A systematic literature search was performed using “PubMed/MEDLINE”, “Web of Science Core Collection”, “Cochrane Library” from 1974 to 2025. The extended timeframe ensured inclusion of seminal foundational studies alongside the most recent advances in B cell immunology.

Search terms included combinations of: “nephrotic syndrome”; “B cells”; “B lymphocytes”; “memory B cells”; “plasma cells”; “plasmablasts”; “regulatory B cells”; “rituximab”; “CD20”; “minimal change disease”; “membranous nephropathy”; “focal segmental glomerulosclerosis”; “membranoproliferative glomerulonephritis”; “lupus nephritis”; “diabetic nephropathy” and “ hepatitis B-related nephropathy.”

Studies were selected based on relevance to B cell biology in nephrotic syndrome, methodological quality, and contribution to mechanistic understanding or therapeutic approaches. Inclusion criteria encompassed: Original research investigating B cell subpopulations in NS; Clinical trials evaluating B cell-targeted therapies; Studies utilizing standardized immunophenotyping methods; Research with appropriate control groups and adequate sample sizes; Publications in peer-reviewed journals with clear outcome measures

This narrative review synthesized findings from 243 selected references, including prospective and retrospective studies, randomized controlled trials, meta-analyses, and single-cell sequencing investigations. Data extraction focused on study design, patient demographics, B cell analysis methods, key findings, and clinical implications. Given the heterogeneity of study populations (pediatric vs. adult) and methodological approaches, a qualitative synthesis framework was employed to integrate findings and identify key themes in B cell-mediated NS pathogenesis.

The nephrotic syndrome can result from primary (idiopathic) nephropathy or a variety of secondary causes (19). The main pathological types of primary nephrotic syndrome include minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy and membranoproliferative glomerulonephritis (20). While the secondary nephrotic syndrome is commonly seen in lupus nephritis, diabetic nephropathy and hepatitis B-related nephropathy, and each has its unique B cell immune mechanism. Early studies indicated that MCD was primarily caused by T cells, leading to podocyte foot process effacement and massive proteinuria. However, recent research has revealed that B cells play an auxiliary role in MCD pathology by secreting antibodies, providing antigenic stimulation signals to shape protective T cell responses, and regulating cytokines involved in T cell differentiation (21). Furthermore, the investigators found that autoantibodies produced by B cells are also key drivers in the immune pathogenesis of MN.

Notably, B cell dysregulation is also present in adult primary FSGS patients. Studies have shown significantly elevated proportions of CD27⁺IgD^-IgG⁺ class-switched memory B cells in circulation, along with decreased CD38⁺IgG⁺ plasmablast proportions, although their specific pathogenic roles remain unclear (22). Glomerular basement membrane thickening and cellular proliferation in MsPGN patients are commonly associated with B cell-mediated immune complex deposition (23). In summary, B cells exhibit varying roles and levels of involvement across different pathological types (as shown in Table 1 ), suggesting the need for individualized therapeutic strategies based on pathological classification, with prognoses varying accordingly.

In addition to primary nephrotic syndrome, B lymphocyte dysregulation also plays a vital role in secondary nephrotic syndrome. Studies have found that naive B cells can activate naive B cells with many clonalities in LN (24). These clonal naive B cells can produce antibody-secreting cells and persist in circulation for several months, leading to persistent non-remission of the disease (25). In addition, circulating transitional B cells and plasmablast cells are enriched in LN patients (26). A small study of B cells in the peripheral blood of patients with DKD demonstrated elevated levels of CD19lo/⁺CD38⁺ plasma cells relative to healthy controls. CD19lo/⁺CD38⁺ B cell counts were positively correlated with albumin excretion rate and serum IgG level and negatively correlated with estimated glomerular filtration rate, implying that higher plasma cell frequencies were associated with worsening DKD (27). Secondary MN is common in patients with chronic hepatitis B virus infection. The seminal study of Lai et al. (28) demonstrated a fundamental difference in the pattern of B-cell responses between HBV-associated membranous nephropathy and primary membranous nephropathy.

