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Review

Focal and Segmental Glomerulosclerosis: A Comprehensive State-of-the-Art Review

by
Dearbhail Ni Cathain
1,*,
Donnchadh Reidy
1,
Serena Bagnasco
2 and
Sam Kant
1
1
St. Vincent’s University Hospital, D04T6F4 Dublin, Ireland
2
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
*
Author to whom correspondence should be addressed.
Sclerosis 2025, 3(3), 24; https://doi.org/10.3390/sclerosis3030024
Submission received: 9 May 2025 / Revised: 17 June 2025 / Accepted: 27 June 2025 / Published: 1 July 2025
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Abstract

Focal and segmental glomerulosclerosis (FSGS) describes a histological pattern of injury seen by light microscopy in kidney biopsy specimens and is the end result of various injuries to the podocyte. Our understanding of this disease entity has evolved greatly since it was first described, with particular focus on changes in the classification of FSGS as a disease entity and expansion in our understanding of the underlying pathophysiology. The incidence and prevalence of FSGS and FSGS-associated end-stage kidney disease (ESKD) have increased globally, particularly in the United States; it is now the most common primary glomerular disorder in those with ESKD. APOL-1 is likely responsible for this epidemiological trend in kidney disease in the US and is an important focus of clinical trials and potential targeted therapies. Currently, the goal of treatment in FSGS is to achieve remission of proteinuria and to prevent progression to ESKD. Remission is achieved by using immunosuppressive therapies in primary FSGS, but treatment in secondary and genetic FSGS is largely supportive. Recurrent FSGS (rFSGS) post-transplantation remains a significant clinical challenge to nephrologists; current monitoring and treatment strategies are based on retrospective meta-analysis and observational studies with no clear consensus as to the optimum approach. Emerging therapies are focused on developing more targeted interventions in genetic and secondary FSGS. This review article aims to comprehensively explore this multifaceted disease entity.

1. Introduction

Focal and segmental glomerulosclerosis (FSGS) describes a histological pattern of injury seen by light microscopy in kidney biopsy specimens and is the result of varied injuries to the podocyte. It was first described in 1925 by a German pathologist, Theodor Fahr, who initially referred to the findings as “lipoid nephrosis with degeneration” [1] and then by Dr. Arnold Rich in 1957 [2], who noted segmental areas of sclerosis in children dying of nephrotic syndrome. The International Study of Kidney Diseases in Children (1970) eventually reported FSGS, as distinguished from minimal change disease (MCD) by features of steroid resistance and progression to kidney failure [3].
Our understanding of this disease entity has evolved greatly over the last 100 years since it was first described. Historically, FSGS was classified using the Columbia classification system that focused on the morphological injury: collapsing, tip, cellular, peri-hilar and not otherwise specified [4]. This classification system was found to be largely unhelpful from a clinical perspective and non-specific to the underlying aetiology. FSGS is now more routinely classified by the underlying aetiology: primary, secondary, genetic and undetermined forms [5,6].
FSGS is the shared histological end point for a wide variety of conditions that result in podocyte injury. Regardless of the cause of the initial podocyte injury, it triggers a well-observed cascade within the glomerulus: podocyte depletion leaving the glomerular basement membrane uncovered, therefore allowing the interaction between capillary loops and parietal epithelial cells. In response to the reduced number of podocytes, there is residual podocyte hypertrophy and compensatory intracapillary hypertension leading to further podocyte injury, endothelial cell injury and mesangial alterations. This culminates in progressive focal and segmental sclerosis [7].

2. Epidemiology

The incidence and prevalence of FSGS and FSGS-associated end-stage kidney disease have increased over the last 30 years. As a disease entity, FSGS demonstrates geographical and ethnic variation, with APOL-1 playing a significant role in this variation [8]. Differing renal biopsy practices internationally also contribute to the geographical variance of FSGS, as reflected by the high incidence of FSGS in Australian cohorts, where practices tend to favour the pursuit of renal biopsy [7]. The incidence of FSGS ranges from 1.4–21 cases per million population [8,9]. FSGS is seen in approximately 20% of cases of children with biopsy-proven nephrotic syndrome versus up to 40% in the adult population [8]. Adult-onset FSGS has a definite male preponderance with a 1.5–2-fold increased incidence in males [9]. US data assessing incidence rates as patients per million broken down by ethnicity showed the following: 6.8 in blacks, 3.7 in Hispanics and 1.9 in whites [7,10]. In the US, FSGS is now the most common primary glomerular disorder identified in patients with end-stage renal disease [11]. However, in European and Asian populations, patients with nephrotic syndrome who undergo kidney biopsy have a higher incidence of membranous nephropathy [11,12].

