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Focal segmental glomerulosclerosis (FSGS) is histologically characterized by segmental scarring that affects only a portion of the glomerulus and involves some, but not all, glomeruli in a biopsy sample. The causes of FSGS are classified as primary (idiopathic), genetic, or secondary, with causes including infections, drugs, and hemodynamic maladaptations. Accurate identification of the underlying etiology is crucial for guiding treatment decisions, predicting prognosis, and assessing transplant risks. Genetic markers, such as APOL1 variants, are associated with treatment resistance and an increased risk of progression to end-stage renal disease. Patients with FSGS may present with clinical features of nephrotic or nephritic syndrome or renal insufficiency. Nephrotic syndrome is the most common clinical manifestation of FSGS, occurring in over 70% of patients. This condition is characterized by generalized or dependent edema, fatigue, and appetite loss. Hypertension is also a common feature and can be severe, with diastolic blood pressure exceeding 120 mm Hg. Diagnosis requires histopathological confirmation, as proteinuria, low serum albumin, and casts on urinalysis can support clinical suspicion. This activity reviews the evaluation and management of FSGS and emphasizes the crucial role of the interprofessional healthcare team in optimizing care for patients with this condition. Objectives: Identify the clinical features of focal segmental glomerulosclerosis, including nephrotic syndrome, hypertension, and renal insufficiency, to support timely diagnosis. Screen for genetic markers, such as APOL1 variants, in high-risk populations to assess prognosis and treatment resistance. Apply appropriate therapies, distinguishing between immunosuppressive treatment for primary focal segmental glomerulosclerosis and supportive care for secondary focal segmental glomerulosclerosis. Collaborate with nephrologists, pathologists, pharmacists, and other specialists to ensure comprehensive management of focal segmental glomerulosclerosis. Access free multiple choice questions on this topic.

Focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome, accounting for 40% of cases in adults and 20% in children.[1] In FSGS, some glomeruli are sclerosed (focal), with only a portion of each affected glomerulus involved (segmental).[2] FSGS is one of the most prevalent causes of primary glomerulopathy in adults.[3] FSGS can be broadly classified into primary, with no identifiable cause, or secondary. Genetic causes can also be classified either separately or with primary FSGS. Secondary causes of FSGS include infections, certain drugs, hemodynamic maladaptations in the kidney, and genetic factors. Although clinical signs may suggest FSGS, the diagnosis can only be confirmed through histopathological findings.[4] Histologically, FSGS is characterized by segmental scarring that affects part of the glomerulus and involves only a subset of the glomeruli sampled. Recent research has highlighted that the pathogenesis of FSGS involves podocyte injury and damage, which leads to protein loss and the development of focal sclerosing lesions.[5] Categorizing FSGS as primary or secondary has important prognostic and therapeutic implications.[6] The most common clinical manifestation of FSGS, observed in over 70% of patients, is nephrotic syndrome, characterized by generalized or dependent edema, fatigue, and loss of appetite. Hypertension is also common and can be severe, with diastolic blood pressure exceeding 120 mm Hg, particularly in patients of Afro-Caribbean origin.[7]

FSGS can be classified as primary (idiopathic), genetic, or secondary. Primary (Idiopathic) Focal Segmental Glomerulosclerosis Primary FSGS has been associated with unidentified circulating permeability factors or cytokines that cause podocyte foot process effacement and proteinuria, even in transplanted kidneys. Proposed factors include corticotrophin-like cytokine factor 1, apolipoprotein A1-b (apoA1-b), anti-CD40 antibodies, and serum urine-type plasminogen activator receptor (suPAR).[8][9][10][11] Etiologies of primary (idiopathic) FSGS include: FSGS with hyalinosis Progression from immunoglobulin M (IgM) nephropathy Progression from minimal-change disease Progression from mesangial proliferative glomerulonephritis Superimposition on other primary glomerulonephritides, such as IgA nephropathy The following histological variants of primary FSGS are further described in the Histopathology section: Collapsing form Cellular variant FSGS with mesangial hypercellularity FSGS with glomerular tip lesions Genetic Focal Segmental Glomerulosclerosis Genetic testing is recommended for patients with steroid-resistant FSGS, a family history of FSGS, a history of Wilms tumor (nephroblastoma), or other systemic signs suggestive of a genetic syndrome, such as Alport syndrome, Fabry disease, or nail-patella syndrome.[4] Children who present with FSGS at birth or in infancy have a significantly higher likelihood of having a genetic etiology.[2]