B cells change through the system, we found that the secondary and primary nephrotic syndrome in B cell steady state change there are important differences (as shown in Table 2 ):

B lymphocyte development begins with pro-B cells in the bone marrow (as shown in Figure 1 ), where functional rearrangement of immunoglobulin genes, including heavy chain (IgH) and light chain (IgL) recombination, generates a B cell repertoire capable of recognizing diverse antigens. After expressing IgM(Immunoglobulin M) molecules, immature B cells migrate to the spleen through the transitional 1 (T1) stage and subsequently develop into transitional 2 (T2) B cells (32). T2 B cells can further differentiate into three major subsets: B1 cells, follicular B cells, and marginal zone (MZ) B cells. Among these, B1 cells can rapidly differentiate into short-lived plasma cells and secrete autoantibodies through T cell-independent mechanisms in nephrotic syndrome patients (33). Follicular B cells, as the predominant B cell subset, require CD4⁺ T cell help for activation and play a central role in the immune regulatory network of nephrotic syndrome (34).

Recent clinical findings suggest that abnormal involvement of B cells may play a significant role in the pathogenesis and progression of MCD. Studies have shown that patients with MCD often exhibit elevated levels of B cells in peripheral blood, which may secrete cytokines (such as IL-4 and IL-13) that indirectly trigger abnormal T cell immune responses, consequently affecting glomerular permeability (55, 56). In 2022, Watts et al. (57) identified circulating autoantibodies against nephrin, a key podocyte slit membrane protein, for the first time in adults and children with MCD, and the levels of these autoantibodies correlated with disease activity (e.g., significantly higher positivity during flares than during remission). Furthermore, some MCD patients have been found to have anti-neurofascin antibodies, which correlate with disease activity, providing a new perspective on the underlying mechanisms of MCD that could aid early diagnosis in clinical settings (57, 58).

Studies on FSGS have indicated that an increase in the proportion of CD27⁺IgD^-IgG⁺ switched memory B cells is associated with declines in renal function and increased 24-hour urine protein levels in patients (22, 59). This suggests that the activity level of memory B cells may reflect the severity of FSGS. In addition, Delville et al. (60), in their quest for potential biomarkers to predict FSGS recurrence, identified a panel of seven autoantibodies that could predict FSGS recurrence after transplantation with up to 92% accuracy in their cohort. In this population, elevated pre-transplant CD40 autoantibody, a transmembrane protein normally present on B cells, dendritic cells, and macrophages, had the best correlation with FSGS recurrence after transplantation. Moreover, notable infiltration of B cells has been observed in FSGS patients, which, in concert with T cells, may lead to podocyte injury and the development of proteinuria, deepening our understanding of B cell involvement in FSGS (61, 62).

In clinical studies of MN, PLA2R-related and THSD7A-related MN account for about 70%-80% and 1%-5% of primary MN patients, respectively, and are associated with disease activity. Elevated levels of these antibodies usually indicate disease recurrence (28, 63–65). Research indicates that approximately 40% of patients with MN are classified as PLA2R-negative MN. Among this group, exostosin 1/exostosin 2 (EXT1/EXT2) have been identified as the most common specific proteins, along with the discovery of neuro-epidermal growth factor-like 1 protein (NELL-1) and protocadherin 7 (PCDH7). Notably, MN associated with EXT1/EXT2 and NELL1-related malignant tumors may be linked to autoimmune diseases, such as systemic lupus erythematosus and mixed connective tissue disease. These autoimmune diseases are common in secondary MN; however, treatment for underlying secondary conditions (e.g., tumor removal) does not always correlate with improved outcomes in MN (66). Additionally, the proportion of memory B cells in MN patients significantly increases during periods of disease activity and decreases during remission, suggesting that these B cells may serve as biomarkers for disease activity (67, 68).

Minimal change disease is the most common pathological type of nephrotic syndrome in children (over 1 year of age about 70%-90%), while the proportion in adults is low (15%) (69). MCD was first proposed by Shalhoub in 1974 as a T cell-mediated disorder (70). However, recent studies suggest that the interaction between B cells and T cells plays a crucial role in MCD pathogenesis (as shown in Figure 2 ).

The major mechanisms of B cells in minimal change disease include:

Studies suggest that abnormal interactions between B lymphocytes and autoreactive T lymphocytes may play a crucial role in the pathogenesis of FSGS (73). Traditional views hold that B lymphocytes receive signaling stimulation in germinal centers (GC) by presenting antigens to T cells, subsequently differentiating into plasmablasts, antibody-secreting plasma cells, or long-lived memory B cells (59).

