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Focal segmental glomerulosclerosis: Clinical features and diagnosis

Focal segmental glomerulosclerosis: Clinical features and diagnosis
Literature review current through: Jan 2024.
This topic last updated: May 23, 2023.

INTRODUCTION — Focal segmental glomerulosclerosis (FSGS) is a morphologic pattern of glomerular injury primarily directed at the glomerular visceral epithelial cell (the podocyte) and defined by the presence of sclerosis in parts (segmental) of some (focal) glomeruli by light microscopy (LM) of a kidney biopsy specimen. The lesion of FSGS can be classified into primary, secondary, genetic, and undetermined forms using a clinicopathologic approach. This classification step is crucial for determining appropriate therapy; identification of an FSGS lesion solely by LM is never sufficient for management decisions. The lesion of FSGS is distinct from focal global glomerulosclerosis (FGGS), which has a different prognosis and treatment.

The epidemiology, classification, clinical features, and diagnosis of FSGS will be reviewed in this topic. The pathogenesis, genetic causes, and treatment of FSGS as well as recurrent disease in the kidney transplant are discussed separately:

(See "Focal segmental glomerulosclerosis: Pathogenesis".)

(See "Focal segmental glomerulosclerosis: Genetic causes".)

(See "Focal segmental glomerulosclerosis: Treatment and prognosis".)

(See "Kidney transplantation in adults: Focal segmental glomerulosclerosis in the transplanted kidney".)

EPIDEMIOLOGY — FSGS is a common histopathologic lesion among adults with nephrotic syndrome in the United States, accounting for 35 percent of all cases [1]. FSGS is also the most common primary glomerular disease identified in patients with end-stage kidney disease (ESKD) in the United States [2]. The prevalence of FSGS as a "lesion" associated with ESKD has risen. In 1980, FSGS as a "lesion" was the cause of ESKD in only 0.2 percent of patients; by 2000, it was responsible for 2.3 percent of cases (excluding patients with human immunodeficiency virus [HIV]), an 11-fold increase [2]. The lifetime risk of ESKD was fourfold higher in Black individuals compared with White and Asian individuals and 1.5- to 2-fold higher in males compared with females. In another study, incidence rates of FSGS increased from 1.4 per 100,000 person-years between 1994 and 2003 to 3.2 per 100,000 person-years between 2004 and 2013, a 41 percent increase per five years [3].

By comparison, FSGS is a less common cause of nephrotic syndrome in other countries. As an example, in a study of 2000 Spanish patients between 15 and 65 years of age with nephrotic syndrome, the most common histologic lesion was membranous nephropathy (24 percent), followed by minimal change disease (16 percent), lupus nephritis (14 percent), and FSGS (12 percent) [4]. In another retrospective analysis of kidney biopsies performed among Chinese patients ≥65 years of age, the most common diagnoses were membranous nephropathy (29 percent), diabetic nephropathy (9.7 percent), immunoglobulin (Ig) A nephropathy (9.6 percent), and vasculitis (6.8 percent), with FSGS occurring in <5 percent of cases [5,6].

This discrepancy may be explained, at least in part, by the fact that most data originating in the United States previously considered the histopathologic lesion of FSGS as a single disease entity, without distinguishing primary from secondary FSGS. It is now known that FSGS is a histologic pattern of injury that characterizes a wide spectrum of diseases with different pathophysiologies. In addition, most of these studies reported trends in relative disease frequencies among patients undergoing kidney biopsy rather than population-based incidence rates of FSGS. The only population-based study conducted in the United States reported IgA nephropathy, diabetic kidney disease, and FSGS as the most common glomerular diseases [3]. This study also separately analyzed the incidence of presumed primary versus secondary FSGS and showed that two-thirds of the cases of FSGS were due to secondary FSGS (or undiagnosed genetic FSGS). (See "Focal segmental glomerulosclerosis: Pathogenesis".)

It is important to recognize that although the incidence rate of FSGS is increasing, the ratio of primary and secondary FSGS has remained stable over the last two decades, with the majority of cases due to secondary (genetic or unknown cause), not primary, FSGS [3]. Although changes in lifestyle and diet could explain a rise in FSGS caused by obesity, the rise in primary FSGS remains unexplained. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Obesity'.)

CLASSIFICATION AND CLINICAL FEATURES — FSGS can be classified into the following forms, based upon clinical presentation and pathologic findings on kidney biopsy [7].

Primary FSGS — Primary FSGS (also known as permeability factor–related FSGS) is presumed to be caused by a circulating permeability factor that is toxic to the podocyte and causes generalized podocyte dysfunction. The identity of the circulating factor(s) has not yet been clearly established, although several candidates have been proposed. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Pathogenesis of primary FSGS'.)