3. Histopathology

The term focal segmental glomerulosclerosis describes lesions that are (1) focal—some glomeruli but not all glomeruli are affected; (2) segmental—of the glomeruli affected, it initially affects certain areas but not the entire glomerulus; and (3) glomerulosclerosis, or areas of scarring [4]. With time, the initial FSGS pattern can become more diffuse and global. Adequate renal biopsy sampling is imperative, as classically the juxtamedullary nephrons are the first affected.
Over the last few decades, FSGS has been recognised as a separate clinical disorder from MCD, but both primarily affect the podocyte ultrastructure as “podocytopathies” and present with nephrotic syndrome. Distinguishing features of FSGS versus MCD on biopsy include light microscopy evidence of segmental scarring of the capillary loops with obliteration of the normal capillary lumen. The FSGS lesion can have areas of surrounding hyalinosis, macrophage infiltration (particularly in the sclerosed tuft) and adhesion of the sclerosed area to Bowman’s capsule. Immunofluorescence in MCD is usually negative, but FSGS can demonstrate immunoglobulin (IgM) and complement deposition in the areas of sclerosis. Electron microscopy (EM) shows foot process effacement as in MCD. There may be additional evidence of collapsed capillary loops as well as microvillus transformation that may point towards FSGS. EM can help distinguish between primary and secondary causes of FSGS by assessment of the extent of foot process effacement, with ≥80% associated with primary causes [7]. The Columbia Classification system (Table 1), although felt to be less useful clinically, does describe the morphological lesion seen and can be a helpful addition to the etiological classification as a guide to prognosis and risk of progression to end-stage renal disease [13] (Figure 1). The collapsing variant, predominantly seen in the Black population and classically associated with HIV, infers the worst prognosis with a 70% risk of progression to ESKD versus the tip lesion, which in turn is usually seen in primary FSGS with good steroid response and a much lower risk of progression to ESKD [14].