Current studies have shown that memory B cells participate in the development of primary FSGS through a variety of mechanisms:

B lymphocytes are central players in the pathogenesis of MN, directly influencing disease progression through the secretion of autoantibodies (such as PLA2R-Ab) and regulation of immune responses (as shown in Figure 4 ) (80). In contrast, PLA2R-Ab is merely a product of B cell function and cannot comprehensively reflect B cell activity status and their role in immune regulation. Current research has already established memory B cells as biomarkers for MN disease activity and predictors of relapse (68).

The main mechanisms include:

B lymphocytes play crucial roles through multiple pathways in the pathogenesis of MPGN. Primarily, immunoglobulins (such as IgG and IgM) secreted by B lymphocytes form immune complexes with antigens, which deposit in the glomerular basement membrane and mesangial areas. These complexes activate the complement system, triggering inflammatory responses and glomerular injury—a core mechanism in immune complex-mediated MPGN (97). Additionally, antibodies produced by B lymphocytes can exacerbate inflammatory responses through the classical complement pathway. Even in complement-mediated MPGN, complement overactivation may be indirectly influenced by B cell function. In some MPGN patients with chronic viral infections [such as Hepatitis C Virus (HCV) and Hepatitis B Virus (HBV)], B cells maintain chronic immune activation by producing antiviral antibodies, thereby accelerating disease progression (64).

Furthermore, abnormal B lymphocyte proliferation and aggregation may closely correlate with MPGN’s pathological changes and disease severity, particularly in systemic lupus erythematosus-associated MPGN (98). B cells also interact with other immune cells (such as T cells and macrophages) through antigen presentation and cytokine secretion, further aggravating glomerular inflammation and injury (99). B cell-targeted therapy has demonstrated good efficacy in MPGN patients by selectively depleting B cells, reducing antibody and immune complex formation, and suppressing inflammatory responses, thereby improving proteinuria and renal function. In 2012, Dillon et al. treated 6 MPGN patients with rituximab, achieving complete remission in 5 cases (100). Another single-center retrospective study included 2 MPGN patients. One patient achieved complete remission after one or two doses of rituximab (375 mg/m²), while the other achieved partial remission before developing crescentic rapidly progressive glomerulonephritis requiring dialysis. However, this patient discontinued dialysis after 5 months and achieved complete remission at 14 months (101). Moreover, RTX showed remarkable efficacy in HCV-related MPGN patients, with proteinuria decreasing from 8.2g/24h to 0.62g/24h within one year, while serum creatinine and liver function remained stable (102, 103). These findings indicate that B lymphocytes play a vital role in MPGN pathogenesis and progression while serving as important therapeutic targets.

With lupus nephritis is abnormal B cells in secondary nephrotic syndrome is the most typical representative, its characteristic changes include:

Although diabetic nephropathy has traditionally been considered primarily a metabolic disease, recent studies have revealed the important role of B-cell-mediated inflammatory and immune mechanisms in its pathogenesis:

B-cell abnormalities in HBV-related nephropathy (predominantly membranous nephropathy) have unique features:

Minimal Change Disease is the most common type of nephrotic syndrome in children, with its primary characteristic being an excellent response to corticosteroid therapy. Prednisone is the standard first-line treatment, and approximately 80-90% of children achieve remission within 4–6 weeks of starting therapy (110, 111). For patients who are steroid-resistant or experience frequent relapses, alternative treatments such as tacrolimus and mycophenolate mofetil (MMF) have been shown to be effective. Research suggests that these immunosuppressive agents can induce and maintain remission in steroid-resistant cases (112, 113).

In resistant cases of MCD, tacrolimus has proven particularly beneficial, with many patients achieving remission after transitioning to this treatment (113). Additionally, the efficacy of rituximab in adult patients with MCD has been confirmed by multiple studies. A systematic review and meta-analysis indicated that the overall remission rate for MCD patients treated with rituximab was 80.3% (95% CI, 68.5–88.5%) (114). Another retrospective study involving 21 adult patients found that all patients achieved clinical remission after treatment, with 19 (90.48%) attaining complete remission and 2 (9.52%) achieving partial remission (115). Moreover, RTX shows great promise in the treatment of recurrent MCD patients, especially in hormone-dependent or frequent recurrent patients. The 2014 NEMO study reported reduced relapse rates in patients treated with RTX (116). The KDIGO guidelines recommend broader use of RTX, especially in steroid-dependent and frequently relapsing cases (117).

