Immune mechanisms and immunomodulatory therapies in steroid-resistant nephrotic syndrome

Abstract

Steroid-resistant nephrotic syndrome (SRNS) is a complex and refractory kidney disease generally causing chronic kidney dysfunction, characterized by persistent proteinuria despite prolonged corticosteroid therapy. This review comprehensively explores the mechanisms of immunity driving SRNS, mainly focusing on the complex function network within immune cells, pro-inflammatory cytokines, and podocyte injury. Current immunosuppressive therapies show limited efficacy, prompting exploration of precision immunomodulatory strategies. Emerging approaches include IL-17 or low-dose IL-12 modulation, proteasome or CD38 blockade, C5/factor B inhibition, and Rho kinase or caspase inhibition. Additionally, personalized strategies leveraging genetic profiling and biomarker-guided therapies are advancing tailored interventions. These targeted therapies address SRNS heterogeneity while minimizing systemic immunosuppression, offering new promise for halting disease progression. Future directions emphasize combinatorial regimens and mechanistic stratification to optimize therapeutic outcomes.

HIGHLIGHTS

1. Focusing the immune mechanisms in SRNS, including podocyte injury and roles of lymphocytes.

2. Discussions of the immunosuppressive therapies and limitations for related immune pathogenesis in SRNS.

3. Exploration of novel immunomodulatory and personalized therapies against specific immune mechanisms in SRNS.

1. Introduction

Steroid-resistant nephrotic syndrome (SRNS) is a severe form of idiopathic nephrotic syndrome (INS) characterized by persistent proteinuria (urinary protein excretion >3.5 g/day) despite 4–6 weeks of high-dose corticosteroid therapy [1,2]. INS represents a common pediatric glomerular disorder, and 2–6.5 out of 100,000 children are diagnosed with INS annually. Of these cases, 10–15% are classified as steroid-resistant, which significantly impacts long-term kidney prognosis [3]. SRNS accounts for approximately 10–20% of childhood nephrotic syndrome (NS) cases and is more prevalent in certain populations, such as those of South Asian and African descent [4]. SRNS patients usually have poor prognoses, resulting in further severe kidney dysfunction with a significant risk of aggravation to chronic kidney failure, contributing to substantial morbidity and mortality in children worldwide [5]. The dual burden of long-term illness and physical distress in SRNS patients, coupled with the socioeconomic strain on families, underscores the urgent need for optimized therapeutic strategies [6].

Emerging proof highlights the aberrant immune system as a key factor driving pathological developments of SRNS. Podocytes are exclusive epithelial cells, that are situated between glomerular capillary endothelial cells and basal membrane. The glomerular filtration barrier relies on the normal structure and functions of podocytes. Podocyte injury can result from genetic, immunological, infectious, and toxic causes. In SRNS, a complex interplay between adaptive and innate immune responses leads to podocyte injury and persistent proteinuria [7]. T cells, particularly Th17 and Th1 subtypes, are associated with promoting inflammation and autoimmunity in SRNS, while regulatory T cells (Tregs) are often reduced or dysfunctional, resulting in immune tolerance impairment [8]. B cells and autoantibodies targeting podocyte antigens, such as nephrin, further complicate disease progression [9]. Additionally, innate immune mechanisms, including macrophage activation and complement pathway dysregulation play a critical role in mediating glomerular injury [10].

SRNS poses a major clinical challenge due to its insensitivity to standard immunosuppressive therapies and high relapse rates. Corticosteroids, as the first-line medicine for NS, are ineffective in SRNS. Therefore, alternative immunosuppressants such as calcineurin inhibitors (CNIs; e.g., cyclosporine, tacrolimus) and alkylating agents (e.g., cyclophosphamide) are necessary [11]. However, these therapies often have obvious adverse effects, such as nephrotoxicity, infections, and malignancies, limiting their long-term treatment [12]. Moreover, a large number of patients recur after kidney transplantation, further complicating prognostic management [13]. The heterogeneity of SRNS, with both genetic and acquired forms, complicates the development of effective and precision therapeutics [14]. These challenges underscore an urgent need for therapies that reconcile immune modulation with podocyte repair.