4. Pathophysiology and Classification

As mentioned previously, FSGS is typically classified into 4 broad categories with further subcategorisation within these headings. We will now take the opportunity to discuss the pathophysiology and disease course of the three well-defined types of primary, secondary and genetic forms of FSGS. Anything outside of this or yet unknown is deemed to be an undetermined form of FSGS.
A.
Primary FSGS
Primary FSGS generally presents with the full constellation of the nephrotic syndrome and is hypothesised to be caused by a yet unidentified circulating permeability factor (CPF) [7,15,16]. This hypothesis is supported by the recurrence of FSGS post-transplantation [17], the therapeutic response to plasmapheresis and immunoadsorption [18] and a case describing transient nephrotic syndrome in a neonate born to a mother with known FSGS [19]. Despite the well-supported theory, the identification of such a permeability factor has been difficult and reviewed numerous times over the years [15,20,21,22]. To date, the permeability factors with the most promise in studies are soluble urokinase plasminogen activator receptor (suPAR) [23], Cardiotrophin-like cytokine factor-1 (CLCF-1) [24] and anti-CD40 antibodies [25]. Theoretically, these permeability factors are believed to cause podocyte injury with eventual podocyte loss and exposure of the glomerular filtration barrier [26].
Urokinase plasminogen activator receptor (uPAR) is a cell membrane glycosylphosphatidylinositol (GPI)-anchored protein expressed in a multitude of cell types throughout the body [27], including podocytes [28]. When uPAR is cleaved from GPI, the resultant molecule released is suPAR. suPAR is believed to play a role in regulating neutrophil response and the mobilisation of stem cells, and as such, suPAR is detected at low levels in healthy populations and appears to be upregulated in acute inflammation as an acute phase reactant [29,30]. Levels of circulating suPAR have been found to be significantly raised in patients with FSGS, and in particular in those with recurrent FSGS [23]. However, there is conflicting evidence as to whether suPAR is the circulating factor responsible for the development of the glomerular injury or if suPAR, measuring 25–50 kDa, at increasing levels is more a reflection of renal impairment and reduction in eGFR and impaired filtration [31,32].
CLCF-1 is a B-cell stimulating cytokine of the IL-6 family [24]. CLCF-1 concentrations in patients with recurrent FSGS have been shown to be up to 100 times higher than in healthy controls [22]. Although CLCF-1 appears to play a role in the JAK/STAT pathway in glomerular podocytes, it has been difficult to elucidate its clinical importance due to a lack of sensitivity in the currently available assays to measure CLCF-1 levels [22,24].
Delville et al. in 2014 [25] focused on antibodies occurring in the pre-transplant period that could predict recurrence of FSGS post-transplant: pre-transplant anti-CD40 antibody present predicted rFSGS with 78% accuracy [25]. It does not appear to be pathogenic in isolation, as demonstrated by the injection of anti-CD40 into mouse models without the occurrence of robust albuminuria. The interaction between anti-CD40 and suPAR was proposed from this study.
The role of nephrin in congenital nephrotic syndrome and genetic FSGS has been long established [33]. Nephrin is a transmembrane protein present in the slit diaphragm that plays a key role in maintaining the normal structure and function of the podocyte. Anti-nephrin antibodies have been found to be associated with the development of minimal change disease and FSGS, particularly post-transplant recurrence of FSGS [34]. Anti-nephrin antibodies have been successfully demonstrated as a causal permeability factor for the development of primary FSGS, and with recent advances in research, these autoantibodies can now be measured and used as a reliable biomarker of disease activity and recurrence risk [35]. Although a significant advance in our understanding of FSGS, these antibodies have been found in only 9% of adults with primary FSGS [35]. There remain significant questions about the pathogenic role of alternative permeability factors.
Other potential factors gaining recent interest include apolipoprotein A-Ib (Apo A-IB), calmodulin-dependent serine protein kinases (CASK), microRNAs, hemopexin and transforming growth factor-Beta (TGF-B) [26,36]. Fortunately, it remains an area of particular interest, likely due to the risk of recurrence post-transplant and the pursuit of therapeutic targets, but we have yet to identify a definitive therapeutic target. FSGS may well be the culmination of an interplay of many of these factors [15,36].
B.
Genetic FSGS
FSGS as a result of genetic mutations has been an area of particular interest in the last decade with the availability of whole-exome sequencing. Genetic FSGS can be divided into FSGS associated with variation in susceptibility genes, APOL-1 in particular, and FSGS associated with Mendelian or maternally inherited, high-penetrance mutations [5,7].
The identification of the APOL-1 gene on chromosome 22 has transformed our modern understanding of chronic kidney disease in the Black population [37,38,39]. It is now known that two disease-causing APOL1 genetic variants arose in sub-Saharan Africa as an adaptation to confer enhanced protection against African sleeping sickness [17]. These genetic variants are only seen in individuals of African ancestry and are associated with increased susceptibility to HIV-associated nephropathy, hypertension-associated end-stage kidney disease and FSGS [37]. The reported odds ratio for the development of FSGS with two risk variants in APOL-1 is approximately 17 [40].
FSGS due to monogenic gene mutations can be seen with isolated renal involvement or as a syndrome with associated extra-renal manifestations [5]. The way in which FSGS due to a genetic cause presents can be quite varied depending on the gene involved and the mode of inheritance. Childhood genetic FSGS is most commonly associated with autosomal recessive mutations and generally presents clinically as the nephrotic syndrome. In contrast, adult-onset genetic FSGS is classically due to autosomal dominant inherited disease, and the mutation can have variable penetrance with varied clinical phenotypes ranging from slowly progressive CKD with increasing levels of proteinuria to the nephrotic syndrome [41]. Table 2 lists many of the known genetic variants, the mode of inheritance and clinical presentation [5].
C.
Secondary FSGS
Secondary FSGS occurs due to renal adaptation to a variety of different initial insults, such as a reduction in nephron mass or direct toxic injury due to certain drugs or viruses [42]. There is a stepwise adaptation within the glomerulus in response to the initial inciting injury with increased glomerular capillary pressure and filtration flow through the podocyte slit diaphragm with eventual foot process effacement, compensatory podocyte hypertrophy and glomerulomegaly, and resultant distortion of the normal glomerular tuft-bowman’s capsule architecture leading to glomerulosclerosis [42,43]. This gradual adaptation results in a clinical phenotype markedly different from that of primary FSGS with slowly increasing proteinuria that is often sub-nephrotic and kidney function that declines over time [44,45].
Secondary causes can be sub-classified into adaptive with reduced renal mass, adaptive with normal renal mass, drug-induced or viral-induced (Table 3) [42].

