Advances in the Treatment of Refractory Membranous Nephropathy with Integrative Medicine

INTRODUCTION Membranous nephropathy (MN) is a common pathological classification of nephrotic syndrome (NS) in adults characterized by the deposition of immune complexes beneath the podocytes of the glomeruli and the thickening of the basement membrane.[1] Approximately 20% of cases are related to secondary factors, such as systemic diseases, infections, drugs, or tumors, while the remainder are classified as idiopathic membranous nephropathy (IMN) without clear secondary causes. The incidence of MN, which has nearly doubled to range from 9.89% to 18.42% in primary glomerulonephritis, shows an annually increasing trend.[2] The prognosis of IMN patients varies significantly and is related to various factors, such as age, hypertension, pathological staging, and renal tubular interstitial damage. Although about one-third of IMN patients may experience spontaneous remission, the 10-year survival rate can still reach 70%-90%. However, the relapse rate of adult IMN is high, at about 45%, and 6%-25% of patients may progress to end-stage renal disease (ESRD) or death within 5-15 years.[3] IMN is considered an autoimmune disease, and its exact mechanism is not fully understood. It is currently believed that antigens on the podocytes of the glomeruli bind to specific antibodies to form in situ immune complexes, activating the complement system and causing kidney damage. Since the discovery of pivotal podocyte autoantigens, notably PLA2R in 2009 and THSD7A in 2014, these findings have significantly advanced the etiological diagnosis and therapeutic management of IMN.[4] Symptomatic treatment, including controlling blood pressure, reducing edema, and preventing thrombotic events and cardiovascular incidents, is necessary for all IMN patients. Immunosuppressive therapy should be considered for high-risk patients if symptomatic treatment is ineffective or if adverse reactions occur. Current treatment options for IMN patients at moderate risk of renal function progression include rituximab (RTX), calcineurin inhibitors (CNI), or a combination of CNI and glucocorticoids. For high-risk patients, treatment options include RTX or a combination of hormones and cyclophosphamide (CTX) or CNI combined with RTX; for very high-risk patients, a combination of hormones and CTX is used.[5,6] However, some patients still do not improve clinically after full-course immunosuppressive treatment and are defined as having refractory MN, thus presenting a clinical challenge in managing them. ADVANCES IN NOVEL BIOLOGICAL AGENTS FOR THE TREATMENT OF REFRACTORY MN Anti-CD20 B-Cell therapy In recent years, new biological agents have emerged in the field of treatment for RMN. Obinutuzumab, a glycoengineered type II humanized anti-CD20 monoclonal antibody, causes more severe B lymphocyte depletion than the traditional type I anti-CD20 monoclonal antibody RTX.[7] In a retrospective study involving 18 patients with RMN, with a median follow-up time of 13.6 months, 94.4% of patients achieved partial or complete remission after obinutuzumab treatment. Notably, 61.1% of patients who had previously shown a poor response to RTX also demonstrated efficacy. No severe treatment-related adverse events were observed during the follow-up period, indicating that obinutuzumab has good efficacy and safety in inducing remission for refractory MN.[8] Obinutuzumab is a second-generation fully humanized Type I anti-CD20 monoclonal antibody, with a binding epitope close to the cell surface and an extended binding site, which results in stronger complement-dependent cytotoxicity (CDC) activity than RTX. In a study involving 10 patients with RMN treated with obinutuzumab, 85.7% achieved complete or partial remission, demonstrating a more rapid and sustained therapeutic response than RTX.[9] In 7 patients intolerant to RTX and 10 patients resistant to RTX, ofatumumab treatment also led to clinical symptom alleviation.[10] The side effects of obinutuzumab primarily include mild dyspnea, leukopenia, minor infections such as upper respiratory tract and urinary tract infections.[9] Therefore, monitoring and managing these potential side effects in patients undergoing obinutuzumab treatment is crucial. Proteasome inhibitor Bortezomib, a proteasome inhibitor, targets and depletes antibody-producing plasma cells. In a study involving five patients with RMN resistant to RTX treatment, combined treatment with dexamethasone and bortezomib achieved good efficacy. However, since bortezomib may induce adverse reactions, such as infections and neurotoxicity, it requires stringent monitoring and management in clinical applications.[11] Complement-Targeted therapy The complement system is significant to the pathogenesis of MN, making targeted complement therapy an attractive adjunctive treatment.[12] Studies have been conducted on complement B factor inhibitors, such as Iptacopan (clinical trial number: NCT04154787), and MASP-2 inhibitors, such as the nesolisi monoclonal antibody (NCT02682407). However, despite the theoretical therapeutic potential of these complement inhibitors, clinical trial results have not met expectations, leading to the termination of some trials. Anti-Plasma cell therapy CD38+ plasma cells may be a primary source of autoantibodies, particularly in patients with high titers of anti-PLA2R antibodies. Therefore, the depletion of these CD20/38+ plasma cells has become an effective therapeutic strategy. Felzartamab is a fully human IgG1 monoclonal antibody against CD38, which can bind to the CD38 antigen and deplete plasmablasts and plasma cells, leading to a rapid, profound, durable response in anti-PLA2R antibody levels, along with improvements in proteinuria and serum albumin.[13] Felzartamab offers a promising treatment strategy for patients with IMN, especially those with high levels of PLA2R antibodies. Nonetheless, Felzartamab treatments may be accompanied by adverse reactions, primarily including infusion-related reactions, hypogammaglobulinemia, peripheral edema, and nausea.