Genetic testing is recommended for patients with steroid-resistant FSGS, a family history of FSGS, a history of Wilms tumor (nephroblastoma), or other systemic signs suggestive of a genetic syndrome, such as Alport syndrome, Fabry disease, or nail-patella syndrome.[4] Children who present with FSGS at birth or in infancy have a significantly higher likelihood of having a genetic etiology.[2] Several genes encoding proteins involved in the slit diaphragm, cell membrane, cytoskeleton, nuclear, mitochondrial, and lysosomal functions have been identified as abnormal, leading to a loss of integrity in the glomerular filtration barrier and resulting in FSGS.[12] Examples include mutations in NPHS1 and NHPS2, which lead to the absence of essential slit diaphragm components nephrin or podocin, leading to severe congenital nephrotic syndrome. Additionally, polymorphisms in APOL1, commonly found in individuals of African descent, significantly increase the risk of developing FSGS. In fact, approximately 75% of Black patients with FSGS carry a high-risk APOL1 mutation.[13] These patients often present with collapsing FSGS, which rapidly progresses to end-stage renal disease (ESRD).[4][14] Other disease-causing mutations occur, affecting proteins such as nephrin, podocin, α-actinin-4, and β-integrin. Patients with genetic FSGS may have a relevant family history, and they often present at a young age.[14][15] Secondary Focal Segmental Glomerulosclerosis Secondary FSGS can result from various factors, including drugs, inflammation, infections, toxins, and intrarenal or extrarenal hemodynamic alterations, all of which can initiate podocyte injury and lead to glomerulosclerosis. Most cases of secondary FSGS are associated with increased loads on individual nephrons, a phenomenon known as maladaptive responses, which lead to glomerular hypertrophy. Histopathologically, these cases are characterized by large glomeruli, prominent perihilar scarring, and partial foot process effacement.[16][17] Factors related to decreased renal mass include: Solitary kidney Kidney allograft Renal dysplasia Renal agenesis Oligomeganephronia Segmental hypoplasia Vesicoureteral reflux [18] Hemodynamic causes leading to a mismatch between glomerular load and capacity (glomerular hypertension) in patients without decreased renal mass include: Obesity (especially morbid obesity) [19] Sickle cell nephropathy High protein intake

Kidney allograft Renal dysplasia Renal agenesis Oligomeganephronia Segmental hypoplasia Vesicoureteral reflux [18] Hemodynamic causes leading to a mismatch between glomerular load and capacity (glomerular hypertension) in patients without decreased renal mass include: Obesity (especially morbid obesity) [19] Sickle cell nephropathy High protein intake Androgen abuse, which causes increased lean muscle mass [4] Systemic diseases such as diabetes or hypertension [2] Drugs associated with FSGS include:[20][21][22] Intravenous heroin (adulterant) [23] Calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors, which are particularly important in transplant recipients [2] Pamidronate, likely causing damage to the actin cytoskeleton of podocytes [20] Lithium [24] Anabolic steroids, which have a direct toxic effect [4][25] Doxorubicin, daunomycin, and other anthracyclines [2] Interferon (IFN) therapy (podocytes have IFNα and -β receptors) [4] Viruses are well known to be associated with FSGS. HIV, in particular, causes podocyte and renal tubular epithelial cell toxicity. Podocytes can serve as a reservoir for HIV, even in patients on highly active antiretroviral therapy with normal CD4 lymphocyte counts.[26][27] Viral injury can occur through direct toxicity or cytokine release. Other viruses known to cause FSGS include: Hepatitis B and C viruses Parvovirus B19 [28] Cytomegalovirus (CMV) SARS-CoV-2 Other conditions causing FSGS include: Hypertensive nephrosclerosis Sarcoidosis Radiation nephritis Lymphomas and other malignancies [29]