5. Treatment

The goal of treatment for patients with FSGS is complete remission of proteinuria to prevent progression to ESKD. Immunosuppression is the mainstay of treatment for primary FSGS in comparison to secondary causes of FSGS and genetic causes of FSGS, which are largely supportive. KDIGO describes targets for complete remission, partial remission and relapse [7].
Complete remission is considered a reduction in proteinuria <300 mg/day (PCR < 300 mg/g, <30 mg/mmol), a stable serum creatinine and a serum albumin <3.5 g/dL.
Partial remission is considered a reduction in proteinuria to between 300 mg and 3.5 g/day and a decrease of >50% from baseline, with or without a return of serum albumin to normal levels.
A relapse is a return of proteinuria to >3.5 g/day in those who had previously undergone a complete remission or an increase in proteinuria of >50% in patients who had undergone a partial remission.
General treatment measures for FSGS are similar to other forms of glomerular disease. This should include dietary sodium to <2 g/day and stopping smoking. Target blood pressure is a systolic of <120 mmHg using a standardised office BP measurement. Patients should be on an ACE-i/ARB at a maximally tolerated dose and an SGLT2-i. Statins should be considered in all patients with persistent hyperlipidaemia (Figure 2).
For the purposes of this review, we will discuss treatments for primary FSGS. The mainstay of treatment for FSGS has been glucocorticoids. KDIGO recommends prednisolone at a 1 mg/kilogram dose to a maximum of 80 mg per day for at least 4 weeks and up to 16 weeks until remission is achieved as a first-line therapy. Alternatively, 2 mg/kg/day on alternate days (to a maximum dose of 120 mg). If remission is achieved, high-dose glucocorticoids should be continued for a further two weeks with a view to reducing prednisone by 5 mg every 1 to 2 weeks later to a duration of six months. In patients who are intolerant of glucocorticoids, calcineurin inhibitors (CNIs) can be considered. Caution is advised with patients with an eGFR < 30 mL/min/1.73 m2 given the risk of nephrotoxicity. Recommended initial doses include cyclosporine 3–5 mg/kg/day or tacrolimus 0.05–0.1 mg/kg/day in 2 divided doses. Target trough levels are 100–175 ng/mL and 5–10 ng/mL, respectively. Similar to glucocorticoids, CNIs should be continued for 4–6 months prior to considering a patient resistant to treatment. In patients who achieve partial or complete remission, treatment should be continued for at least 12 months to minimise relapses; the dose of calcineurin inhibitors can be gradually tapered over 6–12 months. Similarly, those failing initial treatment with steroids should be considered for calcineurin inhibitors. Patients who are pregnant can generally be safely treated with glucocorticoids or calcineurin inhibitors. For patients who fail treatment with calcineurin inhibitors, other regimens can be considered although there is limited evidence. Treatment options include mycophenolate and high-dose dexamethasone, rituximab and ACTH. Patients should be counselled on further treatment and the risks of further immunosuppression. Further testing, such as genetic testing and re-biopsy, should also be considered.

6. Prognosis

FSGS is a chronic progressive disease with a relatively poor prognosis. Approximately 50% of patients with FSGS will progress to ESKD over a 5–10 year period [47]. The 7-year survival is also lower for FSGS compared to other forms of glomerular disease (69% vs. 88% for membranous nephropathy and 82% for IgA nephropathy) [47]. An analysis of USRDS data from 2008 to 2018 saw the rising prevalence of FSGS progressing to ESKD rising from 76.5 to 96 persons per million despite a mild decrease in incidence from 8.0 to 6.7 per million. This increase in prevalence has been seen in both adult and paediatric patients [48]. Ethnicity remains a significant factor in progression to ESKD, as it disproportionately affects Black and Native Hawaiian or Pacific Islanders [48]. The role of the APOL1 gene is likely a major contributing factor to a patient’s overall risk.
Prognosis is dependent on the type of FSGS. Primary FSGS overall conveys a poor prognosis, which can be largely divided into those responsive to steroids versus patients that are not. Approximately 67% of patients will achieve remission with steroids alone [49]. Remission is associated with a 5-year survival off dialysis of 94% compared to 53% who do not achieve remission. Similarly, genetic causes of FSGS often see similar rates of patients progressing to ESKD, although prognosis is likely dependent on the genetic variant. A cohort examined in China looked at common genetic mutations, including COL4A3, COL4A4 or COL4A5, INF2 heterozygous variants and TRPC6 [50]. In this study, patients with INF2 heterozygous mutation had significantly shorter kidney survival compared to primary FSGS and COL4A3, COL4A4 or COL4A5. Further studies are needed to better inform clinicians on the impact of different genetic causes of FSGS on kidney survival.