2. Methods

To answer the research question, a systematic review was conducted. In this article, the literatures were retrieved from inception to February 2025 in the following databases: PubMed, Embase, Web of Science and Cochrane Library. We retrieved articles importing the combination of MeSH terms and related text-word terms, including ‘nephrology’, ‘kidney disease’, ‘nephrotic syndrome’, ‘steroid-resistant nephrotic syndrome’, ‘immune’, ‘immunomodulating agents’ ‘immunomodulant’, ‘podocyte’, etc. A dual-reviewer methodology was rigorously implemented across two sequential screening phases: initial eligibility assessment based on titles and abstracts, followed by full-text evaluation against predefined inclusion criteria.

3. Immune-mediated pathogenesis in SRNS

The pathogenesis of SRNS is intricately linked to abnormal immunity, including both adaptive and natural immunity. These mechanisms converge on podocyte injury, contributing to proteinuria and glomerular dysfunction. Below, we explore the roles of T cells, B cells, innate immunity, and podocyte injury in SRNS.

3.1. Role of T cells

In the abnormal immunity of SRNS, the role of T cells is essential. Dysregulation of T cell subgroups and associated cytokines can induce glomerular inflammation and podocyte injury.

3.1.1. Th1/Th2 imbalance and cytokine dysregulation

In ordinary physiological circumstances, Th1 and Th2 cells are in a relatively balanced state, maintaining a regular immune function. In a pathological condition, Th1 cells produce and release pro-inflammatory cytokines such as interferon-gamma and tumor necrosis factor-alpha (TNF-α), which promote macrophage activation and glomerular injury [15]. Conversely, Th2 cells release multiple cytokines, especially interleukin with anti-inflammatory effects (e.g., IL-4 and IL-10). Th2 cells are often suppressed, causing further exacerbating inflammation [16,17]. In SRNS, a disruption in the Th1/Th2 balance has been observed, causing an inflammatory milieu that harms podocytes and the glomerular filtration barrier under the predominance of Th1-mediated immune responses.

3.1.2. Th17 cells and IL-17 signaling

Th17 cells, a subtype of T helper cells, featured by the production of interleukin-17 (IL-17), are recognized as crucial factors in SRNS pathogenesis. A large amount of IL-17 can usually be observed in the serum and kidney tissues of SRNS patients, which may be associated with disease severity [18,19]. IL-17 performs strong pro-inflammatory effects by recruiting neutrophils and macrophages to the glomeruli and directly inducing podocyte injury through the activation of pro-apoptotic pathways [20]. Targeting Th17 cells and IL-17 signaling has thus become a potential therapeutic strategy in SRNS.

3.1.3. Tregs and immune tolerance

Tregs are vital to keeping immune tolerance and avoiding auto immunities. In SRNS, the expression and functions of Tregs are often abnormal, leading to unchecked activation of immunity [21]. Tregs typically suppress effector T cells (e.g., Th1 and Th17) by the release of anti-inflammatory factors such as IL-10 and transforming growth factor-beta. The loss of Treg-mediated suppression in SRNS contributes to sustained inflammation and podocyte injury [22].

3.2. Role of B cells and autoantibodies

Plasma cells can be differentiated from B cells, featured by the production and secretion of antibodies that attack kidney components, such as the glomerular basement membrane (GBM). In SRNS, anti-GBM antibodies give rise to glomerulonephritis, which may bond with renal cells and activate complement, leading to inflammation and glomerular injury.

3.2.1. Anti-podocyte antibodies

Autoantibodies targeting podocyte antigens, such as anti-nephrin antibody has been found in both adults and children with minimal changes disease, and the high expression of anti-nephrin is associated with a massive post-transplant recurrence of proteinuria [23]. A cohort study in Japan reported that anti-nephrin antibody was identified in half of the children with steroid-sensitive NS [24]. The combination of these antibodies and critical slit diaphragm proteins leads to the failure of podocyte structure, which causes podocyte skeleton rearrangements and proteinuria [23,25].

3.2.2. Immune complex deposition

Circulating immune complexes, made up of autoantibodies and their corresponding antigens, will accumulate in the GBM. These complexes can be deposited in the glomeruli, which is an additional pathogenetic mechanism in SRNS. This accumulation activates complement and triggers inflammatory responses [26]. Inevitably, these processes lead to more serious podocyte injury and glomerular sclerosis.

3.3. Role of innate immunity

As the first defense of host, innate immunities provide initial nonspecific defense against foreign substances and pathogens. Leukocytes, especially macrophages and dendritic cells, as well as the complement system, play critical roles in the early stages of SRNS pathogenesis.