Emerging therapeutic strategies have shown promise in addressing the pathophysiological basis of MCD. Recent studies demonstrate that natural triterpenoid compounds, particularly those derived from Poria cocos, offer significant nephroprotective effects through multiple mechanisms including inhibition of RAS, TGF-β1/Smad3, and Wnt/β-catenin pathways (118). The integration of gut microbiota modulation strategies presents novel therapeutic opportunities, particularly through restoring the balance of beneficial bacteria such as Lachnospira and reducing harmful bacteria like Shigella and Streptococcus, which have been identified as dysregulated in MCD patients (119).These microbiota-targeted interventions may complement traditional immunosuppressive therapies by addressing underlying immune dysregulation at the gut-kidney axis level.

FSGS presents significant challenges due to its heterogeneous nature and varying treatment responses. Corticosteroids remain the preferred treatment, though their efficacy can vary among patients. While corticosteroids are often used as a first-line treatment, the response rate is considerably lower in adults, necessitating additional treatment options (120).

The combination of corticosteroids with tacrolimus and MMF has shown promise for patients resistant to glucocorticoids. A retrospective study in children with nephrotic syndrome found that this combination achieved a response rate of 75% in refractory cases (121). Furthermore, in patients resistant or dependent on cyclosporine A (CsA), tacrolimus combined with corticosteroids has been effective in inducing sustained reductions in urinary protein (122). Notably, a study involving 25 patients with FSGS who were resistant or dependent on CsA reported that 100% achieved remission after treatment with tacrolimus (122).

Emerging therapies for FSGS, such as sparsentan, have demonstrated effectiveness in clinical trials, particularly in reducing proteinuria and outperforming traditional ACE inhibitors (123). Additionally, anti-CD20 monoclonal antibodies (like rituximab) have shown significant efficacy in resistant FSGS cases, with remission rates exceeding 50% (124, 125). Innovative agents like Barleriside A are also being investigated, acting as aryl hydrocarbon receptor antagonists to ameliorate oxidative stress and inflammation, representing a potential new therapeutic option for FSGS (119).

Advanced therapeutic approaches are emerging based on novel mechanistic insights. Aryl hydrocarbon receptor (AhR) pathway modulation represents a promising therapeutic target, with natural compounds like BSA demonstrating high-affinity AhR antagonist properties that eliminate oxidative stress and inflammation through regulation of IκB/NF-κB and Keap1/Nrf2 pathways (126). Furthermore, comprehensive podocyte protection strategies utilizing traditional Chinese medicines have shown remarkable efficacy through multiple mechanisms including inhibition of JNK/ERK signaling pathways, restoration of podocyte actin cytoskeleton, reduction of C5b-9 complex deposition, and enhancement of Nrf2/HO-1 pathways (127). The application of matrix metalloproteinase (MMP) inhibition strategies represents another innovative approach, targeting the critical role of MMPs in renal fibrosis and matrix remodeling processes that characterize FSGS progression (118).

Membranous nephropathy is a major cause of nephrotic syndrome in adults, necessitating a tailored treatment approach focused on immunoregulation. Corticosteroids remain the cornerstone of therapy for high-risk patients and those with severe symptoms, often combined with other immunosuppressants to enhance efficacy. Recent studies indicate that the combination of glucocorticoids with tacrolimus and mycophenolate mofetil significantly improves outcomes, especially in patients with underlying conditions like type 2 diabetes mellitus (128).

Revolutionary combination therapy approaches have emerged for complex cases. A groundbreaking retrospective study demonstrates that low-dose multi-target therapy (prednisone 10mg/d + tacrolimus 0.05mg/kg/d + mycophenolate mofetil 1g/d) significantly outperforms cyclophosphamide-based regimens in pMN patients with concurrent type 2 diabetes mellitus. This novel approach achieved superior proteinuria reduction (-4800.48 ± 3002.65 vs -1663.32 ± 4113.98 mg/24h at 2 months, P-BH=0.045) while maintaining better glycemic control (128). Such precision therapy approaches represent a paradigm shift toward individualized treatment strategies that consider comorbidity profiles.