Patients with presumed primary FSGS most commonly present with the acute onset of the nephrotic syndrome and the associated features of high-grade (>3.5 g/day) proteinuria, hypoalbuminemia, and peripheral edema [8-14]. Hematuria is common (approximately 50 percent of patients), and hypertension is present in approximately 20 percent of cases [8,9,13,14]. An elevated serum creatinine may be seen in 25 to 50 percent of patients at presentation [8,9,13,14] but may not necessarily reflect chronic kidney damage, since acute tubular necrosis can occur in patients with severe proteinuria. (See "Acute kidney injury (AKI) in minimal change disease and other forms of nephrotic syndrome", section on 'Acute kidney injury in other forms of nephrotic syndrome'.)

Primary FSGS is associated with diffuse (≥80 percent) podocyte foot process effacement on electron microscopy (EM) examination of the kidney biopsy (picture 1). (See 'Pathology' below.)

Secondary FSGS — Secondary FSGS most commonly refers to FSGS that develops as a maladaptive response to glomerular hypertrophy or hyperfiltration. This includes disorders associated with reduced kidney mass and/or renal vasodilation, such as unilateral renal agenesis. Other secondary causes of FSGS include drugs and toxins (including heroin, interferon, and pamidronate) and viral infections (particularly coronavirus disease 2019 [COVID-19] and HIV) (table 1). (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Pathogenesis of secondary FSGS'.)

Patients with secondary FSGS typically present with slowly increasing proteinuria and kidney function impairment over time. The proteinuria in patients with secondary FSGS is often in the non-nephrotic range, serum albumin levels are usually normal, and, often, there is no peripheral edema, even when protein excretion exceeds >3.5 g/day [15-18]. Exceptions include patients with drug-associated FSGS (eg, pamidronate) or viral FSGS (eg, collapsing HIV-associated nephropathy), who can present with the nephrotic syndrome. (See "Overview of kidney disease in patients with HIV", section on 'HIV-associated nephropathy' and "Collapsing focal segmental glomerulosclerosis (collapsing glomerulopathy)", section on 'Bisphosphonates and other drugs'.)

Why patients with secondary FSGS do not develop hypoalbuminemia is unknown. It is possible that the very slow appearance of proteinuria observed in secondary FSGS may allow for compensatory mechanisms to counterbalance the loss of urinary protein.

Secondary FSGS is generally associated with segmental (<80 percent) podocyte foot process effacement on EM examination of the kidney biopsy. (See 'Pathology' below.)

Genetic FSGS — FSGS lesions that develop in patients with mutations in genes encoding podocyte or glomerular basement membrane proteins are classified as genetic FSGS (table 2). (See "Focal segmental glomerulosclerosis: Genetic causes".)

Patients with genetic forms of FSGS may present with a wide range of clinical features, depending upon the particular genetic mutation involved. Most patients with childhood-onset genetic FSGS have autosomal recessive mutations that generally have full penetrance and present with or progress to severe nephrotic syndrome. By contrast, adult-onset genetic FSGS is typically inherited as autosomal dominant disease with variable penetrance, and patients usually have proteinuria of <5 g/day and more slowly progressive chronic kidney disease (CKD). However, there are limited data on the clinical presentation of adult-onset genetic FSGS, and it remains unclear if patients have nephrotic-range proteinuria or nephrotic syndrome [19].

Findings suggestive, but not diagnostic, of genetic FSGS include a family history of proteinuria and/or consanguinity; a documented lesion of FSGS; and disease onset in infancy or early childhood [20].

Glucocorticoid resistance is a consistent feature among patients, particularly children, with monogenic forms of FSGS [21] although this may also be seen in patients with primary FSGS. However, the predictive value of glucocorticoid resistance for genetic FSGS in adults is uncertain, and a small proportion of patients who have FSGS-associated mutations in a few selective genes may respond to glucocorticoid therapy, although lasting complete remissions are rarely seen [22]. A case of adult-onset FSGS with glucocorticoid-dependent nephrotic syndrome caused by a novel TBC1D8B variant has also been reported [23]; whether the response to glucocorticoids was coincidental or a result of the variant is difficult to establish. "Genetic," glucocorticoid-sensitive FSGS may not be a simple Mendelian disorder but may be influenced by a number of modifying genes and environmental factors, which may play a role in addition to the particular gene mutation [22]. This is particularly important in adult patients presenting with full nephrotic syndrome (not just nephrotic-range proteinuria), an FSGS lesion on kidney biopsy, and a potential genetic variant. (See "Focal segmental glomerulosclerosis: Genetic causes", section on 'Clinical presentation'.)

