Paediatric Focal Segmental Glomerulosclerosis (FSGS): From Bench to Bedside and Beyond

Abstract

Paediatric Focal Segmental Glomerulosclerosis (FSGS) is a leading cause of steroid-resistant nephrotic syndrome and progressive kidney failure in children. Early subclassification into primary, secondary, genetic, or undetermined forms is crucial for guiding appropriate management. Primary FSGS typically necessitates immunosuppressive therapy, whereas secondary FSGS benefits from supportive measures and treatment of the underlying cause. Emerging treatments—including SGLT2 inhibitors, endothelin receptor antagonists, and APOL1-targeted agents—show promise in reducing proteinuria and preserving kidney function. Insights into podocyte biology, including TRPC channel dysregulation and fibrotic signalling pathways, are opening new therapeutic avenues. As research continues to evolve, the future of paediatric FSGS management lies in individualised, pathophysiology-driven therapies that may significantly improve clinical outcomes.

1. Introduction

Focal segmental glomerulosclerosis (FSGS) is a histopathological lesion frequently associated with glomerular injury and represents a leading cause of end-stage kidney disease (ESKD) in children. Rather than representing a single disease entity, FSGS encompasses a heterogeneous group of glomerular disorders unified by podocyte injury—disruption of highly specialised cells essential for maintaining the structural and functional integrity of the glomerular filtration barrier. The pathological hallmark of FSGS is the focal involvement of glomeruli with segmental sclerosis, marked by accumulation of extracellular matrix and obliteration of glomerular capillary lumina [1]. These structural alterations disrupt the filtration barrier, ultimately leading to progressive kidney dysfunction and ESKD. This review provides a comprehensive overview of established concepts, emerging insights, and evolving therapeutic strategies in the diagnosis and management of paediatric FSGS.

2. Search Strategy

A literature search was conducted using Medline/PubMed, EMBASE, and ClinicalTrials.gov to identify relevant studies on paediatric FSGS. Keywords and Medical Subject Headings (MeSH) used included: “FSGS”, “steroid-resistant nephrotic syndrome”, “paediatric”, “podocytopathy” and “immunosuppressive therapy”. Searches were limited to English-language articles published between 2000 and 2025. Reference lists of relevant articles and reviews were manually screened to identify additional studies. Clinical trials and ongoing studies were also reviewed to capture recent therapeutic developments.

3. Classification

FSGS can be broadly classified into two principal forms: primary and secondary FSGS, although some of the literature differentiates genetic forms as a distinct category rather than a subset of secondary FSGS. Historically, the terms primary FSGS and idiopathic FSGS were used interchangeably; nevertheless, the revised KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guidelines in 2021 advocate discontinuing the term idiopathic FSGS [2]. While these guidelines primarily focus on adult patients, their diagnostic and therapeutic framework can be reasonably extrapolated to paediatric populations. The updated classification delineates four subtypes of FSGS—primary, secondary, genetic, and FSGS of undetermined cause. This refined classification is clinically significant, as precise aetiological identification informs therapeutic decision-making and prognostication, topics that will be explored in subsequent sections.

3.1. Causal Classification

3.1.1. Primary FSGS

According to the 2021 KDIGO guidelines, primary FSGS is defined as a clinical-pathologic syndrome characterised by the presence of nephrotic syndrome in conjunction with histologic features of FSGS lesions on light microscopy or diffuse foot process effacement on electron microscopy, with no other identifiable cause of FSGS [2]. Primary FSGS has been linked to unidentified circulating permeability factors that induce podocyte dysfunction without underlying structural or systemic pathology—a concept previously associated with idiopathic FSGS. The most compelling evidence supporting this mechanism arises from cases of post-transplant recurrence, notably illustrated by Gallon et al. [3] and further corroborated by Kienzl-Wagner et al. [4], where the re-transplantation of a previously failed allograft into another recipient without recurrence suggested a possible extracorporeal podocytopathic factor in the original host.