3.3.1. Macrophages and dendritic cells

In SRNS, macrophages and dendritic cells are necessary for mediating the inflammatory reactions in the glomerular. Macrophages polarized to M1 type with pro-inflammation effect, infiltrate the glomeruli, release TNF-α, IL-1β, and reactive oxygen species, which directly damage podocytes [27,28]. Dendritic cells, on the other hand, function as antigen-presenting cells, identify pathogens by pattern recognition receptors, present antigens to T cells, and initiate acquired immunity by activating T cells [29]. The crosstalk between innate and acquired immune system intensified the inflammatory cascade reaction in SRNS.

3.3.2. Complement system

The complement system is a group of reactive innate immune proteins with precision regulation mechanisms, which include the classical pathways, lectin pathways and alternative complement pathways. Triggering of the complement system promotes glomerular damage in SRNS. Activation of complement, particularly through the bypass path, results in the formation of the membrane attack complexes (MACs) on podocytes, causing cell lysis and apoptosis [30]. Additionally, complement components as chemoattractants, such as complement anaphylatoxins, recruit inflammatory cells to the glomeruli, further progression into glomerular nephritis leading to SRNS [31].

4. Current immunosuppressive therapies and limitations

The clinical management of SRNS relies heavily on immunosuppressive therapies to control immune-mediated podocyte injury and proteinuria. However, these therapies are often associated with clinical limitations, including incomplete responses, toxicity, and high relapse rates. Below, we discuss the mechanisms, effects, and limitations of current immunosuppressants applied in SRNS (Table 1 and Figure 1).

Table 1.

Current immunosuppressive therapies for SRNS.

Agent	Mechanism	Efficacy	Limitation
Corticosteroids [11,32]	Suppress T cell activation and cytokine production (e.g. NF-κB inhibition).	First-line therapy for nephrotic syndrome, but ineffective in SRNS by definition.	Side effects: Growth retardation, osteoporosis, metabolic disturbances.
Cyclosporine [33,35]	Inhibits calcineurin to block T cell activation (NFAT dephosphorylation).	Induces remission in ∼60–70% of SRNS patients.	Nephrotoxicity, hypertension, infection risk, and potential for relapse after discontinuation.
Tacrolimus [34–36]	Similar to cyclosporine; inhibits calcineurin to suppress T cell activation.	16.7% incidence of side effects vs. Cyclosporine	Nephrotoxicity, hypertension, and increased risk of infections.
Cyclophosphamide [37–40]	Cross-links DNA to induce apoptosis of rapidly dividing immune cells (e.g. B cells and T cells).	53.8% of SRNS patients achieved remission	Severe toxicity: Bone marrow suppression, gonadal toxicity, and increased malignancy risk.
Chlorambucil [37,40]	Alkylating agent that induces DNA damage and apoptosis in immune cells.	Limited use due to toxicity; historically used in steroid-resistant cases.	High risk of bone marrow suppression and long-term malignancy.
Mycophenolate Mofetil [41,42,48]	Inhibits IMPDH to block purine synthesis in lymphocytes, reducing T and B cell proliferation; MMF de-esterized into mycophenolic acid (MPA) to reduce immune-mediated inflammation and podocyte injury	44.8% advantageous outcome vs. tacrolimus (90.3%)	Gastrointestinal disturbances, leukopenia, and increased infection risk.
Rituximab [43–47,49,50]	Monoclonal antibody targeting CD20 on B cells; depletes B cells, reduces autoantibody production, and attenuate aberrant T cell activation; stabilizes podocyte cytoskeleton and restore glomerular filtration barrier	Relapse-free period 267 vs. 101 days (p < 0.01), 72%–80% proteinuria reduction	20%–40% intolerance in the membranous nephropathy, 28% relapse, 20%–40% rituximab intolerance

NF-κB: nuclear factor-kappa B, SRNS: steroid-resistant nephrotic syndrome, NFAT: nuclear factor of activated T cells, IMPDH: inosine monophosphate dehydrogenase, MMF: Mycophenolate Mofetil, MPA: mycophenolic acid.

Figure 1.

Current and emerging therapies for SRNS.