7. Post-Transplant FSGS

Recurrent FSGS (rFSGS) refers to the development of primary FSGS in the transplanted kidney of patients who had ESKD due to primary FSGS [51]. Patients present with nephrotic range proteinuria, hypoalbuminemia with or without edema. Diagnosis is made by allograft biopsy. rFSGS remains a significant problem with both significant clinical and economic burden. As there is a significant risk of recurrence, prospective transplant patients should be extensively counselled on the risk of recurrence. Given the risk of recurrence, some nephrologists have advocated for the use of deceased donor transplantation over living donor transplantation; however, this remains controversial [51]. The Post-Transplant Glomerular Disease Consortium, which includes 39 transplant centers across five continents, reported an incidence of recurrence of FSGS to be 32% of patients following a kidney transplant [52]. In patients that have recurrence of FSGS in their graft, there was a 39% rate of graft failure over 5 years with a median time to graft loss of 7 months [52]. This is similar in the paediatric cohort, with a graft survival of 69% in rFSGS versus 93% measured in a cohort with a minimum 4-year follow-up period [53]. Risk factors for recurrence include older age at native kidney disease onset (HR 1.37 per decade), white race (HR 2.14), BMI at transplant (HR 0.89 per kg/m2) and native kidney nephrectomies (HR 2.76). Neither duration of dialysis nor type of post-transplant immunosuppression influences the risk of recurrence [54,55].
The timing of recurrent FSGS can vary significantly from early recurrence (within 48 h of transplant), intermediate recurrence (2 days to 1 month) or infrequent and late recurrence (≥1 month) [56]. It is important to differentiate recurrence of a primary FSGS from other de novo secondary causes such as chronic T-cell or antibody-mediated rejection, calcineurin inhibitor toxicity with arteriolar hyalinosis, recurrent glomerulonephritis, renal artery stenosis, atheroembolism, thrombotic microangiopathy, reflux nephropathy, viral infections (HIV, parvovirus, cytomegalovirus or coronavirus disease 2019 [COVID-19]), drug-induced injury (interferon, lithium or pamidronate) and light chain podocytopathies [51,57].
The risk of recurrent proteinuria with genetic forms of FSGS is generally regarded as low; however, some patients with the NPHS1 pathogenic variant may develop anti-nephrin antibody, resulting in nephrotic range proteinuria [58,59]. Remission of rFSGS is an important factor for graft survival, where patients who have complete remission have comparable graft survival to those without recurrence of FSGS. Unfortunately, rates of FSGS in subsequent transplants are very high, supporting the theory that primary FSGS is mediated by a CPF. A recent observational study in France reported recurrence rates as high as 76.9% in patients receiving subsequent transplants. Current recommendations for monitoring for rFSGS include daily creatinine and urine protein for 1 week, twice weekly in week 2, weekly for 4 months, monthly for the first year and every 3 months thereafter with use of a first void sample [51].
To date there is no consensus on the treatment of rFSGS, as there is a lack of clinical trials. Current treatment options include plasmapheresis or immunoadsorption therapy and the use of anti-CD20 monoclonal antibodies for B-cell depletion. Pulse methylprednisolone has been shown to be effective in a few studies [60,61]. However, current recommendations are prompt treatment with plasmapheresis and that this should not be delayed for biopsy if clinical suspicion is high [51]. The suggested regimen for plasmapheresis is daily for 3 days, then 3 times a week for 2 weeks. Exchanges of 1 to 1.5 plasma volumes using citrate or heparin anticoagulation with replacement by human albumin or hemofiltration solution should be targeted; fresh frozen plasma should be used as replacement fluid if plasma fibrinogen is low. Plasmapheresis may be terminated after reduction of proteinuria (<1 g/d) [51]. The above regimen can be combined with other immunosuppressive agents, including rituximab or intravenous cyclosporine. A meta-analysis of 8 observational studies demonstrated a remission rate of 72.7%, showing some promise for this therapy, although clinical trials in this area are needed [62].
Preemptive strategies, including plasmapheresis, rituximab or cyclosporine, have been suggested as possible preventive measures for FSGS. A meta-analysis examined rates of recurrence following plasmapheresis with or without rituximab, finding no significant difference compared to patients who received no treatment, however, there has yet to be a randomised controlled trial published [63]. A more recently published observational study in France showed no difference in rates or time to recurrence following kidney transplant in those receiving preemptive plasma exchange, rituximab or cyclosporine [64]. Despite these interventions, 5-year graft survival remained at 67.7% [64]. Overall, routine use of preemptive plasmapheresis or rituximab is not recommended in patients receiving a second transplant.

