blood stasis and water, the treatment should be to strengthen the spleen and warm yang, promote blood circulation and diuresis, and choose the combination of solid spleen drink and tonifying yang and restoring five decoction; For patients with kidney yang deficiency and stagnation of blood stasis and water syndrome, the treatment should be warming the kidney to assist yang, promoting blood circulation and promoting diuresis. Zhenwu Tang combined with Taohong Siwu Tang with modified Chinese herbal medicine should be selected for treatment. Professor Liu Yuning, et al. classified MN into four types based on syndrome differentiation: stasis and water obstruction type, treating when resolving phlegm and diuresis, promoting blood circulation and eliminating blood stasis, and selecting Guizhi Fuling Pills with modifications; The internal type of dampness and heat should focus on clearing and promoting dampness and heat, clearing the three jiao, and selecting Sanren Tang; The liver depression and qi stagnation type should pay attention to soothing the liver and regulating qi, and choose Chaihu Shugan San with modifications; Spleen and kidney qi deficiency type is treated by tonifying the spleen and kidney, promoting diuresis and removing blood stasis, and selecting modified Yiqi Bushen Tang for treatment. Yu Dongrong, et al., divided MN into two types: the spleen and kidney qi (yang) deficiency type was treated with tonifying qi, strengthening spleen and warming kidney drugs, and raw astragalus, Codonopsis pilosula, Atractylodes macrocephala, Poria cocos, prepared aconite, Xianling spleen, dodder seed, etc; Qi and Yin deficiency type should be treated with Qi tonifying and Yin nourishing drugs, such as Taizi Shen, Zhimu, Shengdi, Ligustrum lucidum, Arid lotus root, and Baimao root.

Staged Treatment: Professor Chen Yiping divided MN into two types of syndromes based on different stages of the disease: spleen deficiency and damp heat syndrome was treated with Qingre Membrane Kidney Granule, with the main drugs being Codonopsis pilosula, Atractylodes macrocephala, Salvia miltiorrhiza, Angelica sinensis, Motherwort, Hedyotis diffusa, Scutellaria baicalensis, Shiwei, Plantago asiatica, and Atractylodes macrocephala; Spleen and kidney yang deficiency type should be treated with tonifying kidney membrane kidney granules. The drug composition includes Astragalus membranaceus, Codonopsis pilosula, Atractylodes macrocephala, Yam yam, Yiyanglei, Cistanche deserticola, Red dates, Coix seed, Atractylodes macrocephala, Danshen, and Leonurus heterophyllus. Professor Lv Renhe, et al., divided MN into edema phase, urine turbidity phase, and renal failure phase based on the progression of the disease and treated them in stages. The edema phase was treated using the diuretic method, while the urine turbidity phase was treated from different perspectives of spleen and kidney, wind, and dampness. In the early stage of renal failure, the spleen and kidney should be treated together to support the right and eliminate evil. If the condition persists, it should be cleared and supplemented to provide a way out for evil and protect stomach qi [38]. The pathological staging of membranous nephropathy in stages I and I-II is mostly in the early stage of disease development.

Professor Wang Yaoguang, et al., believes that the traditional Chinese medicine syndrome differentiation is more common in the spleen kidney qi deficiency syndrome. Therefore, in the treatment, a combination of tonifying spleen qi and promoting blood circulation and diuresis drugs is often used; Phase II is more common in cases of spleen and kidney yang deficiency and blood stasis. Treatment mainly involves tonifying the spleen and kidney, strengthening the kidney and astringent essence, and promoting blood circulation and diuresis, with the addition of blood breaking and stasis removing drugs as appropriate. Stages III and IV are mostly characterized by the combination of blood stasis and water. Therefore, drugs for tonifying the spleen, tonifying the kidney, resolving blood stasis, and promoting water retention are selected, and insect and ant search drugs may be added as appropriate [39].

In summary, with the deepening understanding of MN in modern medicine, significant progress has been made in pathogenesis. However, it is still worth our continuous research on how to choose treatment plans more accurately and effectively in terms of treatment. At present, clinical treatment focuses on two aspects: basic supportive therapy and immunosuppressive therapy. In immunosuppressive therapy, the therapeutic status of CTX and CNIs is still very stable, and the advantages of RTX are gradually emerging, but still need to be studied in large samples. In addition, the advantages of traditional Chinese medicine in treating MN have been continuously revealed, but a large amount of basic experimental research is still needed to prove it. In the future, we should focus on developing more personalized and targeted treatment plans to improve efficacy, reduce adverse reactions, and improve patient quality of life.

Acknowledgements

None.

Conflict of Interest

None.

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