The prevalence of FSGS appears to be increasing worldwide. However, determining its exact incidence and prevalence accurately remains challenging due to geographical variations in access to renal biopsy.[30] FSGS occurs more frequently in males and Black patients, with males affected approximately 1.5 to 2 times more often than females.[4] FSGS accounts for approximately 40% of nephrotic syndrome cases in adults and 20% in children.[1] Idiopathic FSGS most commonly occurs in individuals aged 18 to 45, although it can affect any age group.[7] Approximately 50% of patients with persistent nephrotic-range proteinuria progress to ESRD within 3 to 8 years of an FSGS diagnosis.[7][31] An international literature review reported the annual incidence of FSGS to range from 0.2 to 1.8 per 100,000 population.[1] The yearly incidence is 5 cases per million in White individuals compared to 24 cases per million in the Black population. In the United States, ESRD caused by FSGS occurs in 1.9 per million White patients and 6.8 per million Black patients.[32] FSGS is 3 to 7 times more common in young Black males than in their White counterparts. This higher incidence is partly attributable to variants of 2 important podocyte proteins—APOL1 and non-muscle myosin heavy chain-9 (MYHC9)—which are present in about 5% of White patients, as opposed to 60% of Black patients.[33]

The pathogenesis of FSGS involves a complex interplay among several cell types, including podocytes, endothelial cells, and the basement membrane. Podocytes are terminally differentiated cells that provide structural support to the glomerulus and are crucial for maintaining the integrity of the glomerular filtration barrier, preventing nephrotic-range proteinuria. Injury and loss of podocytes lead to hypertrophy of the remaining podocytes to compensate for the loss, covering the glomerular capillary surface. This results in foot process effacement and subsequent protein loss.[34][35] Foot process effacement, along with the proliferation of mesangial, endothelial, and epithelial cells, occurs early in the disease course. This is followed by the collapse or shrinkage of glomerular capillaries, ultimately leading to scarring (glomerulosclerosis).[36] As previously mentioned, proposed soluble factors that may mediate these structural changes include corticotrophin-like cytokine factor 1, apoA1-b, anti-CD40 antibodies, and suPAR.[8][9][10][11] The proposed mechanisms of podocyte injury are initiated by viral infections, immune responses, adverse medication effects, or toxin exposure, leading to intrarenal hemodynamic alterations such as increased intraglomerular capillary pressure and glomerular hyperperfusion. Primary FSGS typically progresses much faster than secondary FSGS, which is usually the result of a sustained insult.[4] The understanding of FSGS pathophysiology has advanced with the discovery that mutations in several proteins responsible for maintaining podocyte structure and function can result in FSGS and predict disease characteristics, including steroid responsiveness.[37] For instance, FSGS with mutations in NPHS2 or TRPC6 is challenging to treat with immunosuppressive therapy, and the disease typically does not recur after kidney transplantation. APOL1 variants have been associated with a poor renal prognosis and steroid-resistant FSGS and about a 17-fold increase in the odds of developing FSGS.[13][38]

The understanding of FSGS pathophysiology has advanced with the discovery that mutations in several proteins responsible for maintaining podocyte structure and function can result in FSGS and predict disease characteristics, including steroid responsiveness.[37] For instance, FSGS with mutations in NPHS2 or TRPC6 is challenging to treat with immunosuppressive therapy, and the disease typically does not recur after kidney transplantation. APOL1 variants have been associated with a poor renal prognosis and steroid-resistant FSGS and about a 17-fold increase in the odds of developing FSGS.[13][38] Minimal change disease (MCD) and FSGS are the primary etiologies of nephrotic syndrome, and they are thought to represent 2 ends of a spectrum of podocytopathies. MCD accounts for 70% to 90% of nephrotic syndrome cases in childhood and 10% to 15% in adolescence. MCD is almost always steroid-responsive and rarely progresses to ESRD, in contrast to FSGS. Several case reports have documented a transition from MCD to FSGS. Additionally, early FSGS often histologically resembles MCD, further supporting this theory.[39][40]