8. Emerging Therapies and Future Directions

Therapies emerging in the treatment of FSGS have a wide range of potential targets [65]. There are novel immunosuppressive therapies, specific podocyte therapies, anti-fibrotic agents and agents that alter renal hemodynamics (Table 4). Specific disease subtype targets are also gaining interest, including antiviral agents, obesity management strategies and APOL-1 antagonists [66]. We will focus on some of the latest clinical trials taking place and their proposed sites of action.
Endothelin 1 is associated with glomerular vasoconstriction and therefore increased intraglomerular pressure/hypertension. Endothelin 1, in conjunction with angiotensin II, can mediate podocyte apoptosis and changes to the podocyte cytoskeleton. Sparsentan, a dual endothelin A and angiotensin II antagonist, has therefore been proposed as a therapy for FSGS and is in phase 3 clinical trials [67]. Phase 2 studies are taking place in isolated endothelin A antagonists also (Atrasentan), with evidence of reduced renal events in patients with diabetes and CKD [68].
The TRPC6 gene was discussed earlier as a gene associated with autosomal dominant FSGS. This notable gain-of-function mutation that appears to be disease-causing has resulted in a focus on the TRPC family, TRPC 5 and TRPC 6 inhibitors in particular. It is hypothesised that inhibition of either of these targets may preserve the podocyte cytoskeleton and reduce podocyte injury; clinical trials are being conducted to investigate this theory [69,70].
Targeted therapies in the treatment of APOL-1 are under investigation, including VX-147 (Inaxaplin), a small-molecule APOL-1 inhibitor. Inaxaplin has been trialed in patients with biopsy-proven FSGS with two APOL1 high-risk alleles confirmed. The results of such studies are eagerly awaited [66,71]. As our understanding of APOL-1 evolves and the mechanism by which it mediates renal disease, alternate therapeutic targets are being proposed, including antisense oligonucleotides. Mouse models using antisense oligonucleotides showed dose-dependent reduction in kidney APOL-1-mRNA [71]. Baricitinib, a JAK inhibitor, has also been proposed as a therapy in APOL-1 mediated kidney disease via downregulation of the JAK/STAT pathway that is felt to be pro-inflammatory [71].
FSGS due to genetic mutations is an area that is expanding rapidly with modern advances in genetic sequencing, and it is an area that is sure to gain more traction with targeted gene therapies [5]. Addressing the underlying cofactor deficiency is the alternate therapeutic target, for example, coenzyme Q10 supplementation in those with genetic mutations leading to mitochondrial dysfunction and coenzyme Q10 deficiency, with promising clinical improvement shown in trials [72,73]. Similarly, vitamin B12 supplementation may be of benefit to those with mutations in the CUBN gene, encoding Cubilin, associated with FSGS and megaloblastic anemia [5].
Progressing the focus of treatment in primary FSGS from broad immunosuppressive therapies and proteinuria-lowering agents [6] to more targeted therapy will likely remain elusive until a clear role for the proposed permeability factors is established [69]. Acknowledging the difficulty in identifying a single CPF to target, research has progressed to investigating in vitro bioassays to identify patients with plasma-derived CPF without a need to identify a singular, specific CPF. Plasma taken from patients with plasmapheresis-responsive FSGS has been shown to cause podocyte cell damage following 24 h of exposure to 10% patient plasma, with damage to the actin cytoskeleton, the generation of reactive oxygen species and eventual cell death [26]. If validated on a larger scale, this study may provide the groundwork for identifying FSGS due to CPF by measuring reactive oxygen species generated and by assessing the actin cytoskeleton [26]. Initial in vitro studies have used immortalised podocyte cell lines that fail to replicate in vivo podocytes, particularly the expression of the slit diaphragm. This is where interest in using 3-dimensional human organoids for the study of FSGS and CPFs looks promising and may contribute to our understanding of this complex disease [74,75].
The development of high-resolution mass spectrometry has contributed greatly to advancements in the area of proteomics and the identification of urinary and plasma biomarkers of disease. Biofluid analysis presents a potential non-invasive form of testing that may help differentiate primary FSGS from other forms. Recent studies of urinary biomarkers compared urinalysis of patients with primary FSGS versus healthy controls, secondary FSGS and CKD due to other etiologies [76]. A specific urinary peptidomic classifier, pFSGS93, was found in primary FSGS and has potential for use in clinical practice as a diagnostic tool [76].
Artificial intelligence and machine learning models are highly topical in all fields of medicine and have been studied in FSGS to aid diagnosis, risk stratification and treatment [77]. Novel expert systems have been shown to be an aid to clinicians by reducing errors and enhancing diagnosis and efficiency of initiation and progression of treatment [77]. Unfortunately, the use of such systems is not currently generalisable as it relies heavily on the quality of the data collections systems, but with advances in medical record keeping and the move to electronic records, this is likely to improve.