4.1. Corticosteroids

As first-line therapy, corticosteroids suppress T-cell activation and NF-κB signaling [32]. However, SRNS patients exhibit intrinsic steroid resistance, and prolonged treatment of high-dose corticosteroids causes growth retardation, osteoporosis, and metabolic disturbances [11]. Therefore, it is necessary for effective alternative therapies.

4.2. CNIs (cyclosporine, tacrolimus)

CNIs, for instance, cyclosporine and tacrolimus, inhibit calcineurin-nuclear factor of activated T cells (NFAT) signaling, stabilizing podocyte cytoskeleton [33]. While cyclosporine induces remission in 60–70% of SRNS patients, tacrolimus shows comparable efficacy with fewer side effects (16.7% vs. 50% with cyclosporine) [34]. Both agents carry risks of nephrotoxicity, hypertension, and infections [35,36].

4.3. Alkylating agents (cyclophosphamide, chlorambucil)

Alkylating agents, such as cyclophosphamide and chlorambucil, are applied in SRNS because of their potent immunosuppressive effects by inducing apoptosis of rapidly dividing immune cells [37]. Cyclophosphamide achieved 53.8% remission versus dexamethasone (47.8%) in SRNS patients [38], particularly those with minimal change disease or focal segmental glomerulosclerosis (FSGS) [39]. But side effects, including bone marrow suppression, gonadal toxicity and malignancy risks, cannot be ignored [40].

4.4. Mycophenolate mofetil

Mycophenolate mofetil (MMF) inhibits inosine monophosphate dehydrogenase (IMPDH) in lymphocytes, offering a nephrotoxicity-free alternative for patients intolerant to CNIs. However, efficacy of MMF (advantageous results rate, 44.8%) is inferior to tacrolimus (advantageous results rate, 90.3%) [41], with gastrointestinal disturbances, leukopenia, and risk of infections [42].

4.5. Rituximab

Rituximab, a monoclonal anti-CD20 antibody, depletes B cells, prolonging relapse-free period (267 vs. 101 days versus placebo, P < 0.01) in steroid-dependent/frequently relapsing NS [43]. Rituximab has considerable efficacy in reducing persistent proteinuria in NS, including post-transplantation recurrent FSGS [44]. However, 20–40% of membranous nephropathy patients exhibit rituximab intolerance [45], and relapse rates reach 28% [46], possibly due to the chronic or irreversible glomerular damage and anti-rituximab antibody production [47].

5. Emerging immunomodulatory therapies

The limitations of current immunosuppressive therapies for SRNS have catalyzed the development of novel immunomodulatory strategies. These aim to specifically target immune responses involved in SRNS pathological mechanisms, offering the potential for more efficient and individualized therapies. Below, we discuss the most promising approaches, including T cell subgroups modulation, B cell targeting, complement inhibition, podocyte protection, and personalized therapeutic frameworks (Table 2 and Figure 1).

Table 2.

Emerging immunomodulatory therapies for SRNS.