Histologically, FSGS is characterized by sclerosis, hyalinosis, and adhesion (or synechiae) formation, resulting in segmental obliteration of glomerular capillaries. The predominant finding on electron microscopy is the effacement of the foot process without significant abnormalities in the basement membrane. Immunofluorescence reveals IgM and C3 deposition in sclerotic areas. Juxtamedullary nephrons are affected first, and inadequate sampling may miss focal lesions. In cases of recurrent FSGS post-transplantation, a different variant may be observed in the allograft biopsy. Electron microscopy is crucial for evaluating the degree of podocyte foot process effacement, which helps differentiate primary from secondary FSGS. Primary FSGS typically affects more than 80% of the basement membrane surface area, whereas maladaptive secondary forms of FSGS usually show patchy involvement. Immune deposits and abnormal basement membrane components can also be evaluated with electron microscopy to exclude other disease processes.[4] Histological Variants of Focal Segmental Glomerulosclerosis Histologically, FSGS is classified into 5 variants—perihilar, tip, cellular, collapsing, and not otherwise specified (NOS).[6][41][42][43] Perihilar variant: The sclerosing lesion is localized at the vascular pole of the glomerulus, near the afferent arteriole. This variant is commonly observed in adaptive FSGS and is caused by increased glomerular pressure. Foot process effacement is typically mild, leading to subnephrotic proteinuria and relatively preserved serum albumin levels. Tip variant: This variant is characterized by a segmental lesion involving the proximal tubular pole of the glomerulus (at least the outer 25%). This variant is more common in White patients and presents with diffuse foot process effacement and abrupt onset of nephrotic syndrome. Patients typically have lower baseline creatinine levels, excellent treatment response, and the lowest rate of disease progression.[44][43] Cellular variant: This variant is the least common form of FSGS and is characterized by a hypercellular glomerulus, including endocapillary proliferation and glomerular epithelial cell hyperplasia. This variant presents with diffuse foot process effacement and full-blown nephrotic syndrome.[45]

Tip variant: This variant is characterized by a segmental lesion involving the proximal tubular pole of the glomerulus (at least the outer 25%). This variant is more common in White patients and presents with diffuse foot process effacement and abrupt onset of nephrotic syndrome. Patients typically have lower baseline creatinine levels, excellent treatment response, and the lowest rate of disease progression.[44][43] Cellular variant: This variant is the least common form of FSGS and is characterized by a hypercellular glomerulus, including endocapillary proliferation and glomerular epithelial cell hyperplasia. This variant presents with diffuse foot process effacement and full-blown nephrotic syndrome.[45] Collapsing variant: This variant is characterized by hyperplasia and hypertrophy of visceral glomerular epithelial cells, leading to the collapse of the glomerular tuft. Proteinaceous droplets may be seen in the podocytes. This form is commonly associated with viral-induced and drug-associated FSGS, particularly in patients receiving interferons or pamidronate. Collapsing FSGS presents with diffuse foot process effacement and heavy proteinuria, has the lowest remission rate, and carries the worst prognosis.[46][47][48] Not otherwise specified variant: The NOS variant is the most common subtype of FSGS and does not fit into any other morphological forms. This variant presents a variable degree of podocyte foot process effacement and proteinuria. An increase in the mesangial matrix may also be observed in this variant.[43] FSGS histopathology may sometimes resemble nodular sclerosis, which is commonly observed in diabetes and other conditions.[49]

Children with FSGS typically present with nephrotic syndrome, which is characterized by edema, massive proteinuria, hypoalbuminemia, and hypercholesterolemia. Please see StatPearls' companion resources, "Congenital Nephrotic Syndrome" and "Nephrotic Syndrome," for more information. In adults, symptoms may include nephrotic or sub-nephrotic proteinuria, hypertension, microscopic hematuria, or renal insufficiency. Patients with primary FSGS often experience severe hypoalbuminemia and edema, although these findings are rare in secondary forms. Nephrotic syndrome develops in 54% to 100% of patients with primary FSGS, depending on the study.[2] Obtaining an extensive medical history is essential, which includes inquiries about birth history (such as low birth weight, premature birth, and congenital renal malformations) and medical comorbidities, preexisting renal disease, exposure to drugs or toxins, recent viral illnesses, and family history to identify secondary causes of FSGS. Edema generally develops over a few weeks, but its onset can be abrupt, with sudden weight gain of 20 lbs (9 kg) or more. Often, a recent upper respiratory tract infection precedes the onset of edema. Pleural effusion and ascites may be present, although pericardial effusions are rare. Gross edema can predispose patients to infections and ulcerations in dependent areas, such as the lower extremities. Abdominal pain may indicate peritonitis, which is a common finding in children. Xanthomas may occasionally appear in cases of severe hyperlipidemia. The physical examination is otherwise normal in many patients except for edema. Severe hypertension is not uncommon, especially in Black patients with renal impairment.[7] Severe renal failure with features of advanced uremia, such as nausea, vomiting, seizures, bleeding, or altered mental status, is rarely seen. Patients with secondary FSGS, such as those with reflux nephropathy, morbid obesity, or renal dysplasia/agenesis, typically present with non-nephritic proteinuria. These patients may experience worsening renal function over months to years.