[14] Daratumumab, another anti-CD38 monoclonal antibody, has also shown good efficacy in treating patients with refractory MN.[15] THE UNTAPPED POTENTIAL OF INNOVATIVE THERAPEUTIC STRATEGIES IN THE MANAGEMENT OF REFRACTORY MN CAAR-T cell therapy has made significant progress in cancer treatment and has shown great potential in treating autoimmune diseases. A German research team successfully identified and eliminated cells expressing specific B-cell receptors (BCRs) by modifying natural killer (NK) cells and T cells with chimeric autoantibody receptors (CAARs).[16] This method can specifically eliminate cells producing pathogenic autoantibodies, providing a new strategy for IMN treatment. Sweeping antibody technology is an innovative therapeutic antibody technique capable of eliminating soluble antigens from circulation. Sweeping antibodies, such as GYM329, have already entered clinical research stages.[17] The Fab region of the sweeping antibody comprises a PLA2R domain rich in cysteine residues (CysR). This antibody can bind to circulating PLA2R autoantibodies, resulting in the formation of immune complexes taken up by the liver or endothelial cells, leading to the degradation of PLA2R autoantibodies and the recycling of therapeutic sweeping antibodies. Sweeping antibody technology is expected to contribute to the treatment of MN.[18] Existing research has confirmed that fecal microbiota transplantation (FMT) has promising effects for autoimmune disease treatment. A case report indicated that a patient with refractory MN experienced clinical symptom improvement and a decrease in PLA2R antibody titers following FMT treatment.[19] This finding suggests that gut microbiota is essential to the treatment of MN. FMT emerges as a promising biotherapy for MN, necessitating further research to validate its efficacy and underlying mechanisms. Studies on gut microbiota may contribute to elucidating the pathogenesis of this disease. TRADITIONAL CHINESE MEDICINE (TCM) IN REFRACTORY MN In animal and cellular models related to MN, positive therapeutic effects and the mechanisms of action of TCM have been observed. Podocyte injury is central to glomerular damage in MN and may lead to glomerulosclerosis and chronic renal failure. TCM can improve podocyte injury by stabilizing podocyte function and regulating autophagy.[20] Sanqi oral solution (SQ) has also shown significant effects in MN treatment. In one study, SQ reduced proteinuria levels in MN rats induced by cationized bovine serum albumin (cBSA), alleviated kidney damage, and inhibited the deposition of complement component C3 and immunoglobulin G (IgG). Furthermore, SQ could inhibit the activation of the nuclear factor-kappa B (NF-κB) signaling pathway and restore podocin expressions.[21] As a component of TCM, the total coumarins of Hydrangea paniculata have also been proven to improve renal damage and dyslipidemia in MN models. This improvement is achieved by inhibiting complement activation and the phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) signaling pathway, which significantly alleviates glomerulosclerosis and tubulointerstitial injuries.[22] TCM has also shown good effects in the clinical treatment of MN, reducing proteinuria in patients, improving serum albumin, and slowing the progression of IMN, while avoiding side effects caused by the long-term use of immunosuppressants.[23] Tripterygium wilfordii (GTW), a TCM extract, is commonly used to treat NS. Due to its anti-inflammatory, anti-immunological, antiproliferative, and proapoptotic effects, GTW is widely used in the treatment of various autoimmune and inflammatory diseases. Previous clinical trials using GTW to treat IMN have shown that GTW can effectively reduce proteinuria in MN patients.[24] In a study involving 15 patients with refractory idiopathic MN, the Jian Pi Qu Shi Formula was applied to treat the patients, with a follow-up period of 12 months. The study results showed a clinical response rate of 80%, and no significant adverse reactions were observed during the one-year follow-up period. This finding confirms the effectiveness of the formula in treating refractory MN and demonstrates its safety.[25] For refractory MN patients resistant to steroid and immunosuppressant treatment, the Shulifenxiao formula has also shown positive therapeutic effects.[26] Its formula contains saponins from astragalus, which can effectively protect the integrity of vascular endothelial cells, inhibit the abnormal proliferation of mesangial cells, and significantly promote the humoral metabolic process, therefore optimizing blood rheological characteristics and protecting key podocytes from damage. Furthermore, the formula can reduce the occurrence of renal interstitial fibrosis and alleviate the progression of glomerular sclerosis. CONCLUSION The treatment of refractory MN remains a clinical challenge. Although new biological agents and TCM treatments have brought new therapeutic options to this field in recent years, their efficacy and safety in clinical applications must be further verified through larger-scale clinical trials. In refractory MN treatment, it is crucial to consider the specific conditions of the patient comprehensively, including disease severity, complications, patient preferences, and economic conditions in adopting a personalized treatment plan. A personalized plan helps improve treatment effects and improves the quality of life of patients, reducing unnecessary medical interventions and side effects. Future research should prioritize the following: Conducting large-scale randomized controlled trials should be conducted to evaluate the efficacy and safety of new biological agents and TCM treatments in refractory MN. Exploring more potential therapeutic targets and mechanisms to develop new treatment strategies is also essential. Furthermore, identifying biomarkers associated with the efficacy of TCM in treating RMN can provide a basis for personalized treatment. Given the unique genetic backgrounds and disease phenotypes of patients, future research should also focus on developing tailored TCM treatment strategies that aim to enhance therapeutic efficacy and minimize adverse effects.