Agent	Mechanism	Current stage/progress	Key challenges
Targeting T Cell Subsets
Secukinumab (anti-IL-17A) [51]	Neutralizes IL-17A to reduce Th17-mediated inflammation and podocyte injury.	Preclinical success in reducing proteinuria; pending clinical trials in SRNS.	Limited human data; potential systemic immunosuppression risks.
Low-dose IL-2 [53,54]	Expands and activates regulatory T cells (Tregs) to restore immune tolerance.	Pilot studies show improved Treg function in autoimmune kidney diseases.	Optimal dosing unclear; long-term safety and efficacy unknown.
Targeting B Cells/Plasma Cells
Bortezomib [56,57]	Induces plasma cell apoptosis by inhibiting proteasome-mediated protein degradation.	Effective in lupus nephritis and antibody-mediated rejection; early SRNS trials ongoing.	Neuropathy, thrombocytopenia; limited SRNS-specific data.
Daratumumab (anti-CD38) [58,59]	Depletes CD38+ plasma cells to reduce autoantibody production.	Case reports show remission in refractory SRNS; trials in progress.	High cost; risks of long-term B cell depletion and infections.
Targeting Complement Activation
Eculizumab (anti-C5) [60–63]	Blocks C5 to prevent membrane attack complex (MAC) formation and complement-mediated injury.	Case reports suggest efficacy in complement-driven SRNS.	Requires evidence of complement activation; high cost.
Iptacopan (Factor B inhibitor) [64–66]	Inhibits alternative complement pathway via Factor B blockade.	Early-phase trials show reduced complement activity in kidney diseases (e.g. C3 glomerulopathy).	Limited SRNS data; long-term safety and efficacy unknown.
Podocyte-Targeted Therapies
Fasudil (Rho kinase inhibitor) [67–70]	Stabilizes podocyte actin cytoskeleton by inhibiting RhoA/ROCK signaling.	Preclinical models show reduced proteinuria; no human trials in SRNS.	Lack of clinical data; potential off-target effects.
Emricasan (caspase inhibitor) [63,64]	Blocks apoptosis pathways to protect podocytes from immune-mediated injury.	Experimental models show preserved glomerular function.	No human data; uncertain specificity and safety.
Personalized Medicine
Biomarkers (e.g. anti-nephrin antibody [23,24])	Combination with critical slit diaphragm proteins contributing to podocyte structure failure	High expression of anti-nephrin antibody is associated with proteinuria relapse in SSNS	The significance of anti-nephrin antibody in nephrotic syndrome needs further study.
Genetic testing [14,76,77]	Identifies genetic variants (e.g. NPHS1, COQ6) to tailor therapies (e.g. coenzyme Q10) and gene-editing technologies (e.g. CRISPR-Cas9).	Genetic diagnosis guides therapy in ∼30% of pediatric SRNS cases.	High cost; limited access to genetic testing and targeted therapies.

IL-17: interleukin-17, IL-2: interleukin-2, SRNS: steroid-resistant nephrotic syndrome, MAC: membrane attack complex, ROCK: Rho kinase, SSNS: steroid-sensitive nephrotic syndrome, COQ6: coenzyme Q6, NPHS1: Nephrin

5.1. Targeting T cell subgroups

In SRNS pathogenesis, T-cell abnormality is a key factor, and emerging therapies focus on its subtype-specific immunomodulation.

5.1.1. Inhibition of Th17 pathway (e.g., Secukinumab)

Th17 cells, featured by the generation of IL-17A to IL-17F, are key drivers of inflammation and podocyte injury in SRNS. Secukinumab, an IL-17A antagonist, through reducing expression of IL-17A and blocking its pro-inflammatory effect, shows efficacy in autoimmune diseases such as psoriasis and ankylosing spondylitis [51]. Preclinical studies suggest that IL-17 inhibition can reduce glomerular inflammation and proteinuria in experimental models of SRNS [20]. Currently, clinical trials are essential for appraising the clinical effect and medication safety of Secukinumab and other IL-17 inhibitors in SRNS patients.

5.1.2. Enhancement of Treg function (e.g., low-dose IL-2)

Tregs are indispensable to keeping immunosuppression, as their dysfunction contributes to SRNS pathogenesis. Low-dose interleukin-2 (IL-2) therapy has been shown to selectively restore the number, and activate and enhance Tregs without stimulating effector T cells [52]. In pilot studies, with the intervention of low-dose IL-2 in autoimmune kidney diseases, the function of Tregs can be improved and proteinuria can be reduced [53,54]. This approach represents a promising strategy for restoring immune balance in SRNS.

5.2. Targeting B cells and plasma cells

In SRNS, B cells and plasma cells play key roles by generating autoantibodies and immune complexes. Emerging therapies aim to deplete or modulate these cells to reduce podocyte injury.

5.2.1. Proteasome inhibitors (e.g., bortezomib)

Proteasome inhibitors work via blocking proteasome activity, and target plasma cells through inhibiting the function of the 26S proteasome, leading to endoplasmic reticulum stress and apoptosis [55]. For example, Bortezomib inhibits proteolysis of misfolded proteins and contributes to the deposition of these proteins in cells. Bortezomib shows significant effects in treating kidney diseases mediated by antibodies, including lupus nephritis and immune rejection response after transplant [56,57]. In SRNS, Bortezomib may reduce the production of pathogenic autoantibodies and improve podocyte function. Clinical trials are ongoing to assess its value in SRNS management. Researchers are conducting clinical trials to analyze its potential in SRNS management.