In patients with FSGS, urinalysis typically shows large amounts of protein and casts, usually hyaline or broad waxy casts, while red blood cell casts are generally absent. In the early stages of the disease, serum creatinine and creatinine clearance are often within the reference range. Features of nephrotic syndrome, including proteinuria greater than 3.5 g/dL and serum albumin less than 3.0 g/dL, may be present with or without edema. In idiopathic FSGS, investigations for an underlying etiology are usually negative. Commonly investigated processes include: Systemic lupus erythematosus Hepatitis B or C viral infection Vasculitis Gammopathy In patients suspected of having secondary FSGS, the following studies should be performed: HIV antibody, CD4 lymphocyte count, and viral load Serology for hepatitis B and C viruses Parvovirus B19 testing Antinuclear antibodies and anti–double-stranded DNA antibodies C3/C4 serum levels Urine and serum protein electrophoresis Antineutrophil cytoplasmic antibody titers FSGS is a diagnosis of exclusion in patients with morbid obesity. Common features in obesity-related FSGS include glomerular hyperfiltration and activation of the renin-angiotensin-aldosterone system.[50] FSGS should be considered in patients with proteinuria, particularly in younger individuals with no red blood cell casts and negative serological studies. The definitive diagnosis is typically made through a kidney biopsy in these cases. As mentioned above, genetic testing should be performed on children who present with FSGS at birth or in infancy. Patients with a family history of FSGS should also be referred to specialized centers for further genetic testing.[2] Histological Findings

FSGS is a diagnosis of exclusion in patients with morbid obesity. Common features in obesity-related FSGS include glomerular hyperfiltration and activation of the renin-angiotensin-aldosterone system.[50] FSGS should be considered in patients with proteinuria, particularly in younger individuals with no red blood cell casts and negative serological studies. The definitive diagnosis is typically made through a kidney biopsy in these cases. As mentioned above, genetic testing should be performed on children who present with FSGS at birth or in infancy. Patients with a family history of FSGS should also be referred to specialized centers for further genetic testing.[2] Histological Findings A kidney biopsy is the most specific diagnostic modality for FSGS, as it is for many other glomerulopathies. The characteristic finding in FSGS is segmental solidification of the glomeruli.[51] In the affected glomeruli, the accumulation of acellular matrix and hyaline deposits leads to the obliteration of capillaries in a segmental pattern. Coarse, granular deposits of C3 and IgM are commonly observed in these regions. Diffuse foot process fusion is primarily observed in the sclerotic segments, while partial effacement affects the normal-appearing lobules. In HIV-associated FSGS, electron microscopy may reveal tubuloreticular inclusions in mesangial and endothelial cells, serving as an indirect indicator of viral involvement.[52] Ultrasonography In the early stages of the illness, ultrasonography typically shows normal or enlarged kidneys with increased echogenicity, indicating diffuse intrinsic renal disease.[53] The kidneys may appear shrunken and small in advanced stages, suggesting severe interstitial fibrosis and glomerular scarring. In HIV-associated FSGS, ultrasonography generally reveals large, echogenic kidneys.