9. Conclusions

Our understanding of FSGS has evolved greatly over the last one hundred years. We now understand FSGS to be a histological pattern of injury common to a growing list of clinical diagnoses. It is currently the most common glomerular disorder associated with end-stage kidney disease in the US, and, owing to this prevalence, FSGS promises to be an area of expanding research interest in the coming years. APOL-1-related kidney disease and recurrent FSGS post-transplant are two areas, in particular, at the forefront of this expansion. Progress in the area of primary FSGS will be limited until we have a conclusive understanding of the underlying aetiology but developments are ongoing.

10. Search Strategy

Articles selected for review were selected from PubMed following a search of the title terminology, focal segmental glomerulosclerosis/FSGS. Additional searches for specific subtitles were explored. Historical articles were reviewed to provide context to the paper, but an effort was made to focus on the best quality evidence and papers published in the last ten years.

Author Contributions

Conceptualization, D.N.C., D.R. and S.K.; writing—original draft preparation, D.N.C., D.R. and S.B.; writing—review and editing, D.N.C. and S.K.; supervision, S.K.; project administration, D.N.C.; All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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Sclerosis 03 00024 g001
Figure 1. FSGS Histology.
Figure 1. FSGS Histology.
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Figure 2. Diagnosis and treatment.
Figure 2. Diagnosis and treatment.
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Table 1. Columbia Classification.
Table 1. Columbia Classification.
VariantHistological FeaturesClinical Features
Not otherwise specifiedCriteria for other FSGS variants not met.Varies from sub-nephrotic to nephrotic range proteinuria. Most common variant.
PerihilarLesions at the glomerular vascular pole. Hyalinosis and sclerosis in a perihilar distribution in the majority of glomeruli with segmental lesions.Common in secondary/adaptive FSGS, usually presenting with sub-nephrotic proteinuria.
CellularSegmental lesions expanded with endocapillary hypercellularity (can include foam cells and leucocytes), with a degree of glomerular epithelial hyperplasia.Least common variant. Usually associated with primary FSGS presenting with nephrotic syndrome.
TipSegmental lesion at the tubular pole. Either cellular or sclerosing lesion with adhesion or confluence of podocytes with tubular epithelial cells. Best prognosis. Often seen in primary FSGS that is steroid responsive with the lowest risk of progression to ESKD.
CollapsingSegmental or global collapse with overlying podocyte hypertrophy and hyperplasiaWorst prognosis. Classically seen in HIV but also other secondary causes: viral and drug-induced.
Table 2. Genetic causes of FSGS.
Table 2. Genetic causes of FSGS.
InheritanceGene (Protein)Clinical Presentation
Autosomal Recessive
NPHS1 (Nephrin)Congenital nephrotic syndrome
NPHS2 (Podocin)Congenital/Childhood nephrotic syndrome
PLCε1 (Phospholipase Cε1)Adult-onset nephrotic syndrome.
CD2AP (CD2 associated protein)FSGS in childhood
MYO1E (Non muscle class I myosin 1E)FSGS in childhood
Lamb2 (Laminin-beta2)Pierson Syndrome
ITGB4 (Integrin-beta 4)Epidermolysis bullosa, atresia of pylorus and early onset FSGS.
SCARB2 (Scavenger receptor class B member2)Action myoclonus-renal failure syndrome
Col4A3 (Alpha 3 type 4 Collagen)Alport syndrome
CUBN (Cubilin)Megaloblastic anaemia and childhood nephrotic syndrome
COQ2, COQ6, PDSS2 and ADCK4 (Mitochondrial disorder-Coenzyme Q 10 Deficiency)FSGS with optical and sensorineural involvement
Autosomal Dominant
TRPC6 (Transient receptor potential cation channel 6)Familial or sporadic FSGS
ACTN4 (alpha-Actinin-4)Familial or sporadic adult onset FSGS
INF2 (Inverted formin 2)Familial or sporadic adolescence FSGS and adult onset FSGS
Laminin alpha 5 (LAMA5)Adult onset FSGS
MYH9 (Myosin heavy chain 9)Epstein-Fechtner syndrome
WT1 (Wilms Tumour 1)Frasier Syndrome, Denys-Drash syndrome
LMNA (Lamin A/C)Familial partial lipodystrophy and adult onset FSGS
Table 3. Causes of Secondary FSGS.
Table 3. Causes of Secondary FSGS.
Sub-ClassificationCauses
Reduced renal mass [42]Congenital absence: Oligomeganephronia, unilateral renal agenesis and vesico-ureteric reflux.
Acquired reduction: Post-nephrectomy or post-renal ablation, renal transplant chronic allograft nephropathy
Normal renal mass [42]Obesity, diabetic nephropathy, sickle cell anemia, cyanotic heart disease and hypertension.
Drug-induced [7]Heroin, interferon, bisphosphonates (particularly pamidronate), anabolic steroids, anthracyclines, calcineurin inhibitors, lithium and sirolimus.
Viral-induced [46]HIV, parvovirus B19, CMV, EBV, Hep C, Simian Virus 40 and SARS-CoV-2.
Abbreviations: HIV, Human immunodeficiency virus; CMV, cytomegalovirus; EBV, Epstein-Barr virus; Hep C, hepatitis C; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Table 4. Emerging therapeutics in the treatment of FSGS.
Table 4. Emerging therapeutics in the treatment of FSGS.
DrugActionGoal
SparsentanEndothelin A and Angiotensin II antagonistPreservation of the podocyte cytoskeleton
AtrasentanEndothelin A antagonistPreservation of the podocyte cytoskeleton
GFB-887Small molecule inhibitor of TRPC5Prevent podocyte damage.
BI 764198Selective oral TRPC6 inhibitorPrevent podocyte damage.
BaricitinibJanus kinase-STAT inhibitorPrevention of cytokine-induced APOL-1-related glomerulopathy
VX-147 (Inaxaplin)APOL-1 antagonistPrevention of APOL-1-related kidney disease
Antisense oligonucleotide inhibitor of APOL-1Modify RNA expression of APOL-1.Prevention of APOL-1-related kidney disease
Co-enzyme Q10Restore normal mitochondrial function and reduce reactive oxygen species.COQ6, ADCK4 and COQ2 mutations—Genetic FSGS. Prevent podocyte damage and cell death.
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Ni Cathain, D.; Reidy, D.; Bagnasco, S.; Kant, S. Focal and Segmental Glomerulosclerosis: A Comprehensive State-of-the-Art Review. Sclerosis 2025, 3, 24. https://doi.org/10.3390/sclerosis3030024

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Ni Cathain D, Reidy D, Bagnasco S, Kant S. Focal and Segmental Glomerulosclerosis: A Comprehensive State-of-the-Art Review. Sclerosis. 2025; 3(3):24. https://doi.org/10.3390/sclerosis3030024

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Ni Cathain, Dearbhail, Donnchadh Reidy, Serena Bagnasco, and Sam Kant. 2025. "Focal and Segmental Glomerulosclerosis: A Comprehensive State-of-the-Art Review" Sclerosis 3, no. 3: 24. https://doi.org/10.3390/sclerosis3030024

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Ni Cathain, D., Reidy, D., Bagnasco, S., & Kant, S. (2025). Focal and Segmental Glomerulosclerosis: A Comprehensive State-of-the-Art Review. Sclerosis, 3(3), 24. https://doi.org/10.3390/sclerosis3030024

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