Calcineurin inhibitors, such as tacrolimus and cyclosporine, have effectively reduced proteinuria and improved renal function (129, 130). Cyclophosphamide may also be employed in certain cases of immune-mediated MN (131). Clinical trials have demonstrated RTX’s superior efficacy in MN compared to traditional therapies. The GEMRITUX trial (132) indicated a remission rate of 64.9% for RTX patients after 17 months, compared to 34.2% for those receiving supportive care. The MENTOR trial (133) further established RTX’s effectiveness, with 62% of the RTX group achieving complete or partial remission at two years, versus 20% in the cyclosporine group. RTX’s efficacy involves dismantling autoreactive B lymphocyte clones that produce pathogenic anti-PLA2R antibodies (134), with a meta-analysis confirming a total remission rate of 67% and an average proteinuria reduction of 4.90 grams/day in MN patients. Additionally, B-cell targeted therapies, including rituximab and belimumab, have shown promising outcomes in enhancing patient prognosis (135).

Innovative integrated approaches combining low-dose cyclophosphamide with traditional Chinese medicine formulations represent a breakthrough in personalized medicine. The Shulifenxiao formula combined with low-dose cyclophosphamide has demonstrated excellent efficacy and safety across different risk stratifications of primary MN patients, offering a novel Chinese-Western integrated therapeutic paradigm (136).

Comprehensive network Meta-analysis of 31 randomized controlled trials involving 2,195 patients has established the superior efficacy of multiple Chinese medicine formulations. Fifteen distinct Chinese medicine preparations including Wuweizi capsules (WZC), Leigongteng multiglycoside tablets (LGT), Shengmai injection (SMI), Shenshen Kang capsules (SFC), Bailing capsules (BLC), Dihuangye total glycoside capsules (DHT), Qingre Qushi granules (QRG), Shenyan Kangfu tablets (SYT), Qiqi Yishen capsules (QQC), Huangqi injection (HBT), Renkang injection (SKI), and Huangkui capsules (HKC) have demonstrated superior outcomes in improving 24-hour proteinuria, serum albumin, creatinine, total cholesterol, and triglycerides compared to conventional therapy alone (137).

CD4+ T cell subset modulation represents another innovative therapeutic approach. Jianpi Qushi Heluo Formula (JQHF) has demonstrated remarkable efficacy in correcting CD4+ T cell subset imbalances characteristic of pMN patients (elevated Th1/Th17 cells, reduced Th2/Treg cells) while significantly reducing CXCL10 levels, which correlate with 24-hour proteinuria levels (138). This targeted immune regulation approach addresses the fundamental pathophysiological mechanisms underlying MN progression.

In addition to conventional therapies, recent research has explored the potential of Chinese herbal medicine to inhibit podocyte damage as a therapeutic strategy for MN. This approach may serve as a valuable adjunct to standard treatments (139). The traditional use of Poria cocos has also been examined for its nephroprotective properties, with studies focusing on its triterpenoid components and their pharmacological effects (118).

Advanced podocyte protection strategies utilizing traditional Chinese medicines represent a comprehensive therapeutic approach addressing multiple injury mechanisms. These strategies target complement system activation (C5b-9 membrane attack complex, C3a/C3aR pathways), pyroptosis and autophagy dysregulation (NLRP3 inflammasome activation, mTOR pathway abnormalities), and oxidative stress (increased ROS production, NADPH oxidase upregulation). Specific interventions include Astragalus IV for JNK/ERK pathway inhibition and podocyte actin cytoskeleton restoration, Triptolide for C5b-9 complex deposition reduction and p38MAPK pathway inhibition, Curcumin for PI3K/AKT/mTOR pathway inhibition and Nrf2/HO-1 pathway enhancement, Zhenwu decoction for NF-κB pathway and NLRP3 inflammasome inhibition, and Sanqi oral solution for Nrf2/HO-1 pathway activation and NF-κB pathway inhibition (127).

B cell-targeted therapies, particularly anti-CD20 monoclonal antibodies, have revolutionized nephrotic syndrome management, highlighting the critical role of B cells in disease pathogenesis and offering alternative options for patients with limited therapies. Anti-CD20 monoclonal antibodies like RTX exert therapeutic effects through various mechanisms. In addition to direct B cell depletion, RTX modulates T cell function by depleting a small percentage of circulating T lymphocytes (140), disrupting autoreactive loops between B and T cells, thereby reducing inflammation and tissue damage (21). RTX also interferes with antigen presentation, modulates T cell proliferation, and affects natural killer cells and macrophage activities (141). Moreover, in recurrent FSGS, RTX appears to protect the renal filtration barrier through direct actions on podocytes (142).

Sustained depletion of CD27+ memory B cells and the return of naive B cells correlate with effective treatment (143). Delays in memory B cell reconstitution following RTX treatment may reduce relapse risks (35), underscoring that specific B cell subsets, rather than total numbers, drive disease pathology and treatment outcomes.