Distinguishing primary from secondary FSGS is essential, as secondary FSGS does not benefit from immunosuppression or steroids and may even be harmed by such treatments. Management of secondary FSGS focuses on treating the underlying condition, underscoring the importance of comprehensive serological evaluation and identifying secondary etiologies. Kidney survival closely correlates with proteinuria levels. Patients without nephrotic-range proteinuria have a 10-year survival rate exceeding 90%, even without immunosuppression. Reducing nephrotic-range proteinuria to non-nephrotic levels significantly improves kidney survival outcomes.[2] The 2021 Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for the Management of Glomerular Diseases provide the below-mentioned definitions for remission, relapse, resistance, and dependence in FSGS.[2] Complete remission: Proteinuria reduced to less than 300 mg/d, protein-creatinine ratio (PCR) less than 0.3, serum albumin greater than 3.5 g/dL, and stable serum creatinine. Partial remission: Proteinuria reduced to levels between 300 and 3500 mg/d, PCR of 0.3 to 3.5, and a decrease in proteinuria of 50% from baseline. Relapse: Proteinuria greater than 3500 mg/d, PCR greater than 3.5 after complete remission, or a 50% increase in proteinuria over partial remission. Steroid-resistant FSGS: Proteinuria greater than 3500 mg/d or PCR greater than 3.5 after 16 weeks of prednisone at 1 mg/kg (or equivalent). Steroid-dependent FSGS: Relapse occurring during or within 2 weeks of completing glucocorticoid treatment. CNI-resistant FSGS: Proteinuria greater than 3500 mg/d or PCR greater than 3.5 after 16 weeks despite therapeutic levels. CNI-dependent FSGS: Relapse occurring during or within 2 weeks of completing CNI therapy for 12 months. Corticosteroids

Steroid-dependent FSGS: Relapse occurring during or within 2 weeks of completing glucocorticoid treatment. CNI-resistant FSGS: Proteinuria greater than 3500 mg/d or PCR greater than 3.5 after 16 weeks despite therapeutic levels. CNI-dependent FSGS: Relapse occurring during or within 2 weeks of completing CNI therapy for 12 months. Corticosteroids According to the KDIGO 2021 Clinical Practice Guidelines, corticosteroids remain the cornerstone of treatment for FSGS.[2] High-dosage corticosteroid therapy with prednisolone is initiated at 1 mg/kg/d as a single daily dose (maximum 80 mg) or 2 mg/kg/d on alternate days (maximum 120 mg). This regimen is continued for at least 4 weeks, until complete remission is achieved, or for a maximum of 16 weeks, whichever comes first.[54][55] Patients with the potential for remission typically show a decline in proteinuria before 16 weeks of high-dose corticosteroid therapy. Therefore, it is unnecessary to continue high-dose corticosteroid treatment for the full 16 weeks if proteinuria persists or worsens, especially in patients experiencing adverse effects related to steroids.[56] If complete remission is achieved, steroid tapering should begin after 2 weeks or once proteinuria resolves, whichever is longer. Prednisolone is reduced by 5 mg every 1 to 2 weeks over a total duration of 6 months. If partial remission occurs within 8 to 12 weeks of high-dose corticosteroid therapy, treatment should continue until 16 weeks to achieve complete remission. Afterward, the prednisolone dosage is reduced by 5 mg every 1 to 2 weeks, completing a total duration of 6 months. Patients with a genetic etiology are more likely to have steroid- and immunosuppressant-resistant disease. However, these patients rarely experience recurrent disease in a transplanted kidney, making them good transplant candidates. Genetic testing may also be advisable in cases involving a living-related donor, especially if the donor carries high-risk APOL1 mutations.[2] Calcineurin Inhibitors For patients who are steroid-resistant or experience adverse effects from steroids, alternative immunosuppressants such as CNIs should be considered. The options are listed below. Cyclosporine: The dosage is 3 to 5 mg/kg/d, with target trough levels ranging from 100 to 175 ng/mL (or 83-146 nmol/L).

Patients with a genetic etiology are more likely to have steroid- and immunosuppressant-resistant disease. However, these patients rarely experience recurrent disease in a transplanted kidney, making them good transplant candidates. Genetic testing may also be advisable in cases involving a living-related donor, especially if the donor carries high-risk APOL1 mutations.[2] Calcineurin Inhibitors For patients who are steroid-resistant or experience adverse effects from steroids, alternative immunosuppressants such as CNIs should be considered. The options are listed below. Cyclosporine: The dosage is 3 to 5 mg/kg/d, with target trough levels ranging from 100 to 175 ng/mL (or 83-146 nmol/L). Tacrolimus: The dosage is 0.05 to 0.1 mg/kg/d, with target trough levels ranging from 5 to 10 ng/mL (or 6-12 nmol/L).[57] Trough levels should be monitored to prevent drug toxicity. A minimum of 6 months is required to assess the efficacy of cyclosporine or tacrolimus; if no improvement is seen after this period, the patient may be classified as CNI-resistant. CNIs should be continued for at least 12 months in patients with partial or complete remission to prevent relapse. The dose should be gradually tapered over 6 to 12 months as tolerated. In patients with subnephrotic proteinuria or adaptive FSGS, a trial of renin-angiotensin system inhibition with sodium restriction can be attempted. In other secondary forms of FSGS, removing the offending agent or treating the underlying disorder is recommended. In addition, blood pressure optimization, edema treatment with diuretics, statin therapy for hypercholesterolemia, and anticoagulation in select patients at risk for thromboembolic events are indicated. Children usually respond to CNI therapy within a few weeks, whereas adults may take months to show a response. Glucocorticoids are associated with a remission rate of approximately 30%, compared to about 50% in patients treated with CNI. Renal Transplantation