5.2.2. Anti-CD38 antibodies (e.g., daratumumab)

CD38 is a surface marker expressed on plasma cells and some B cell subgroups. Daratumumab, a monoclonal antibody targeting CD38, has been approved for the treatment of multiple myeloma [58]. By depleting plasma cells, daratumumab may reduce the production of autoantibodies in SRNS. Preliminary case reports suggest that daratumumab can induce remission in refractory SRNS patients with high levels of circulating autoantibodies [59]. Its efficacy and safety in SRNS need to be confirmed in further studies.

5.3. Targeting complement activation

Complement overactivation contributes to glomerular and podocyte injury in SRNS. Inhibiting specific components of the complement cascade is a promising therapeutic strategy.

5.3.1. C5 inhibitors (e.g., eculizumab)

Eculizumab, specifically combined with complement component C5, prevents C5 lysis into 2 active peptides (C5a and C5b) to prevent the generation of the MAC and subsequent cell lysis. It has been successfully used in complement-mediated kidney disorders, such as atypical hemolytic uremic syndrome [60,61]. In SRNS, Eculizumab may reduce complement-mediated podocyte injury and glomerular inflammation. Case reports and small studies have shown promising results in Glomerulopathy patients with evidence of complement activation [62,63]. Larger clinical trials are needed to validate its efficacy.

5.3.2. Factor B inhibitors (e.g., iptacopan)

Complement factor B is a crucial element within the bypass complement activation pathway. Iptacopan, an oral Factor B inhibitor, has shown potential in reducing complement-mediated damage in kidney diseases [64,65]. By selectively inhibiting the alternative pathway, Iptacopan may offer a safer and more targeted approach compared to broad complement inhibitors. Early-phase clinical trials are proceeding to investigate its value in SRNS and other complement-driven kidney disorders [66].

5.4. Targeting podocyte injury

Podocytes are the primary targets of immune-mediated injury in SRNS. Therapies that stabilize podocyte structure and function or prevent apoptosis, are critical for preserving glomerular integrity.

5.4.1. Stabilization of the podocyte skeleton (e.g., Rho kinase inhibitors)

The complete cytoskeleton of actin is key to keeping the complete podocyte structure and function. Small GTPases are principal regulator proteins for the cellular cytoskeleton, of which RhoA is associated with podocyte injury before glomerular meniscus formation. Rho kinase (ROCK) inhibitors, stabilize the actin cytoskeleton by inhibiting RhoA/ROCK signaling, which is dysregulated in kidney disease [67,68]. Preclinical studies have demonstrated that ROCK inhibitors. For example, fasudil reduces proteinuria and podocyte injury by inhibiting RhoA activation in animal models [69,70]. It is necessary to verify the clinical effects and drug safety of these inhibitors in clinical trials.

5.4.2. Inhibition of apoptosis (e.g., caspase inhibitors)

Apoptosis of podocytes is a hallmark of glomerular damage in SRNS. Caspase inhibitors, such as emricasan, block the caspase-dependent apoptosis and prevent immune-mediated podocyte injury. In experimental models, caspase inhibitors show a significant effect in reducing proteinuria and preserving glomerular function [71,72]. These agents represent a novel approach to preventing podocyte loss in SRNS.

5.5. Personalized medicine approaches

The heterogeneity of SRNS necessitates personalized treatment strategies based on individual patient characteristics, including biomarkers and genetic profiles.

5.5.1. Biomarker-guided therapy

Biomarkers such as anti-podocyte antibodies, urinary cytokines, and complement activation products can help identify specific disease mechanisms and guide treatment decisions [73]. For example, patients with elevated levels of anti-nephrin antibodies may benefit from B cell-targeted therapies such as rituximab, while those with complement activation may respond to eculizumab. Biomarker-guided therapy holds promise for optimizing treatment efficacy and minimizing side effects.

5.5.2. Genetic testing and targeted therapies

In pediatric patients with SRNS, podocyte-associated gene variants are frequently observed (e.g., NPHS1, NPHS2, WT1) [74]. Earlier genetic testing can identify these variants and guide the use of targeted therapies to avoid unnecessary steroid treatments. For example, patients with variants in the COQ2 or COQ6 genes, which are involved in coenzyme Q10 biosynthesis, may benefit from coenzyme Q10 supplementation [75]. Advances in gene-editing technologies, such as CRISPR-Cas9, also show the potential for correcting genetic defects in podocytes [76].