Advanced mechanistic insights reveal the complex interplay between traditional immunosuppressive approaches and emerging pathway-specific interventions. The gut-kidney axis modulation through microbiota restoration represents a novel therapeutic strategy where specific bacterial populations and their metabolites directly influence renal immune responses and disease progression (119). This mechanism demonstrates how probiotic therapy can be strategically integrated with conventional B cell-targeted approaches to achieve synergistic therapeutic effects.

Precision medicine approaches utilizing biomarker-guided therapy selection are becoming increasingly sophisticated. The identification of distinct immunological patterns and the application of network pharmacology approaches in traditional Chinese medicine provide unprecedented opportunities for developing combination therapies that target multiple disease mechanisms while minimizing treatment-related toxicities (136).

Future therapeutic directions incorporate multi-pathway targeting strategies that simultaneously address B cell dysfunction, complement activation, podocyte injury, and gut-kidney axis dysregulation. The integration of traditional Chinese medicine network pharmacology with modern immunological approaches offers unprecedented opportunities for developing combination therapies that target multiple disease mechanisms while minimizing treatment-related toxicities (119).

The B-cell system in children is in a developmental stage and exhibits characteristics that are significantly different from those in adults (as shown in Table 3 ). Morbach et al. studied 261 healthy individuals of different ages and showed that the proportion of CD27⁺ memory B cells increased with age, gradually increasing from 4-8% in infancy to 30-40% in adults (144). Blanco et al. Analysis of the 609 healthy subjects (0-80) of peripheral blood B cell subsets, confirm CD24^hiCD38^hi transitional CD19 + B cells (with functions of regulating) in children (especially under the age of 5) is significantly higher than that among adults, and gradually decline with age (145). Meanwhile, CD27⁺IgM⁺ marginal zone B cells and CD27⁺IgD^- class-switching memory B cells are low in children and only approach adult levels after puberty (145, 146).

Differences in B cell function between children and adults are mainly shown in the following aspects:

B cell-related immunopathology offers crucial insights into the classification and differential diagnosis of NS. Advances in B cell subset analysis have enhanced our understanding of pathological subtypes and their immunological characteristics.

Immunofluorescence and immunohistochemistry reveal distinct B cell-related immune complex patterns across NS subtypes. In MN, granular IgG and C3 deposits along glomerular basement membranes indicate immunoglobulin-mediated autoimmunity (175), while unique IgG4 subclass compositions help differentiate primary from secondary forms (176). FSGS may present with mesangial IgM and C3 deposits (177), although their pathogenic significance remains debated. MPGN typically shows strong immunoglobulin and complement deposition, with monoclonal immunoglobulins potentially indicating monoclonal gammopathy of renal significance.

Flow cytometric analysis of peripheral blood B cell subsets provides additional diagnostic value. In primary MN, significantly elevated CD19+CD27+IgD- memory B cells correlate with disease-specific anti-PLA2R antibodies (178). FSGS patients exhibit increased CD19+CD27+IgD-IgG+ class-switched memory B cells, correlating with disease severity and renal function deterioration (22). Such B cell subset profiles may complement traditional histopathology in distinguishing FSGS subtypes and identifying patients likely to benefit from immunosuppressive therapy (179).

Integrating clinical parameters, traditional histopathology, and B cell phenotyping creates a comprehensive diagnostic framework, especially in challenging cases such as atypical presentations and differentiating minimal change disease from FSGS (35, 180). B cell markers may also help identify patients with immune-mediated components amenable to targeted therapy, even when histology does not support this (as shown in Table 4 ) (23).

Flow cytometry enables precise identification of B cell subsets in various functional states, including resting naive B cells, regulatory B cells, and memory B cells (181). Dynamic changes in these subsets provide valuable insights into B cell functional status, disease activity, and prognostic trajectories in nephrotic syndrome patients (182).

The distribution and phenotype of B cell subsets correlate strongly with NS disease states. In acute MN, the proportion of naive B cells in peripheral blood increases, while switched and unswitched memory B cells decrease (93), closely correlating with proteinuria severity (128). Elevated B lymphocyte infiltration in renal tissue indicates worsening acute injury (183), as demonstrated by Du et al., who found positive correlations between renal B cell infiltration and disease severity (184).