In patients with subnephrotic proteinuria or adaptive FSGS, a trial of renin-angiotensin system inhibition with sodium restriction can be attempted. In other secondary forms of FSGS, removing the offending agent or treating the underlying disorder is recommended. In addition, blood pressure optimization, edema treatment with diuretics, statin therapy for hypercholesterolemia, and anticoagulation in select patients at risk for thromboembolic events are indicated. Children usually respond to CNI therapy within a few weeks, whereas adults may take months to show a response. Glucocorticoids are associated with a remission rate of approximately 30%, compared to about 50% in patients treated with CNI. Renal Transplantation FSGS is the leading primary glomerular disorder causing ESRD. According to KDIGO guidelines, patients with primary FSGS are eligible for renal transplants, but they should be informed about the risk of recurrence.[58] A study found a 32% rate of recurrent FSGS in the allograft. Of the patients with recurrent FSGS, 39% experienced graft loss at a median of 5 years. KDIGO guidelines recommend against the routine use of plasmapheresis or rituximab for rejection prevention.[59] However, a recent study found that pretransplant prophylactic plasmapheresis significantly reduced FSGS recurrence (9% versus 35%) in the treated group.[60] Most graft losses occur within the first 2 years after transplantation, with therapeutic plasmapheresis recommended as a first-line treatment, particularly when significant proteinuria is present. Secondary FSGS due to hyperfiltration of the transplanted kidney is also common.[4] In addition, transplant patients are at risk for CMV and BK virus (human polyomavirus 1) infections, new-onset diabetes (associated with steroids and CNIs), and other adverse medication effects.[59][61] Other Therapeutic Interventions

Most graft losses occur within the first 2 years after transplantation, with therapeutic plasmapheresis recommended as a first-line treatment, particularly when significant proteinuria is present. Secondary FSGS due to hyperfiltration of the transplanted kidney is also common.[4] In addition, transplant patients are at risk for CMV and BK virus (human polyomavirus 1) infections, new-onset diabetes (associated with steroids and CNIs), and other adverse medication effects.[59][61] Other Therapeutic Interventions Sparsentan, a dual endothelin and angiotensin receptor antagonist, has been approved by the US Food and Drug Administration (FDA) for the treatment of IgA nephropathy.[62] A phase III trial (DUPLEX study) compared sparsentan with irbesartan in patients with primary FSGS. After 2 years, no significant difference was observed in estimated glomerular filtration rate preservation, although the sparsentan group showed a significant reduction in proteinuria.[63] Based on these results, the FDA did not approve sparsentan for the treatment of primary FSGS and requested additional data. Glucocorticoids, administered daily or every other day, are the first-line treatment for children and adults with primary FSGS. For patients who are resistant or intolerant to steroids and CNIs, various immunosuppressive therapies have been explored, including mycophenolate mofetil, rituximab, cyclophosphamide, mTOR inhibitors, azathioprine, levamisole, mizorbine, adalimumab, pirfenidone, fresolimumab, saquinavir, abatacept, and adrenocorticotropic hormone gel.[3][64][65][66][67][68][69] Adrenocorticotropic hormone gel, a preparation of melanocortin peptides, has been used in small studies to treat resistant forms of podocytopathies, such as membranous nephropathy and FSGS. Some evidence suggests it may be more effective when combined with tacrolimus; however, responses vary widely, and consistent positive results have not been demonstrated.[70][71][72] Plasmapheresis, plasma exchange, and immunoadsorption have been utilized to remove the "circulating factor" implicated in FSGS.[73] Therapeutic plasmapheresis, combined with immunosuppression, has also shown success in treating FSGS in pediatric renal transplant patients.[74]