6. Future directions and challenges

Despite significant advances in the comprehension of pathological mechanisms of SRNS and the development of novel therapies, several challenges remain. Overcoming these challenges requires multidisciplinary cooperation, including basic science, translational exploration, and clinical trials. Below, we summarized potential instructions and challenges in future SRNS research and management.

6.1. Elucidating the complex interaction between immune cells and podocytes

The interaction between immune cells and podocytes is central to SRNS pathogenesis, but certain mechanisms are still unclear. Future studies ought to prioritize investigating the mechanism of the interaction between specific immune cell subgroups (e.g., Th17, Tregs, macrophages) and podocytes to induce injury [78,79]. Single-cell RNA sequencing and spatial transcriptomics can be utilized to map immune-podocyte interactions at the cellular and molecular levels [80]. More accurate animal models should be developed, which really simulate the immune and podocyte dysfunction observed in human SRNS.

6.2. Developing more specific and effective immunomodulatory agents

Current immunosuppressive therapies lack specificity and have obvious adverse effects. Future efforts should aim to develop therapies that selectively target specific pathways (e.g., IL-17, complement activation) while sparing protective immune responses [20,30]. Targeted drug design can directly protect podocytes from immune-mediated injury by inhibiting ROCK or caspase [68,71]. Meanwhile, expand the use of biomedicines, such as monoclonal antibodies and fusion proteins, to achieve more precise immune modulation [49].

6.3. Well-designed clinical trials to evaluate emerging treatment

Well-designed clinical trials provide opportunities for the transformation of the preclinical research results into clinical applications. Key considerations include homogeneity of study populations and description of endpoints, such as complete relief, reduction of urine protein levels, and protection of kidney function. In clinical trials, strictly monitoring the prolonged safety and adverse effects of novel treatment is essential, particularly for pediatric populations.

6.4. Implementing personalized medicine approaches in SRNS management

Personalized medicine shows great promise for improving outcomes in SRNS. However, due to inadequate biomarkers, quantification of treatment outcomes is difficult to achieve in personalized and precision therapy. Identification of reliable biomarkers (e.g., anti-podocyte antibodies, urinary cytokines) is a key barrier to breakthroughs for biomarker-guided therapy.

Incorporating genetic testing into routine clinical practice to identify patients with monogenic forms of SRNS, which improves diagnostic accuracy and provides guidance to tailor therapies accordingly. This approach requires a large database and ability to parse data accurately for clinical treatment. At present, large sources of data and accurate analysis will become a new challenge. Developing integrated platforms that combine clinical, genetic, and biomarker data to formulate individual therapy algorithms has great potential.

7. Conclusion

In conclusion, the pathogenesis of SRNS primarily involves podocyte injury mediated by immune dysregulation. Key immune mechanisms include dysregulation of T cells, involvement of B cells, activation of complements and dysregulation of innate immunity. Elucidating these pathways not only refines deeper understanding of SRNS heterogeneity but also unveils actionable targets for precision immunomodulation, such as cytokine inhibitors (e.g., IL-17) and complement blockers (e.g., anti-C5). Concurrently, genetic discoveries (e.g., variants in NPHS1/2 or WT1) highlight the intersection of immune and hereditary factors, providing a dual framework for developing individualized therapies guided by both immune profiling and genomic data.

Current immunosuppressive therapies, such as CNIs, alkylating agents, and rituximab, have improved outcomes for some SRNS patients but are limited by incomplete responses, toxicity, and high relapse rates. These challenges emphasize the urgent need to transition from broad immunosuppression to mechanism-targeted therapies. Promising therapies in preclinical development include podocyte-protective agents, T/B cell-targeted therapies, and gene-editing approaches. However, translating these innovations into clinical practice demands prioritization of three critical areas: (1) large-scale multicenter trials to validate biomarkers for patient stratification and therapy monitoring; (2) integration of multi-omics data to match therapies to molecular profiles; and (3) multidisciplinary care models to optimize therapeutic strategies and mitigate comorbidities. Beyond biological complexity, SRNS imposes profound humanistic burdens. Prolonged proteinuria and edema restrict physical function and cause anxiety or depression, while steroid-induced complications and treatment costs devastate quality of life in patients and familial stability. Addressing the challenges requires parallel advancements in socio-medical support systems, including high-cost biologics and psychological interventions for patient’s families.

Funding Statement

There is no funding.

Disclosure statement

All authors declare no conflict of interest.