In SSNS, B lymphocyte subsets undergo distinctive changes across disease phases, with total B cell counts and memory B cells (especially class-switched memory B cells) increasing during active disease. Research indicates that plasmablast levels in relapsing MCD patients correlate with low albumin levels, high proteinuria, and hypogammaglobulinemia (56). These findings highlight the potential of B cell subset analysis as a non-invasive method to monitor disease activity.

Longitudinal changes in B cell subsets provide critical prognostic information as well. Pediatric NS patients with elevated memory B cells at onset, particularly class-switched memory B cells, have observable recovery patterns following RTX treatment that can predict relapse (185). Colucci et al. noted that the timing and composition of B cell reconstitution after RTX strongly predict clinical outcomes (35). Increased CD27+IgD-IgG+ class-switched memory B cells in primary FSGS correlate with estimated glomerular filtration rate (eGFR), 24-hour proteinuria, and serum IgG levels, serving as sensitive biomarkers for disease severity (22). Meanwhile, regulatory B cells may indicate immune quiescence or future relapses (69).

The predictive value of B cell monitoring extends to treatment response assessment. During remission, total B cell counts and subset distributions normalize, while imbalanced reconstitution (especially elevated memory B cell proportions) following depletion therapy may indicate increased relapse risk (22). This differential pattern can guide individualized follow-up and treatment protocols.

Monitoring B cell subsets is vital for therapeutic decision-making in B cell-targeted therapies. While B lymphocyte depletion after RTX is expected, it alone does not guarantee clinical response (5, 186). Studies suggest that recovery of specific B cell subsets rather than total numbers predicts treatment outcomes better (35, 55).

Memory B cells are particularly significant; their sustained depletion corresponds with reductions in proteinuria (8), while early repopulation may indicate relapse risks (187). In pediatric NS, class-switched memory B cell reconstitution typically occurs before clinical relapse (185). Comprehensive immunophenotyping shows that long-term responders maintain lower levels of memory and switched memory B cells (35).

Plasmablast monitoring offers additional insights, as their reappearance often precedes clinical relapse (11) and anti-PLA2R antibody elevation in MN patients (188). Detecting circulating CD19-CD38++ plasma cells can help identify early disease recurrence, even when total B cell counts are low.

These findings have led to tailored monitoring protocols, where regular assessment of B cell subsets informs treatment strategies and optimal retreatment timing. Integrating B cell subset analysis with serum autoantibody monitoring (e.g., anti-PLA2R in MN) provides a comprehensive evaluation of immunological activity (23, 68).

Moreover, serial biopsies or novel non-invasive techniques to monitor tissue-resident B cells may further enhance treatment precision (183). Emerging biomarkers like BAFF levels and B cell cytokine signatures can identify patients at risk for inadequate response or early relapse (78, 189).

Despite their effectiveness, current B cell-targeted therapies have limitations, with a significant number of patients failing to achieve satisfactory proteinuria reduction due to individual variations, dosing differences, underlying disease heterogeneity, prior immunosuppression, and pharmacokinetic factors (64, 187, 190, 191). Current monitoring practices remain suboptimal, as routine assessments of CD19+ and CD20+ B cells show weak correlations with treatment response (132). Certain B cell subsets, particularly memory B cells, may evade RTX-mediated depletion or repopulate earlier, promoting relapse (192).

To address these issues, newer anti-CD20 agents, including ocrelizumab, ofatumumab, and obinutuzumab, are being explored, along with emerging therapeutic targets beyond CD20, such as Bruton’s tyrosine kinase inhibitors and proteasome inhibitors, which offer potential for precise interventions in B cell-mediated pathologies (193). Dynamic monitoring of treatment resistance patterns and assessing post-treatment B cell recovery characteristics will be essential for tailoring treatment strategies to each patient’s unique clinical profile.

Existing studies show marked differences in patient population characteristics. Some studies focus on pediatric idiopathic NS patients, while others concentrate on adult patients or specific pathological types (such as MN, MCD, or FSGS). For example, research on pediatric idiopathic NS demonstrates specific patterns in B cell subset distribution (35, 185) (34, 56), while adult MN patients exhibit unique B cell characteristics associated with anti-PLA2R antibodies (134).

