Traditional Chinese Medicine as a Promising Therapy for Patients with Membranous Nephropathy

TO THE EDITOR: Membranous nephropathy (MN), the predominant cause of nephrotic syndrome in adults worldwide, is characterized by distinctive glomerular basement membrane thickening with subepithelial immune complex deposition. The available evidence suggests that patients with MN irreversibly progress to end-stage renal disease and require replacement therapies, such as peritoneal dialysis, hemodialysis, and kidney transplantation.[1] Current supportive therapeutic approaches, including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, demonstrate variable efficacy. Immunosuppressive treatments have suggested their efficacy in idiopathic MN, whereas these agents frequently lead to the severe adverse effects and high relapse rates.[1] This therapeutic conundrum underscores the urgent need for alternative treatment modalities with improved safety profiles and sustained efficacy. Traditional Chinese medicine (TCM) has long been used in the clinical settings and has been demonstrated to be a compelling therapeutic option for MN treatment, which confers the beneficial effects of both immunological dysregulation and renal parenchymal protection. A recent study by Zeng et al. published in Integrative Medicine in Nephrology and Andrology provides compelling evidence that Jianpi Qushi Heluo Formula (JQHF) not only improves renal functions but also restores immune homeostasis in MN patients.[2] These findings demonstrate significant improvements in proteinuria and renal function concomitant with the modulation of cluster of differentiation 4+ (CD4+) T cell subsets, particularly shifting the inflammatory profiles of Th1/Th17 cells to Th2/Treg. This work represents a significant advancement in our understanding of TCM’s immunomodulatory potential in MN.[3,4] The immunological findings of this study are particularly noteworthy. The observed helper T cell 1 (Th1 cell) expansion and Treg cell depletion in MN patients corroborate previous reports of Th1/Th2 axis dysregulation in this condition.[5] However, several critical questions regarding the mechanistic underpinnings of JQHF’s immunomodulatory effects remain unanswered. TCM, a distinctive medical system with the important feature of the use of multicomponent drugs, can hit multiple targets with multiple compounds. JQHF can exert therapeutic effects through a network of synergistic pathways rather than by targeting a single molecular target. Comprehensive mechanistic investigations employing cutting-edge technologies such as single-cell ribonucleic acid (RNA) sequencing and high-dimensional flow cytometry can elucidate whether JQHF primarily influences T cell differentiation pathways,[6] alters the cytokine microenvironment, or modulates antigen-presenting cell function.[7] While Zeng et al.’s study provides valuable preliminary evidence, certain methodological limitations must be acknowledged. The relatively small sample size (n = 25) and absence of a placebo-controlled arm may affect the generalizability of the findings.[8] To establish JQHF as a viable therapeutic option, we strongly recommend expanding the sample size and a phase II/III randomized controlled trial comparing JQHF against standard immunosuppressive regimens. Such a trial should incorporate rigorous endpoints, including complete and partial remission rates, time to relapse, and assessment of podocyte injury biomarkers. Furthermore, given the increasing use of rituximab as a first-line therapy for MN, an investigation of the potential synergistic effects of JQHF and B-cell depletion therapy would be of particular clinical relevance.[9] The potential molecular mechanisms behind these synergies warrant dedicated exploration. JQHF may enhance the efficacy of rituximab through several plausible pathways: (1) potentiating B-cell depletion by modulating macrophage-mediated antibody-dependent cellular cytotoxicity, (2) preventing the emergence of rituximab-resistant B-cell clones, or (3) promoting the generation of regulatory B cells.[1,10] These hypotheses could be tested in well-designed preclinical studies employing animal models of MN, followed by translational validation in human subjects. The integration of TCM into contemporary nephrology practice presents both unprecedented opportunities and formidable challenges that must be rigorously addressed. Foremost among these is the critical need for pharmaceutical standardization of TCM formulations, requiring the development of robust analytical methods (such as high performance liquid chromatography-mass spectrometry [HPLC-MS] and nuclear magnetic resonance spectroscopy [NMR] fingerprinting) to ensure batch-to-batch consistency in bioactive compound composition and concentration. This standardization must extend beyond simple chemical characterization to include functional bioassays that verify consistent biological activity across production batches. Equally imperative are comprehensive pharmacokinetic-pharmacodynamic studies that employ advanced techniques such as mass spectrometry imaging and microdialysis to identify the bioactive metabolites of complex herbal formulations, map their tissue distribution (particularly renal accumulation), and establish scientifically validated dose-response curves that account for interindividual metabolic variability. Perhaps most crucially, the systematic evaluation of potential herb-drug interactions demands particular attention in nephrology patients, requiring sophisticated in vitro (e.g., cytochrome P450 [CYP450] assays) and in vivo studies to assess how TCM components may alter the metabolism or efficacy of conventional immunosuppressants, such as calcineurin inhibitors or rituximab. These investigations should be complemented by real-world pharmacovigilance programs to detect unexpected adverse events in diverse patient populations. Only through such rigorous, multidisciplinary approaches can TCM achieve its full potential as an evidence-based therapeutic option in mainstream nephrology practice. In conclusion, Zeng et al.’s study makes a valuable contribution to the growing body of evidence supporting TCM as a promising therapeutic strategy for MN. Their findings highlight the potential of JQHF to modulate the immunological disturbances underlying MN pathogenesis. Whereas, translation of these findings into clinical practice will require the following: (1) larger-scale controlled clinical trials, (2) deeper underlying molecular mechanistic understanding through multiomics approaches, and (3) the development of standardized treatment protocols. We commend the authors for their important work and hope that these suggestions will guide future research in this promising field of integrative nephrology.