Differentiating FSGS from other glomerulopathies and podocytopathies in patients presenting with nephrotic syndrome can be challenging. Therefore, the following differential diagnoses should be considered: Mesangial proliferative glomerulonephritis Membranoproliferative glomerulonephritis Systemic lupus erythematosus Diabetes IgA nephropathy Amyloidosis

Mortality and Morbidity The natural history of FSGS varies significantly. It is characterized by edema, proteinuria that is often refractory to steroids or other immunosuppressive treatments, worsening hypertension, and progressively declining renal function.[75] In cases that are unresponsive to treatment, the average time between the onset of gross proteinuria and progression to ESRD is 6 to 8 years, although variations may exist in the course of the disease. Achieving remission, whether spontaneous or induced, is associated with favorable renal outcomes.[76] The prognosis is significantly worse in the Black population compared to White patients, likely due to APOL1 gene variants. The collapsing form of FSGS is characterized by severe hypertension, a poor response to corticosteroids, massive proteinuria, and a much faster progression to ESRD. Several factors predict the outcome in FSGS, including ethnicity, degree of proteinuria, presence of renal insufficiency, histological variant (with the tip variant showing the best outcome and the collapsing variant the worst), degree of interstitial fibrosis or tubular atrophy, and response to treatment. Patients who achieve partial or complete remission tend to have a better prognosis. Additionally, patients with primary FSGS generally fare worse than those with adaptive or secondary causes of FSGS.[55]

FSGS, similar to all other glomerulopathies, can lead to various complications. The potential complications of this disease include: Uncontrolled high blood pressure Anemia Advanced renal failure Venous thromboembolism [77] Recurrent infections [78] Thrombotic microangiopathy [79] Complications of prednisone therapy include: Infections Hypertension Hyperglycemia Complications of cyclophosphamide therapy include: Infections Leukopenia Hemorrhagic cystitis [80] Complications of cyclosporine therapy include: Renal insufficiency Gingival hyperplasia [81] Infections

Healthcare providers should educate patients on the importance of managing hypertension and lipid levels, as well as understanding chronic kidney disease and the various renal replacement therapy options, such as hemodialysis, peritoneal dialysis, and kidney transplantation. Patients should be informed about the signs and symptoms of worsening conditions and when to seek medical attention. Dietary modifications should be emphasized, including restricting salt intake to 2 g of sodium per day. Potassium supplements may be necessary for patients on diuretics who develop hypokalemia. As high protein intake may impact renal function, current guidelines recommend an intake of 1 to 1.3 grams of high biological value protein per kilogram of body weight. Additionally, reducing fat intake can help manage dyslipidemia.

FSGS is a common cause of nephrotic syndrome, accounting for 40% of cases in adults and 20% in children. Due to its multiple causes and varied presentations, the condition is most effectively managed by an interprofessional healthcare team comprising a nephrologist, internist, pathologist, nurses, and pharmacist. These clinicians collaborate to guide care, with nurses playing a key role in coordinating activities between disciplines, assisting in patient evaluation, and providing patient counseling. Pharmacists ensure appropriate medication dosing, conduct medication reconciliation, provide patient counseling, and address medication-related questions. All healthcare team members must maintain accurate and up-to-date patient records, thereby ensuring access to the same information. Open communication among healthcare team members is essential for achieving optimal patient outcomes. A strategic approach is essential, utilizing evidence-based strategies to optimize treatment plans and minimize adverse effects. Ethical considerations should guide decision-making, ensuring informed consent and respecting patient autonomy in treatment choices. Each healthcare professional must recognize their responsibilities and contribute their unique expertise to the patient's care plan, fostering a multidisciplinary approach. Effective interprofessional communication is crucial, enabling seamless information exchange and collaborative decision-making among team members. Care coordination is vital in ensuring that the patient's journey from diagnosis to treatment and follow-up is well-managed, minimizing errors and enhancing patient safety. Healthcare professionals can deliver patient-centered care by embracing the principles of skill, strategy, ethics, responsibility, interprofessional communication, and care coordination, ultimately improving patient outcomes and enhancing team performance in the management of FSGS.