Several candidate permeability factors have been proposed in primary FSGS, including apolipoprotein A1-b (apoA1-b), corticotropin-like cytokine factor 1, anti-CD40 antibodies, and soluble urokinase-type plasminogen activator receptor (suPAR) [5], though none of these factors have been definitively established as causative agents. One challenge highlighted by Salfi et al. [6] is that these circulating factors have been predominantly studied in steroid-resistant FSGS cases without prior transplantation, whereas their specificity appears more pronounced in cases of post-transplant recurrence. This is supported by findings from Batal et al. [7], who observed that all 17 of 38 patients without post-transplant recurrence were negative for anti-nephrin autoantibodies, while the presence of these antibodies pre-transplant was associated with a higher risk of disease recurrence. A recent study by Hengel and colleagues [8] discussed the challenges in detecting anti-nephrin autoantibodies and highlighted the advantages of current detection techniques, including immunoprecipitation, enzyme-linked immunosorbent assay (ELISA), and combinatory approaches. Despite these challenges, the ability to detect such autoantibodies holds promise for developing non-invasive biomarkers for diagnosing anti-nephrin-associated diseases, offering a significant advantage over kidney biopsy, the current diagnostic gold standard. Enhanced antibody detection methods could potentially transform clinical practices in kidney transplantation, serving as an auxiliary tool for evaluating post-transplant proteinuria or as a screening measure to assess transplant suitability. Additionally, efforts to establish preclinical in vivo models for demonstrating the pathogenicity of these circulating factors have yielded limited success. For example, Braanker et al. [9] reported that none of the proposed factors consistently induced proteinuria across various models. The absence of a reliable animal model for primary FSGS has remained a significant obstacle to mechanistic studies. Nevertheless, recent advancements utilising novel technologies, including proteinuria models in zebrafish larvae [10] and human-induced pluripotent stem cells [11], hold promise for uncovering disease mechanisms and enabling future therapeutic discovery.

Foot process effacement refers to the loss of the characteristic interdigitating architecture of podocyte foot processes. Although its biological significance remains uncertain—whether as a cellular survival response or a manifestation of podocyte dysfunction—it is widely recognised as a hallmark of primary FSGS, often evident even in glomeruli lacking overt sclerosis on light microscopy [12,13]. While light microscopy remains a cornerstone in the histopathological diagnosis of FSGS, its resolution is limited and subject to operator variability. In contrast, electron microscopy provides superior sensitivity in detecting early ultrastructural alterations, such as diffuse foot process effacement, which is often diagnostic in primary FSGS. Interestingly, morphometric studies challenge the traditional notion of focality in primary FSGS. In an analysis of 182 glomeruli, Fuiano et al. [14] demonstrated that glomerular sclerosis may be more diffuse than previously appreciated, with small, discrete lesions scattered across multiple glomeruli. Based on this, they recommend that renal biopsies include at least eight glomeruli, sampled from both cortical and juxtamedullary regions, to accurately assess the burden of sclerosis. Recent advances in molecular profiling have deepened our understanding of disease mechanisms. In a genome-wide transcriptomic study of 38 primary FSGS cases, region-specific small RNA alterations were identified, with compartmentalised patterns of upregulation and downregulation. These findings highlight localised molecular drivers underlying progressive glomerular injury and may pave the way for novel therapeutic strategies [15].

3.1.2. Secondary FSGS

Secondary FSGS, in contrast to primary FSGS, is associated with identifiable underlying conditions that contribute to podocyte injury and glomerular sclerosis. Recognised aetiologies include drug-induced nephrotoxicity (e.g., calcineurin inhibitors, mTOR inhibitors, interferons), infections (e.g., HIV, cytomegalovirus), and chronic inflammation states. Additionally, non-kidney factors such as reduced nephron mass due to surgical resection, renal hypoplasia, trauma, anabolic steroid use, or obesity-related injury are established contributors [16]. In most cases, increased hemodynamic load on individual nephrons leads to maladaptive responses, triggering compensatory glomerular hypertrophy. This is histologically characterised by enlarged glomeruli, perihilar sclerosis, and segmental foot process effacement, consistent with the adaptive changes observed in kidney biopsies [17]. Clinically, individuals with secondary FSGS typically present with sub-nephrotic or nephrotic-range proteinuria but retain normal serum albumin concentrations. Accurate identification of secondary FSGS is critical, as it has significant implications for prognosis and management, often necessitating treatment of the underlying cause rather than immunosuppression.

While viral infections are a less common cause of secondary FSGS in children than in adults, it remains crucial to exclude viral aetiologies before initiating immunosuppressive therapy, the mainstay treatment for primary FSGS. This diagnostic step is particularly critical in paediatric populations, where the clinical presentation may overlap with primary disease but necessitates a fundamentally different therapeutic approach. A review by Dettmar and Oh [16] highlights several viruses implicated in FSGS pathogenesis, including HIV, cytomegalovirus, hepatitis B, and Epstein–Barr virus; however, the causal mechanisms underlying post-infectious glomerulopathies in children remain less well understood compared to adults. In the context of HIV-associated nephropathy (HIVAN), for instance, podocytes have been shown to serve as reservoirs for HIV replication, facilitating direct cytotoxic injury and cytokine-mediated damage to glomerular and tubular epithelial cells. This typically manifests histologically as collapsing FSGS, a highly aggressive variant associated with rapid progression to ESKD [18]. Notably, genetic predisposition plays a central role in HIVAN pathogenesis, with APOL1 risk alleles (G1 and G2) significantly increasing susceptibility in individuals of African ancestry [19]. The influence of APOL1 will be further elaborated in the subsequent section. Beyond these well-established associations, emerging data suggest a broader viral spectrum implicated in FSGS. For instance, two recent case reports described FSGS variants following dengue virus infection in adults [20]. Although these observations are preliminary and the pathophysiological mechanisms remain undefined, they underscore the potential for viral triggers beyond the traditionally recognised agents, warranting further research, particularly in endemic regions.

While viruses and drugs are well-established contributors to secondary FSGS, there is evidence of glomerular injury following vaccination, particularly in the wake of widespread COVID-19 immunisation efforts. A recent review highlighted that the tip variant is the most prevalent histological pattern in vaccine-associated cases [21]. These patients typically present with an abrupt onset of heavy proteinuria, often in the nephrotic range, shortly after vaccination. Despite the severity of proteinuria, clinical outcomes appear generally favourable, with the majority of the reported cases demonstrating robust responsiveness to immunosuppressive therapy.

3.1.3. Genetic FSGS

Genetic FSGS is associated with mutations in genes encoding proteins essential for the structural and functional integrity of the glomerular filtration barrier, including podocytes, the glomerular basement membrane, and the glomerular capillary endothelium. To date, over 50 genes have been implicated in FSGS pathogenesis, though several mutations occur with greater frequency and clinical relevance. Among the most extensively studied are NPHS1 (19q13.1) and NPHS2 (1q25.2), which encode nephrin and podocin, respectively—both critical components of the slit diaphragm. Mutations in these genes are typically inherited in an autosomal recessive manner and are associated with congenital nephrotic syndrome (NPHS1) and early-onset steroid-resistant nephrotic syndrome (SRNS) (NPHS2) [22,23]. In contrast, autosomal dominant mutations in genes such as TRPC6 (11q22.1) and ACTN4 (19q13.2) contribute to familial forms of FSGS. TRPC6 encodes a cation-selective calcium channel, while ACTN4 is involved in actin filament crosslinking, impacting cytoskeletal organisation and motility. Despite the distinct function of each gene, crosstalk among podocyte-associated proteins contributes to the shared phenotype of FSGS. For instance, WT1 (11p13), also referred to as NPHS4, encodes a zinc finger transcription factor that directly upregulates NPHS1 expression, further reinforcing its regulatory role in podocyte maintenance and differentiation [24].

A groundbreaking discovery in 2010 identified variants in the APOL1 gene as an increased risk of FSGS and other APOL1-associated nephropathies, particularly among individuals of African ancestry [19,25,26]. The G1 and G2 alleles confer significantly increased susceptibility to podocyte injury when present in the homozygous or compound heterozygous state, with up to a 10-fold higher risk of progression to ESKD [27]. Since this discovery, extensive research has focused on elucidating the mechanistic role of APOL1-induced cytotoxicity and developing targeted therapies, which will be discussed in the following section. Importantly, unlike primary FSGS, genetic FSGS has a significantly lower recurrence rate following kidney transplantation. A study by Jungraithmayr and colleagues [28] demonstrated that patients harbouring biallelic NPHS2 (podocin) mutations rarely experienced recurrence following kidney transplantation. These findings underscore the prognostic value of genetic testing, which can guide therapeutic decision-making and optimise transplant planning through individualised risk stratification.

3.1.4. FSGS of Undetermined Cause

In cases where FSGS presents without full features of nephrotic syndrome, lacks an identifiable genetic or secondary aetiology, and does not exhibit diffuse foot process effacement on electron microscopy, the condition is categorised as FSGS of undetermined cause rather than primary FSGS [2]. These patients may have a more indolent disease course with a lower risk of progression to ESKD compared to those with primary FSGS.

3.2. Morphological Classification

A separate classification was introduced in 2004 by the Columbia Classification to stratify FSGS into five distinct variants based on the morphological pattern and intraglomerular distribution of sclerotic lesions: collapsing, cellular, perihilar, tip, and not otherwise specified (NOS) [29], as summarised in

Table 1. Columbia classification according to sclerotic lesions.

Variant	Histologic Features	Clinical Association	Prognosis
Tip	Involvement of the outer 25% of the glomerular tuft next to the tubular pole, in the absence of collapsing or perihilar lesions.	Often presents with full nephrotic syndrome More common in steroid-sensitive nephrotic syndrome High likelihood of remission with steroid therapy	Best Poor
Cellular	≥1 glomerulus with segmental endocapillary hypercellularity involving >25% of the glomerular tuft, leading to occlusion of the capillary lumen; requires exclusion of collapsing and tip variants.	Considered an early-stage of other FSGS variants May transition into other variants over time
Perihilar	≥50% of the sclerotic glomeruli have sclerosis and/or hyalinosis in the perihilar area in at least 1 glomerulus.	Strongly linked to adaptive/maladaptive responses (e.g., obesity, nephron mass reduction)
Collapsing	Glomerular capillary collapse, podocyte hypertrophy and hyperplasia in at least 1 glomerulus. The findings of other variants in other glomeruli do not affect the diagnosis.	Often associated with viral infections (e.g., HIVAN), drugs, and APOL1 risk alleles More common in Black/African descendents Usually poor response to immunosuppressive therapy
Not otherwise specified (NOS)	Segmental increase in matrix obliterating the capillary lumen, but does not satisfy the inclusion within any of the 4 other variants; the most common variant.	Most common variant in both adults and children

. While this classification was initially developed in adult cohorts, it has also been applied in paediatric studies to assess prognostic implications. In a study from India involving 138 children with idiopathic nephrotic syndrome, the NOS variant emerged as the most prevalent, followed by collapsing, tip, and perihilar variants [30]. Similar findings were observed in cohorts from Brazil and Korea [31,32]; however, the relatively small sample sizes in certain subtypes have limited the statistical power to establish strong predictive correlations between histological variants and disease outcomes in paediatric populations.

D’Agati and colleagues [33] analysed 138 kidney biopsies from patients aged 2 to 38 years and reported that, among paediatric cases, the NOS variant was the most prevalent (71 out of 89 cases; 79.8%), followed by the collapsing (11.2%) and tip (9%) variants. Although the study did not stratify outcome data by age group, it demonstrated significant differences in the progression to ESKD across histologic subtypes. Within a 3-year follow-up, 47% of patients with the collapsing variant progressed to EKSD, compared to 20% of those with the NOS variant, and only 7% of those with the tip variant. A recent analysis of 49 biopsy reports from 64 patients carrying transient receptor potential canonical 6 (TRPC6) mutations—a calcium ion channel located in the podocyte slit diaphragm—identified not otherwise specified (NOS) as the predominant FSGS subtype. These cases also exhibited a high degree of foot process effacement, with an average of 80% [34]. Another study involving 247 children with primary FSGS reaffirmed the prognostic value of the Columbia classification in paediatric populations [35]. This study not only reported similar frequencies of morphologic subtypes but also validated the classification system’s utility in stratifying risk for disease progression among Chinese children.

Despite established classification systems, distinguishing between primary and secondary FSGS remains diagnostically challenging. A study in adult patients proposed a podocyte foot process width threshold of 1500 nm as a discriminatory marker, demonstrating 100% sensitivity and 72% specificity for differentiating primary from secondary FSGS [36]; patients with primary FSGS exhibited foot processes exceeding this threshold. Clinically, primary FSGS typically presents with nephrotic-range proteinuria (>3.5 g/day), microhaematuria, hypertension, and abrupt disease onset [37]. These findings are consistent with the diagnostic algorithm proposed by Sethi et al. [38], which highlights that the presence of nephrotic syndrome, diffuse foot process effacement (≥80%) on electron microscopy, and the absence of identifiable secondary risk factors (e.g., drug exposure or viral infections) strongly indicate primary FSGS; however, this distinction is not always clear-cut. Certain cases of secondary FSGS, particularly those induced by nephrotoxic agents such as pamidronate, or associated with viral infections, can also exhibit sustained podocyte injury with widespread foot process effacement [39,40]. Furthermore, genetic forms of FSGS frequently demonstrate similar ultrastructural features, including diffuse effacement, further complicating the distinction between primary and secondary aetiologies [23].

To enhance diagnostic precision, the International Pediatric Nephrology Association (IPNA) guidelines recommend genetic testing in all children diagnosed with primary steroid-resistant nephrotic syndrome (SRNS) [41]. The IPNA further advocates for kidney biopsy in paediatric SRNS patients unless there is a clear secondary aetiology, such as an identifiable infection, malignancy-associated glomerulopathy, or a confirmed genetic cause. Despite the growing emphasis on personalised diagnostics, resource constraints significantly limit the application of these recommendations in low- and middle-income countries. A recent global survey revealed that only 26% of centres in resource-limited regions had access to genetic testing, and many facilities lacked electron microscopy capabilities, relying solely on light microscopy, which is suboptimal for distinguishing between subtypes of FSGS [42]. These infrastructural deficiencies underscore the urgent need for capacity-building initiatives, including investment in molecular diagnostic and nephrology services, to ensure equitable and accurate diagnosis of SNRS in paediatric populations globally.

Advancements in biomarker discovery and machine learning have enabled the development of urinary peptidomic classifiers as promising non-invasive diagnostic tools for distinguishing primary from secondary FSGS. In a recent study, a classifier comprising 93 distinct urinary peptides achieved a sensitivity of 84% and specificity of 100%, highlighting its high diagnostic accuracy and clinical potential [43]. These findings suggest that urinary peptidomics may serve as a complementary or alternative strategy to invasive biopsy procedures, particularly in cases where histological data are inconclusive. However, larger multicentric validation studies and standardisation of analytical platforms are needed before these classifiers can be integrated into routine clinical workflows.

4. Management

As previously discussed, categorising FSGS cases into four subgroups is a crucial first step in guiding appropriate therapeutic interventions.

This subclassification is not merely academic—it holds direct clinical relevance, as treatment responsiveness varies considerably between subtypes. Primary FSGS often responds to corticosteroids or other immunosuppressive agents, supporting an immune-mediated pathogenesis. In contrast, secondary FSGS is typically non-responsive to immunosuppression, and management focuses on ameliorating the underlying insult, such as discontinuing offending drugs, treating infections, or reducing hemodynamic stressors. Therefore, comprehensive clinical, histopathological, and genetic assessment is critical in identifying secondary risk factors, preventing misclassification and avoiding inappropriate immunosuppression, which may confer additional harm.

The 2021 KDIGO Clinical Practice Guidelines for the Management of Glomerular Diseases define the target goal for FSGS as follows [2]:

• Complete remission: Reduced proteinuria to <300 mg/day, OR protein–creatinine ratio (PCR) < 300 mg/g, AND serum albumin > 3.5 g/dL, AND stable serum creatinine.
• Partial remission: Reduced proteinuria to 300–3500 mg/day, OR PCR of 300–3500 mg/g, AND a decrease of >50% in proteinuria from baseline.
• Relapse: Proteinuria > 3500 mg/day, OR PCR > 3500 mg/g after achieving complete remission, OR a 50% increase in proteinuria during partial remission.
• Steroid-resistant FSGS: Persistent proteinuria > 3500 mg/day OR PCR > 3500 mg/g with <50% reduction from baseline even after prednisone therapy for at least 16 weeks.
• Steroid-dependent FSGS: Relapse occurring during or within 2 weeks of completing glucocorticoid therapy.
• Calcineurin inhibitor-resistant FSGS: Persistent proteinuria > 3500 mg/day OR PCR > 3500 mg/g with <50% reduction from baseline even after 4–6 months of cyclosporine or tacrolimus therapy at therapeutic levels.
• Calcineurin inhibitor-dependent FSGS: Relapse occurring during or within 2 weeks of completing cyclosporine or tacrolimus therapy for >12 months.

The management of secondary FSGS is primarily supportive, including optimising blood pressure control, the use of renin-angiotensin-aldosterone system (RAAS) blockers, and dietary salt restriction, while addressing the underlying secondary cause. Unlike primary FSGS, steroids and immunosuppressants are generally discouraged, as their use is associated with adverse outcomes that often outweigh potential benefits. RAAS blockade has demonstrated efficacy in reducing proteinuria in FSGS; however, in some cases, additional agents are required to sustain remission. In recent years, sodium-glucose cotransporter-2 (SGLT2) inhibitors, such as empagliflozin and dapagliflozin, have emerged as promising adjunctive therapies alongside RAAS blockers in proteinuric kidney diseases. A recent multi-centre study involving 104 adults with biopsy-proven FSGS randomised patients to receive either dapagliflozin (10 mg) or placebo. The study found that patients receiving dapagliflozin experienced a slower decline in kidney function and had fewer serious adverse events compared to the placebo group [44]. While these findings are encouraging, previous studies have reported downregulation of SGLT2 expression in the kidneys of FSGS patients, suggesting a limited short-term impact of SGLT2 inhibitors on kidney haemodynamics [45]. Further research is warranted to clarify their long-term efficacy and potential role in FSGS management.

The KDIGO 2021 guidelines recommend high-dose immunosuppressive therapy as the first-line treatment for primary FSGS, with prednisone being the preferred agent (see Table 2). Although high-quality evidence supporting prednisone use in primary FSGS remains limited, its recommendation is primarily based on clinical experience and observational evidence suggesting its potential to prevent disease progression by achieving partial or complete proteinuria remission. The therapeutic rationale lies in preventing irreversible kidney damage secondary to persistent podocyte injury. Nevertheless, the use of prolonged glucocorticoid therapy carries significant risks, particularly in the paediatric population. Adverse effects such as metabolic disturbances (e.g., hyperglycaemia, dyslipidaemia), linear growth suppression, osteopenia, and increased infection risk necessitate vigilant monitoring. Consequently, treatment decisions should weigh the benefit of proteinuria remission against the risk profile of long-term corticosteroid exposure, with particular emphasis on individual patient characteristics and response to initial therapy.

For patients with primary FSGS who are unresponsive to high-dose glucocorticoids or for whom corticosteroids are contraindicated, calcineurin inhibitors (CNIs) such as tacrolimus or cyclosporine are recommended. The standard dosing regimen includes cyclosporine at 3–5 mg/kg/day (administered in two divided doses) or tacrolimus at 0.05–0.1 mg/kg/day (also in divided doses). Close monitoring of serum creatinine and drug trough levels is essential to reduce the risk of CNI-induced nephrotoxicity, a well-recognised adverse effect. Evidence supporting the efficacy of CNIs in children with steroid-resistant nephrotic syndrome (SRNS) comes from a quasi-experimental study in Pakistan involving 88 paediatric patients. The study reported a complete remission rate of 98% in the tacrolimus group compared to 81% in the cyclosporine group [46]. Additionally, a retrospective study from the same region found that tacrolimus and cyclosporine were more effective in sustaining long-term remission than alternative therapies. Tacrolimus achieved a 69.2% complete remission rate (9/13 cases), and cyclosporine reached 66.2% (43/65 cases), compared to only 40% in patients treated with methylprednisolone pulses and cyclophosphamide [47].

The use of CNIs has been associated with a reduction in glucocorticoid dependency, as noted in a small observational study, where six patients achieved partial remission using tacrolimus monotherapy [48], suggesting its potential as a standalone treatment option. Although randomised controlled trials (RCTs) on CNI monotherapy are currently lacking, a recent retrospective study of 66 adults with primary FSGS reported comparable outcomes between patients treated with initial CNI plus low-dose glucocorticoid therapy and those receiving high-dose glucocorticoid therapy. Both groups exhibited similar rates of complete remission, relapse, and 5-year kidney survival [49]. Additionally, the administration of CNIs, with or without adjunctive glucocorticoids, has been associated with a slower progression to ESKD, although these findings did not reach statistical significance [50]. While these results raise important considerations regarding the potential of CNIs as monotherapy for proteinuria remission, existing studies remain underpowered, and definitive conclusions cannot yet be drawn.

The use of steroid-sparing agents such as rituximab, a monoclonal antibody targeting CD20-expressing B lymphocytes, has garnered increasing interest, particularly following case reports and observational studies demonstrating its efficacy in children with refractory SRNS [51] and complicated steroid-dependent nephrotic syndrome [52]; however, most studies on rituximab are largely non-randomised and may overestimate treatment benefits. A multicentre RCT involving 30 children found that Rituximab was not inferior to glucocorticoids in managing steroid-dependent nephrotic syndrome [53]. Given its potential role in FSGS management, several large-scale trials are currently underway. These include the TURING trial (NCT03298698), which evaluates rituximab versus continued high-dose prednisolone in idiopathic nephrotic syndrome, and the JSKDC08 trial (UMIN000014895), which investigates rituximab plus methylprednisolone pulse therapy in childhood-onset complicated SRNS. While the long-term efficacy of rituximab remains to be fully elucidated, existing evidence has demonstrated its safety, with no serious adverse events reported to date [51,52,53]. Further robust RCTs are essential to establish rituximab’s role in primary FSGS treatment protocols.

Disturbances in intracellular calcium homeostasis play a critical role in podocyte injury, contributing to ion channel dysregulation, mitochondrial dysfunction, apoptosis, and inflammation. Among the implicated molecular pathways, mutations in the TRPC gene, particularly those affecting TRPC5 and TRPC6 channels, have been shown to induce excessive calcium influx into podocytes. This dysregulation triggers their apoptosis and actin cytoskeleton remodelling [54,55], ultimately compromising the structural integrity of the glomerular barrier. Preclinical studies in animal models have demonstrated that TRPC5 blockade can effectively suppress proteinuria and protect against podocyte loss in proteinuric rats [56]. These findings provided the rationale for the ongoing TRACTION-2 trial, which investigated GFB-887, a TRPC5 inhibitor, in adults with FSGS [57]. Unfortunately, the trial was prematurely terminated due to business-related reasons. In parallel, another clinical trial targeting TRPC6, using the selective inhibitor BI 764198, has recently concluded (NCT05213624) [58]. While the trial’s results are pending, it reflects a growing interest in ion channel modulation as a novel therapeutic strategy for FSGS.

Beyond TRPC channels, endothelin-1 has emerged as another pivotal molecule in podocyte apoptosis and cytoskeleton remodelling. Its synergistic interaction with angiotensin II contributes to nephroprotection by promoting vasoconstriction, attenuating proteinuria, and limiting glomerulosclerosis, as highlighted in a recent review [59]. Sparsentan, an oral dual endothelin-1 receptor and angiotensin II receptor antagonist, has shown promise as a therapeutic agent for FSGS. The DUET trial (NCT01613118) demonstrated that Sparsentan significantly reduced blood pressure, achieved greater reductions in proteinuria, and better-preserved kidney function over an 8-week period compared to Irbesartan, a standard angiotensin receptor blocker (ARB) [58]. To evaluate long-term efficacy and safety, the DUPLEX trial (NCT03493685) enrolled 371 children and adults with biopsy-confirmed FSGS [60]. Interim 9-month analysis revealed a higher rate of partial remission in the Sparsentan group versus the Irbesartan group (42% vs. 26%), along with earlier and more frequent complete remission, and sustained proteinuria reduction over the 2-year follow-up. However, no significant difference was observed in the primary endpoint of preserving the estimated glomerular filtration rate between the two treatment arms. Due to this, the FDA declined the approval of Sparsentan for FSGS, citing insufficient evidence regarding long-term renal outcomes. Nonetheless, following FDA approval of Sparsentan for IgA nephropathy, the manufacturer has submitted a priority review request for its use in FSGS, with hopes it may become the first FDA-approved drug for this condition. Meanwhile, the AFFINITY trial (NCT04573920) is investigating Atrasentan, an endothelin receptor antagonist that lacks angiotensin II inhibition, as a potential FSGS treatment option [61]. The results of this trial are anticipated to further clarify the therapeutic value of endothelin receptor blockade in FSGS management.

Advancements in our understanding of cytokine signalling, metabolic pathways, and genetic contributions to FSGS pathogenesis have catalysed the development of several novel therapeutic approaches. Among these are, Fresolimumab, a monoclonal antibody targeting transforming growth factor-beta, a key driver of kidney fibrosis, currently in Phase 2 trial (NCT01665391) [62]; R3R01, a drug aimed at reducing lipid accumulation in podocytes, also in Phase 2 trial (NCT05267262); Metformin, traditionally used in type 2 diabetes, is under investigation as an adjunctive therapy to standard-of-care drugs in FSGS given its proposed renoprotective and anti-fibrotic effects, currently in Phase 2 trial (NCT06090227) [63]. Other ongoing and completed clinical trials exploring emerging FSGS therapies have been extensively reviewed elsewhere [64,65]. Notably, therapeutics targeting the APOL1 gene variants (VX-147/Inaxaplin; phase 2a trial, NCT04340362), a well-established genetic risk factor for FSGS, have been conducted with early findings demonstrating early and sustained reductions in proteinuria reduction over a 13-week treatment period [66]. Complementing these pharmacologic advances, APOL1-targeted antisense oligonucleotides have shown efficacy in APOL1-transgenic mouse models, where they downregulated APOL1 expression in both the kidney and liver, resulting significant reduction in proteinuria [67]. Collectively, these emerging therapies reflect a paradigm shift in the management of FSGS, one that embraces precision medicine by targeting the molecular and genetic underpinnings of the disease. This evolving landscape offers renewed hope for improving outcomes in patients with this complex and heterogeneous glomerulopathy.

Table 2. Immunosuppressive therapies for primary FSGS.

Drug	Mechanism of Action	Dosage	Side Effects
Prednisone (glucocorticoid) [2]	Broad immunosuppression, reduces podocyte injury	1 mg/kg/day (max 80 mg) or 2 mg/kg/day on alternate days (max 120 mg), administered for a minimum of 4 weeks. Continue until complete remission is achieved, up to a maximum duration of 16 weeks.	Growth suppression, hyperglycaemia, hypertension, increased risk of infection
Calcineurin inhibitors
Cyclosporine [2,46]	Inhibits calcineurin, suppresses T-cell activation, stabilises podocytes	3–5 mg/kg/day in 2 divided doses	Nephrotoxicity, headache, gingival hyperplasia, hyperkalaemia, fever, hypertension, hypertrichosis
Tacrolimus [2,46,68]	More potent calcineurin inhibition, stabilises podocyte actin cytoskeleton	0.05–0.1 mg/kg/day in two divided doses	Nephrotoxicity, tremors, hyperglycaemia, seizures, headache, nausea, blurred vision, alopecia
Steroid-sparing agents
Cyclophosphamide [69,70]	Crosslinks DNA, suppresses T and B cells	2–3 mg/kg/day for 8–12 weeks	Haemorrhagic cystitis, risk of malignancy, alopecia, nausea and vomiting, diarrhoea, cystitis, oral ulcers, bone marrow suppression, hyponatremia
Mycophenolate Mofetil [71,72]	Inhibits purine synthesis, reducing B and T cell proliferation	600 mg/m2/day in 2 divided doses	Constipation, GI bleeding, abdominal pain, nausea and vomiting, weight loss, colitis, headache, eczema
Rituximab (Anti-CD20 Monoclonal Antibody) [51,52]	Depletes B cells, possibly affecting T-cell interactions and podocyte function	375 mg/m2 IV weekly for 4 weeks	Neutropenia, infections, hypogammaglobulinemia, myalgia, arthralgia, fatigue, fever, skin rash

Table 2. Immunosuppressive therapies for primary FSGS.

Drug	Mechanism of Action	Dosage	Side Effects
Prednisone (glucocorticoid) [2]	Broad immunosuppression, reduces podocyte injury	1 mg/kg/day (max 80 mg) or 2 mg/kg/day on alternate days (max 120 mg), administered for a minimum of 4 weeks. Continue until complete remission is achieved, up to a maximum duration of 16 weeks.	Growth suppression, hyperglycaemia, hypertension, increased risk of infection
Calcineurin inhibitors
Cyclosporine [2,46]	Inhibits calcineurin, suppresses T-cell activation, stabilises podocytes	3–5 mg/kg/day in 2 divided doses	Nephrotoxicity, headache, gingival hyperplasia, hyperkalaemia, fever, hypertension, hypertrichosis
Tacrolimus [2,46,68]	More potent calcineurin inhibition, stabilises podocyte actin cytoskeleton	0.05–0.1 mg/kg/day in two divided doses	Nephrotoxicity, tremors, hyperglycaemia, seizures, headache, nausea, blurred vision, alopecia
Steroid-sparing agents
Cyclophosphamide [69,70]	Crosslinks DNA, suppresses T and B cells	2–3 mg/kg/day for 8–12 weeks	Haemorrhagic cystitis, risk of malignancy, alopecia, nausea and vomiting, diarrhoea, cystitis, oral ulcers, bone marrow suppression, hyponatremia
Mycophenolate Mofetil [71,72]	Inhibits purine synthesis, reducing B and T cell proliferation	600 mg/m2/day in 2 divided doses	Constipation, GI bleeding, abdominal pain, nausea and vomiting, weight loss, colitis, headache, eczema
Rituximab (Anti-CD20 Monoclonal Antibody) [51,52]	Depletes B cells, possibly affecting T-cell interactions and podocyte function	375 mg/m2 IV weekly for 4 weeks	Neutropenia, infections, hypogammaglobulinemia, myalgia, arthralgia, fatigue, fever, skin rash

5. Prognoses

Remission of proteinuria is a key prognostic factor for long-term kidney survival in FSGS [73,74], as depicted in a landmark study that demonstrated that patients with non-nephrotic range proteinuria (<3.5 g/day) had 10-year survival rates exceeding 90% [75]. Recent findings from a Chinese cohort of 247 children with primary FSGS reported kidney survival rates of 80.73% at 5 years, 62.58% at 10 years and 34.66% at 15 years [35]. Notably, the collapsing variant of FSGS and chronic tubulointerstitial damage > 25% emerged as significant predictors of poorer renal outcomes. Similar observations were reported in another Indian study, where segmental sclerosis > 25% and the collapsing histologic variant were also associated with advanced kidney disease progression [76].

The response to immunosuppressive therapy is another crucial determinant of disease trajectory. Patients who achieved complete or partial remission exhibited a significantly slower progression to CKD stages 2–5, with a median of 4 years compared to just 1 year in those without remission. A recent analysis of prognostic factors in children with SRNS identified high initial proteinuria (>8000 mg/g), low baseline kidney function, and persistent hypoalbuminemia as negative predictors for both remission and kidney survival [77]. Children with a monogenic cause of nephrotic syndrome generally tend to fail to achieve proteinuria remission, consistent with previous findings by Trautmann et al. [41]. Clinical features that may suggest monogenic aetiology include early-onset disease, positive family history, consanguinity, and syndromic manifestations [77].

Beyond renal outcomes, children with FSGS-associated CKD face a higher cardiovascular risk compared to those with CKD from other glomerular disease or non-glomerular diseases [78]. These patients tend to present with elevated systolic blood pressure, triglycerides, and non-high-density lipoproteins, as well as a faster decline in left ventricular mass index and greater odds of left ventricular hypertrophy (LVH). This cardiovascular burden is particularly pronounced among African-American children carrying high-risk APOL1 mutations, who demonstrated greater odds of LVH and obesity [79]. These findings underscore the importance of a comprehensive management approach that extends beyond nephroprotection alone in children with FSGS.

6. Conclusions

FSGS remains a complex and heterogeneous glomerular disorder with profound implications for kidney survival and overall health. Advances in our understanding of its pathophysiology—ranging from dysregulated intracellular calcium signalling, podocyte dysfunction, to genetic predispositions—have facilitated the development of novel therapeutic strategies aimed at preserving kidney function. Emerging treatments, such as TRPC inhibitors, endothelin receptor antagonists, APOL1-targeted therapies, and metabolic modulators, have shown promising efficacy in clinical trials; nonetheless, substantial regulatory and translational challenges remain before these therapies can be widely implemented in clinical practice. Looking ahead, future research must prioritise translational approaches that bridge basic science with clinical utility, including the non-invasive biomarkers (e.g., anti-nephrin antibodies, urinary podocyte markers) to improve diagnosis, risk stratification, and treatment monitoring, potentially reducing reliance on invasive kidney biopsy. Likewise, genetic screening should be incorporated in the diagnosis of paediatric FSGS, helping to distinguish monogenic cases from immune-mediated disease and guiding management decisions. Furthermore, the future of FSGS management is likely to be shaped by the increasing integration of multi-omics data, enabling precision medicine with therapies tailored to individual profiles. Large, multicentre paediatric trials and international registries will be vital in validating these tools and treatment options. Ultimately, beyond pharmacologic advancement, achieving and sustaining proteinuria remission remains a consistent determinant of long-term kidney outcomes.