More importantly, B cell subset definitions and phenotyping strategies vary considerably. Earlier studies primarily monitored total CD19⁺ B cells (132, 133), while recent research employs more refined multi-marker combinations (56, 181). For instance, memory B cells are defined variously across studies as CD19⁺CD27⁺, CD27⁺IgD⁺/CD27⁺IgD^- (distinguishing non-switched and switched memory cells), or CD19⁺CD27⁺IgD^-IgG⁺ (22, 185). These definitional differences directly influence measurement results and their correlation analyses with clinical parameters.

Significant variations exist in flow cytometry technical parameters (such as instrument configuration, antibody clones, compensation strategies) and sample processing methods across studies (187, 194). More critically, sample collection timepoints relative to disease activity status (initial onset, relapse, or remission) and treatment intervention timing differ substantially (8, 56). For example, B cell reconstitution monitoring frequency after RTX treatment ranges from monthly to quarterly (35, 132), potentially missing critical features of subset recovery.

Additionally, clinical outcome assessment criteria lack consistency. Different studies employ varying methods of proteinuria assessment (24-hour urine protein vs. urine protein/creatinine ratio), remission definition thresholds, and follow-up durations (ranging from months to years) (116, 133), directly affecting result interpretation and inter-study comparisons.

These methodological heterogeneities have led to several key contradictions in the literature, such as inconsistent reports on the correlation between B cell subsets and disease activity (181, 195), divergent observations regarding B cell recovery patterns (35, 143), and controversies surrounding treatment response predictors (177).

Through methodological standardization, future research will provide more reliable and comparable evidence for the application of B cell analysis in NS diagnosis, prognosis assessment, and treatment monitoring.

In the study of B cell subset changes, understanding the distinction between causality and correlation is crucial. Current literature indicates that there is a statistical correlation between B cell subset changes and disease progression in patients with kidney disease. For example, some studies have shown that the number of memory B cells and plasma cells significantly increases in NS, and these changes correlate positively with disease activity (56, 184, 196). Despite these observations providing important clinical clues, they do not establish that changes in B cell subsets are the direct cause of disease progression. This raises an urgent question for researchers: how should we interpret these observed correlations?

Specific controversies include the following key questions:

We plan to critically assess how these differences in B-cell behavior and function challenge conventional paradigms that currently dominate the understanding of nephrotic syndrome. This critical evaluation will focus on three key areas:

With the advancement of single-cell sequencing technology, future research should establish more precise B cell subset classification systems (63, 181). Through integrating multi-omics analysis strategies, we should deeply analyze the functional heterogeneity of key subsets such as transitional B cells, memory B cells, and regulatory B cells (36, 188), identify specific B cell clones driving disease progression, and elucidate the precise molecular mechanisms of B-T cell interactions (21).

Based on the specific alterations of B cell subsets in different pathological types revealed in this review, standardized B cell monitoring protocols should be established in the future (181). We should develop multidimensional disease activity assessment systems integrating B cell subset characteristics, functional states, and autoantibody profiles, particularly targeting key biomarkers for different types such as MCD, MN, and FSGS (22, 68, 185). Standardized flow cytometry analysis procedures (181) and novel point-of-care testing technologies should be established to provide precise guidance for clinical decision-making.

Building upon existing rituximab therapy, future research should develop next-generation B cell-targeted drugs such as obinutuzumab, ofatumumab, and daratumumab (72, 193), exploring therapeutic strategies beyond CD20 targets. Individualized “precision dosing” protocols should be developed based on B cell subset monitoring results, guiding optimal treatment timing through memory B cell recovery patterns (35, 187). Meanwhile, combining emerging technologies such as chimeric antigen receptor T cell therapy provides additional therapeutic options for immune regulation.

Future studies should deeply explore age-related differences in B cell mechanisms between pediatric and adult nephrotic syndrome (144–146), establishing age-stratified treatment protocols (154, 156). Utilizing artificial intelligence and machine learning technologies, we should integrate multi-omics data to construct molecular networks of B cell-mediated diseases and establish disease stratification and treatment response prediction models. Multi-center prospective studies should validate the clinical application value of B cell biomarkers (195).

Through in-depth exploration of these research directions, we expect to significantly enhance our understanding of B cell mechanisms in nephrotic syndrome within the next 5–10 years, translating these findings into precision diagnostic and individualized therapeutic strategies to ultimately improve patient prognosis and quality of life.

Utilizing artificial intelligence and machine learning technologies will facilitate the integration of multi-omics data, allowing for the construction of comprehensive molecular networks related to B cell-mediated diseases. These networks can aid in the development of disease stratification and treatment response prediction models by integrating key biomarkers: