Advances in the pathophysiology and treatment of focal segmental glomerulosclerosis: The importance of a timely and tailored approach

Abstract

Focal segmental glomerulosclerosis (FSGS) is a histological pattern of glomerular damage that significantly contributes to chronic kidney disease and end-stage renal disease. Its incidence is rising globally, necessitating timely and personalized management strategies. This paper aims to provide an updated overview of the pathophysiology, diagnosis, and therapeutic strategies for FSGS, emphasizing the importance of early interventions and tailored treatments. This editorial synthesizes key findings from recent literature to highlight advancements in understanding and managing FSGS. Emerging evidence supports the role of targeted therapies and personalized approaches in improving outcomes for FSGS patients. Advances include novel biomarkers, genetic testing, and innovative therapeutics such as transient receptor potential ion channel blockers and antisense oligonucleotides for apolipoprotein 1-related FSGS. Effective management of FSGS requires a combination of timely diagnosis, evidence-based therapeutic strategies, and ongoing research to optimize patient outcomes and address gaps in the current understanding of the disease.

Key Words: Focal segmental glomerulosclerosis; Chronic kidney disease; Glomerulonephritis; Renal failure; Immunosuppressive therapy; Calcineurin inhibitors; Mycophenolate mofetil; Rituximab; Sparsentan; Plasmapheresis

Core Tip: Focal and segmental glomerulosclerosis is currently considered a histologic pattern encompassing several clinicopathologic entities. Its incidence is increasing worldwide. The rising prevalence is likely due to improved diagnosis and recognition of the disease, combined with a better understanding of the pathophysiology of podocyte damage and the development of therapeutics targeting the mediators underlying this clinicopathologic condition.

INTRODUCTION

Focal segmental glomerulosclerosis (FSGS) is an important cause of chronic end-stage renal failure worldwide and represents a significant burden on the healthcare system. FSGS is a histological lesion characterized by the presence of sclerosis in some (segmental) portions of some (focal) glomeruli and is associated with podocyte damage. Although FSGS has been considered in the past as a single disease, it represents a heterogeneous entity in terms of etiology, clinical course and therapeutic approach. The common feature is podocyte damage and loss, which may be a primary or secondary consequence of maladaptive responses to glomerular stressors[1].

FSGS has an annual incidence of 0.2-1.8 cases per 100000 persons, with a higher prevalence in the black population and a male-to-female ratio of 1.5[2]. The incidence of FSGS has steadily increased over the years, making it the most common glomerular disease leading to end-stage renal disease (ESRD) in the United State and the most common glomerulopathy leading to ESRD[3].

The increasing prevalence is likely due to improved diagnosis and recognition of the disease, coupled with a deeper understanding of the pathophysiology of podocyte injury and the development of therapies that target the mediators of this injury.

Several aspects are associated with a more severe prognosis in FSGS patients, including genetic influences, which are an important part of the more aggressive clinical pattern.

Current clinical guidelines emphasize the need for a better understanding of the pathogenesis, particularly the immunological etiology, and the development of more targeted therapies.

This editorial addresses the current classification of FSGS, pathophysiologic mechanisms of injury, therapeutic guidelines, and novel therapies currently under investigation[4].

We synthesized insights from recent literature published over the last decade. Articles were selected from PubMed, Web of Science and Scopus databases. The search terms used were tailored to each database to retrieve studies related to of FSGS, pathophysiologic mechanisms of injury, therapeutic guidelines, and novel therapies currently under investigation. The reference lists of the selected studies were also screened and underwent the same selection process.

ETIOPATHOLOGY OF PRIMARY FSGS

The etiopathogenesis of FSGS involves a complex interplay of podocyte injury, proteinuria, circulatory factors, and genetic predispositions. Podocyte injury represents the initial step, characterized by loss of cytoskeletal integrity and detachment from the glomerular basement membrane, leading to segmental scarring. This process is exacerbated by proteinuria, which triggers tubular injury via inflammatory pathways and endoplasmic reticulum stress. Circulatory permeability factors, including soluble urokinase plasminogen activator receptor (suPAR) and cardiotrophin-like cytokine factor 1 (CLCF1), further contribute by interacting with podocyte receptors, inducing foot process effacement and proteinuria. Genetic influences, particularly apolipoprotein 1 (APOL1) mutations, enhance susceptibility to podocyte dysfunction through cytotoxic effects. These mutations, combined with environmental factors, highlight the multifactorial nature of FSGS and the importance of tailored therapeutic strategies.

Podocyte damage

The typical initial event for FSGS is podocyte damage that eventually leads to podocyte depletion. Podocytes are specialized cells in the glomerulus that consist of a cell body, main processes and foot processes (FPs). The FPs form a distinct, interlocking arrangement with the FPs of adjacent podocytes, creating filtration slits that are connected by the glomerular slit diaphragm. The diaphragm, together with the apical and basal membranes of the podocytes, is interconnected by a dynamically regulated actin-based cytoskeleton, which is crucial for preserving the glomerular filtration barrier against proteinuria.

Recent evidence suggests that disruption of the actin cytoskeleton and lacunar membrane in podocytes leads to loss of podocyte FPs, their enlargement, detachment from the glomerular basement membrane and subsequent migration into Bowman's space, ultimately leading to the onset of FSGS[5].

Anti-nephrin antibodies

A recent multi-institutional study of 22 Japanese pediatric patients with FSGS investigated the possible role of anti-nephrin antibodies in recurrent FSGS after renal transplantation. Among the patients studied, 14 had non-genetic primary FSGS, of which 11 developed post-transplant relapses. In these patients, plasma anti-nephrin antibody levels were elevated before transplantation or during relapses, with a median of 899 U/mL compared to the cutoff of 231 U/mL. Renal biopsies during relapses showed punctate immunoglobulin (Ig) G deposits co-localized with nephrin and alterations in nephrin tyrosine phosphorylation, with increased spontaneously hypercholesterolemic and A proteins. After remission, anti-nephrin antibody levels decreased and biopsies showed a normal pattern without IgG deposits. In patients with genetic FSGS or without relapses, antibody levels were similar to controls and no renal changes were observed[6].

These findings suggest that circulating anti-nephrin antibodies may be involved in the pathogenesis of recurrent post-transplant FSGS through a mechanism mediated by nephrin phosphorylation. Larger and more diverse studies are needed to confirm these findings.

Circulating factors

Primary FSGS is associated with an unidentified circulating factor, with no evidence of any other underlying cause. To date, several molecules have been linked: (1) SuPAR; (2) ApoA1 isoform; (3) Cardiotrophin-like cytokine factor; (4) The cMaf-inducing protein; (5) The aAngiopoietin-like-4; and (6) CD40 L[7-11].

Indirect evidence for the existence of a circulating plasma component is the clinical response to plasmapheresis and the possible recurrence after renal transplantation[12].

Idiopathic FSGS recurs after transplantation in approximately 40% of adult and pediatric patients, occasionally within hours or days after renal transplantation[13]. These clinical observations confirm that FSGS can be related to circulating components resulting from cellular or humoral immune responses.

Genetic influence

There is considerable genetic variability in the population worldwide. Expression of the G1 and G2 alleles of the APOL1 gene is common in 35% of African Americans, 26% of Central African communities, and 50% of West African cultures. The G1 and G2 alleles increase the risk of FSGS and resulting chronic kidney disease by 3.5-fold in 16% of cases compared to European populations, with the highest incidence occurring between the ages of 30 years and 50 years[14].

Mutations in more than 50 genes expressed in the podocytes or glomerular basement membrane have been identified as causative factors for inherited variants of FSGS, which occur mainly in adolescence. These genes include INF2, alpha-actinin 4, transient receptor potential ion channel (TRPC) 6, Wilms tumor 1, nephrotic syndrome (NPHS) 1, NPHS2[15]. Santín et al[16]selected individuals with steroid-resistant nephrotic syndrome to undertake a series of studies on podocyte-associated genes. The patients had a familial inheritance pattern, with 57% developing FSGS at remarkably young ages. The NPHS1 gene was the predominant mutant gene among these people, and patients with NPHS1 mutations exhibited a higher likelihood of progressing to ESRD compared to those with mutations in other podocyte genes.

The incidence of genetic FSGS in adults may be underestimated, and its clinical and histologic features are not yet clearly understood. Some limited studies of adult-onset genetic FSGS show heterogeneity of clinical and histologic manifestations. Careful evaluation of adult FSGS cases that do not have characteristic symptoms of primary or secondary FSGS should include genetic testing.

Recognizing the genetic forms of FSGS in adults is crucial as this type of diagnosis significantly influences therapeutic strategies, the choice of a related living donor for kidney transplantation and the chances of success of transplantation[17].

CLASSIFICATION OF FSGS

FSGS is categorized into primary, secondary and genetic forms based on etiopathogenesis or histology[18,19]. Based on the etiopathogenetic classification, we can speak of primary or secondary FSGS. Primary FSGS is probably caused by a circulating permeability factor that is toxic to the podocytes and leads to a general dysfunction of the podocytes. It typically manifests as acute nephrotic syndrome, increased proteinuria, hypoalbuminemia and peripheral edema, with podocyte pedicle processes disappearing on more than 80% of the glomeruli[20].

Based on histology, FSGS is categorized into different histologic variants based on the appearance and location of glomerular lesions detected by renal biopsy. The most important variants[21] are mentioned in Table 1[22-26].

Table 1 Focal segmental glomerulosclerosis histologic variants.

Focal segmental glomerulosclerosis histologic variants	Description
Collapsing	Clinically, the disease manifests as a nephrotic syndrome and a rapid, progressive loss of kidney function. Studies in animal models and investigations in patients have identified several clinical and genetic conditions associated with this form of glomerulopathy, as well as possible pathogenetic mechanisms, which are investigated here
Cellular	Shows a proliferation of cells in the affected glomeruli, with inflammatory proliferation and glomerular segments populated with inflammatory cells
Perihilar	This form mainly affects the perihilar region of the glomerulus and is frequently observed in patients with hyperfiltration and long-term adaptation to an increased renal stress
Apical pole (tip lesion)	It mainly involves the apical region of the glomeruli and is common in patients with nephrotic syndrome and a more favorable clinical prognosis
Not otherwise specified	This is the most common form and is used for cases that do not fall under the variants described above and have a less specific histologic picture

This classification, developed in research contexts such as the CureGN project[27], uses standardized microscopy parameters and aims to improve diagnostic accuracy and allow consistent comparisons between different types of FSGS. This approach is fundamental for establishing clinicopathologic correlations that can guide treatment[28].

TREATMENT OF FSGS

FSGS, a complex and heterogeneous pathology, can result from immunological, genetic causes or secondary conditions such as obesity and viral infections. The difficulty in achieving complete remissions has encouraged the search for new, more effective therapeutic options. So, the treatment of FSGS cannot be interpreted in a single direction. The therapy varies according to the etiopathogenesis, depending on whether it is a primitive, secondary or genetic form. The therapeutic approach for primitive FSGS is complex and requires continuous monitoring, with therapies adjusted according to the patient's response and the occurrence of side effects. The preferred initial therapy is glucocorticoids, with calcineurin inhibitors (CNIs) being an alternative option. In cases of glucocorticoid resistance or dependence, CNIs are the second-line therapy, while other options such as mycophenolate mofetil (MMF), rituximab and adrenocorticotropic hormone (ACTH) are considered in patients who cannot tolerate or are resistant to CNIs. Treatment of relapses and continuous monitoring of renal function and proteinuria are essential for the long-term management of the disease[29,30].

In patients with primary FSGS and nephrotic syndrome (proteinuria > 3.5 g/day and serum albumin < 3.5 g/dL), glucocorticoids rather than CNIs are the first-line therapy of choice. However, in patients with a high risk of glucocorticoid toxicity (e.g. obesity, diabetes or advanced age), CNIs (cyclosporine or tacrolimus) may be an alternative, alone or in combination with a low dose of glucocorticoids. However, CNIs are avoided in patients with impaired renal function [estimated glomerular filtration rate (eGFR) < 30 mL/minute/1.73 m²] due to their potential nephrotoxicity. All patients receiving glucocorticoid or CNI therapy should also follow general supportive measures. In certain situations, such as pregnancy or intolerance to glucocorticoids and CNI, the use of alternative agents such as MMF, rituximab or ACTH gel may be considered, although the evidence for these drugs as an initiation of therapy is limited. During therapy with glucocorticoids or CNI, monitoring is essential: (1) Serum creatinine, electrolytes and proteinuria-creatinine ratio (UPCR) every two to four weeks for the first few months; (2) In patients receiving supportive measures only, creatinine, electrolytes and UPCR every three to four months until the parameters have stabilized; and (3) In patients receiving CNI, it is necessary to monitor blood drug levels to avoid nephrotoxicity and hyperkalemia. Normally, a kidney biopsy is not repeated unless there are signs of disease progression. Relapses are common and treatment is based on the response to initial therapy.

Glucocorticoids

If the patient initially responded positively to glucocorticoids and no significant toxicity occurred, prednisone treatment is repeated. Patients who initially respond to glucocorticoids but then relapse or show no response within 16 weeks are referred to as glucocorticoid-dependent or glucocorticoid-resistant. In these cases, the use of CNI is recommended as second-line therapy in patients who are resistant or dependent on glucocorticoids. For patients who cannot receive CNI due to toxicity or impaired renal function, MMF, rituximab and in some cases cyclophosphamide are alternative options.

CNI

In patients who initially responded to CNI without significant side effects, CNI therapy is repeated. For patients who do not respond to or cannot tolerate CNI, the following alternatives are considered MMF/enteric-coated mycophenolate sodium (EC-MPS) used in combination with low-dose glucocorticoids. It is an option for patients who do not respond to CNI or who have shown a partial response with significant toxicity. Rituximab, which is equally effective in glucocorticoid-dependent patients, but there are limited data for glucocorticoid-resistant cases. Tedesco et al[31] examined the use of rituximab in the management of primary FSGS in adults. Thirty-one patients were followed for at least 12 months, with a median additional follow-up of 17 months in 11 patients. At the time of initial treatment with rituximab, median proteinuria was 5.2 g/24 hours, while median creatinine was stable. Response rates to renal transplant were 39%, 52%, and 42% at 3 months, 6 months, and 12 months, respectively, with improvements in proteinuria and serum albumin levels. Rituximab has allowed many patients to reduce other immunosuppressants. Steroid-dependent patients with proteinuria less than 5 g/24 hours showed a greater probability of response to rituximab. Among patients who responded to initial treatment, many maintained remission without additional immunosuppressants or with preemptive rituximab. However, some required new courses of rituximab to maintain remission. Rituximab may therefore represent a therapeutic option in primary FSGS, particularly effective in steroid-dependent patients with proteinuria less than 5 g/24 hours, although long-term management remains uncertain, with variable responses between patients. As suggested by the studies of Wang et al[32] the efficacy and safety of rituximab for primary FSGS in adults. Total 14 patients were included, mainly with glucocorticoid-dependent or frequently relapsing nephrotic syndrome, treated with 2-4 administrations of rituximab (375 mg/m² every 2-4 weeks) to achieve B cell depletion. After treatment, 7 patients achieved complete remission and most were able to discontinue glucocorticoids within 6 months. An additional 5 patients achieved partial remission, of which one relapsed and one progressed to ESRD. Rituximab has been shown to reduce the risk of relapse and dependence on glucocorticoids and immunosuppressants in adult FSGS. Cyclophosphamide, which is indicated in patients who have only partially responded to prednisone and have significant interstitial fibrosis. Its use is limited to short cycles (8-12 weeks) to reduce toxicity. ACTH is used in some studies and may be effective in glucocorticoid-dependent patients, but data are limited. Sparsentan is a potentially viable alternative that can be safely administered over a prolonged period and has a sustained antiproteinuric effect. Sparsentan appears to be a viable therapeutic option for FSGS, as evidenced by the significant decrease in proteinuria observed in the DUET study[33] and its beneficial antiproteinuric effect. Nevertheless, in the DUPLEX study[34], sparsentan did not result in a significant reduction in the overall or chronic slope of eGFR in individuals with FSGS over a two-year period. Plasmapheresis (PLEX) should also be considered in refractory cases with persistent massive proteinuria despite conventional treatments. Sparsentan, a dual endothelin and angiotensin receptor antagonist, has shown promise in recent trials. The DUET study demonstrated a 42% greater reduction in proteinuria compared to irbesartan over 8 weeks, while the DUPLEX trial confirmed sustained antiproteinuric effects and a slower decline in eGFR over 108 weeks, supporting its potential as a long-term therapy for FSGS.

Over the past, the treatment of FSGS has seen significant developments thanks to the advanced understanding of the pathogenetic mechanisms of the disease and the introduction of innovative therapies. The difficulty in achieving complete remissions has encouraged the search for new, more effective therapeutic options. Among emerging therapies, blockade of TRPC5 and TRPC6 ion channels in podocytes has shown promise for limiting cell damage and proteinuria. Emerging studies emphasize the potential of TRPC blockers in reducing proteinuria and preserving kidney function, particularly in patients with APOL1-related FSGS. Clinical trials on VX-147 have demonstrated significant proteinuria reduction, highlighting its promise in targeting APOL1 mutations[35,36]. TRPC5/6 inhibitors, such as GFB-887, are currently being investigated in clinical trials for their potential to reduce proteinuria and preserve podocyte function. A phase 2 trial of GFB-887 showed a significant reduction in proteinuria levels after 12 weeks of treatment, suggesting its potential to address podocyte injury in primary FSGS. Furthermore, specific antagonists such as sparsentan and atrasentan, which inhibit endothelin and renin-angiotensin system receptors, have shown significant benefits in renal protection. For example, the DUET study demonstrated a significant reduction in proteinuria in patients treated with sparsentan compared to irbesartan, while the DUPLEX trial highlighted its potential long-term efficacy and safety in renal protection[37]. For patients with APOL1 mutations, who are particularly at risk, new targeted therapies, such as the VX-147 inhibitor and antisense oligonucleotides, represent innovative options in clinical trials[38]. In parallel, the personalized approach based on genetic sequencing is becoming essential to identify patients with monogenic forms of the disease who may benefit from targeted therapies, such as coenzyme Q10 supplementation in specific mutations. The future of FSGS management therefore seems oriented towards multi-target and personalized therapies, with the aim of achieving stable remissions and improving patients' quality of life. Despite these promising advancements, gaps remain in translating these therapies into widespread clinical practice. Challenges include variability in patient responses and limited long-term safety data for emerging therapies. For instance, while sparsentan has shown significant short-term benefits, further large-scale studies are required to confirm its long-term renal outcomes[39]. These advances offer encouraging prospects for more effective treatment of FSGS, although there remains a need for further clinical trials to confirm the efficacy and safety of these new therapies on a large scale[38]. Future research should focus on identifying biomarkers to stratify patients for personalized treatments and exploring combination therapies that address multiple pathways involved in FSGS pathogenesis.

The use of PLEX in the treatment of primary FSGS does not find ample space in the guidelines, and is generally limited to the most severe and resistant cases, in particular for patients who, despite adequate treatment with prednisone, CNI, MMF/EC-MPS, and rituximab, still present massive proteinuria and hypoalbuminemia. In recent years, the discovery of anti-antinephrine antibodies in a subgroup of patients affected by FSGS has opened new diagnostic and therapeutic perspectives, suggesting that such antibodies could play a role in determining the increased glomerular permeability that characterizes these pathologies, leading to hypothesis that using PLEX as a good strategy. The case reported by Bressendorff et al[40], suggests that PLEX could be an effective and complementary treatment to glucocorticoids for patients with antinephrin-positive FSGS, especially in those with severe forms or those resistant to conventional therapy. However, the real role of antinephrin antibodies as causal factors in this pathology remains to be clarified, and further studies are necessary to consolidate the efficacy profile of PLEX in cases of FSGS associated with these antibodies. Recent advances in understanding the pathophysiology of FSGS have led to the development of targeted therapies and ongoing clinical trials aimed at improving patient outcomes. Table 2 provides a comprehensive summary of these trials, highlighting the pathways involved and the preliminary findings. These studies underscore the shift towards precision medicine and a multi-target approach in managing FSGS.

Table 2 Summary of ongoing clinical trials and investigational therapies in focal segmental glomerulosclerosis.

Clinical trial	Targeted pathway	Findings/observations
DUET study	Endothelin and RAS receptors	Significant reduction in proteinuria observed; effectiveness on eGFR progression remains under evaluation
DUPLEX study	Sparsentan (endothelin and RAS)	Sustained antiproteinuric effect; no significant reduction in eGFR decline over two years
VX-147 trial	APOL1-targeting	Promising results in patients with APOL1 mutations; significant proteinuria reduction observed
Rituximab trials	B-cell depletion	Reduced relapses in steroid-dependent patients; limited efficacy in steroid-resistant cases
Anti-nephrin trials	Circulating anti-nephrin antibodies	Remission seen in patients with high antibody levels; further studies required to confirm pathogenic role
Adrenocorticotropic hormone gel studies	Mechanism not fully understood	Promising results in steroid-dependent patients; additional confirmation needed in larger clinical trials

APOL1: Apolipoprotein 1; EGFR: Estimated glomerular filtration rate; RAS: Renin-angiotensin system.

The management of FSGS is shifting towards personalized approaches, guided by genetic testing and biomarker identification. Genetic testing plays a pivotal role in diagnosing monogenic forms of FSGS and tailoring treatment strategies. For example, APOL1 risk variants have been strongly associated with FSGS in individuals of African descent, and therapies targeting these variants, such as VX-147, are currently under investigation. Similarly, coenzyme Q10 supplementation has shown promise in patients with podocin mutations.

Although these therapies show promise, their long-term efficacy and safety remain to be fully established. Further large-scale, multicenter trials are needed to confirm their impact on renal survival and patient quality of life.

Circulating biomarkers such as suPAR and CLCF1 provide additional tools for individualizing treatment. Elevated suPAR levels have been associated with podocyte dysfunction and proteinuria, offering potential for targeted immunomodulatory therapies. The integration of genetic and biomarker data into clinical practice has the potential to improve outcomes by optimizing therapy for specific patient subgroups[39].

CONCLUSION

Healthcare providers should prioritize early genetic testing and biomarker assessment to guide treatment decisions. For researchers, addressing gaps in long-term efficacy data for new therapies and developing robust biomarkers for prognosis and treatment response should be key priorities. Future research should also explore combination therapies and personalized approaches to improve patient outcomes in FSGS. FSGS remains a leading cause of ESRD and represents a major challenge due to its heterogeneous and complex pathophysiology. Effective management hinges on accurate differential diagnosis and tailored therapeutic strategies. Genetic testing should be routinely integrated into clinical practice to differentiate hereditary FSGS and inform personalized treatment plans. Therapies targeting proteinuria and preserving podocyte function, such as CNIs and sparsentan, should be prioritized, particularly in patients with nephrotic syndrome. There is an urgent need for large-scale, multicenter trials focusing on the long-term safety and efficacy of emerging therapies, such as TRPC5/6 inhibitors and endothelin receptor antagonists. Additionally, the development of predictive biomarkers, including suPAR and anti-nephrin antibodies, could improve risk stratification and therapeutic decision-making. For patients with APOL1 mutations, further studies are required to validate the efficacy of targeted therapies like VX-147 and explore potential combination treatment.