A discussion of the specific forms of genetic FSGS in adults and children is presented separately:

(See "Focal segmental glomerulosclerosis: Genetic causes".)

(See "Congenital nephrotic syndrome".)

(See "Steroid-resistant nephrotic syndrome in children: Etiology".)

FSGS of undetermined cause — Despite extensive evaluation (including genetic testing), a clear etiology cannot be identified in many patients with an FSGS lesion. Such patients are considered to have FSGS of undetermined cause (FSGS-UC). The clinical features and EM findings on kidney biopsy of patients with FSGS-UC are similar to those of patients with secondary FSGS [3]. One study found that the underlying cause remained unknown in more than 60 percent of patients with the features of secondary FSGS [3,24]. (See 'Secondary FSGS' above.)

PATHOLOGY

Characteristic histologic features — The characteristic histologic features of FSGS are described below.

Light microscopy – FSGS lesions are characterized by segmental consolidation of capillary loops with obliteration of the capillary lumen. FSGS lesions are often accompanied by hyalinosis, macrophage infiltration of the sclerosed tufts, and adhesion of the sclerosed loops to the Bowman capsule. Protein reabsorption granules can be present in the podocytes overlying the FSGS lesion.

On light microscopy (LM), the histologic findings are generally indistinguishable between primary and secondary FSGS, except in patients with the collapsing variant of FSGS. (See 'Histologic variants' below.)

Immunofluorescence microscopy – Immunofluorescence (IF) usually reveals no immune deposits, except for what may represent nonspecific binding of IgM and complement (C3 and variably C1) in sclerotic lesions (picture 2).

Electron microscopy – Electron microscopy (EM) of the FSGS lesions shows collapsed capillary loops often with hyaline entrapment. Electron dense deposits are not present. Podocyte foot process effacement is a characteristic feature.

Assessment of the extent of podocyte foot process effacement by EM can help differentiate primary from secondary FSGS. Primary FSGS is associated with diffuse (≥80 percent) foot process effacement (picture 1); by comparison, this abnormality tends to be segmental (<80 percent) in secondary FSGS [3,15,25,26]. It is important to select nonsclerotic capillary tufts to accurately assess foot process effacement. Other features helpful in identifying primary FSGS include podocytes showing lysosomal vacuoles and microvillous degeneration.

In general, morphologic characteristics seen on kidney biopsy cannot distinguish between genetic and nongenetic forms of FSGS. Exceptions include the distinctive features associated with NPHS1 and actinin alpha 4 gene mutations and the disease-specific lesions of Fabry disease, Alport syndrome, and lecithin-cholesterol acyl transferase deficiency [27-30]. (See "Focal segmental glomerulosclerosis: Genetic causes", section on 'NPHS1 gene' and "Focal segmental glomerulosclerosis: Genetic causes", section on 'ACTN4 gene' and "Fabry disease: Kidney manifestations", section on 'Pathology' and "Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis)", section on 'Kidney'.)

Histologic variants — Traditionally, FSGS was classified based upon the Columbia classification, which defined five morphologic variants of the lesion of FSGS based upon LM examination [31]. Although the appearance of the glomerulus on LM, by definition, differs among these forms, they all share ultrastructural findings of podocyte alterations. The factors responsible for these different histologic variants are unknown. While the Columbia classification may have some prognostic relevance [13], it cannot reliably differentiate between primary versus secondary or genetic FSGS [14].

FSGS not otherwise specified (NOS) – FSGS NOS, formerly called classic FSGS, is the most common histologic variant accounting for approximately 50 percent of cases. To make the histologic diagnosis of FSGS NOS, the collapsing, tip, perihilar, and cellular variants must be excluded [25].

On LM, FSGS NOS is characterized by segmental areas of mesangial collapse and sclerosis in some, but not all, glomeruli (picture 3A-B) [25]. Sclerotic changes occur first in juxtamedullary glomeruli and therefore may be missed in superficial biopsies that only contain cortex. Mild mesangial hypercellularity and partial occlusion of the capillary lumens by hyaline deposits are commonly seen. The latter represent the insudation of plasma proteins into the abnormally permeable glomerular capillary wall [25,26].

Collapsing variant – Collapsing FSGS, which can be induced by HIV infection or other conditions (such as COVID-19, parvovirus B19 infection, drugs, lupus, hemophagocytic syndrome) or may be idiopathic, is characterized by collapse and sclerosis of the entire glomerular tuft, rather than segmental injury (picture 4). Given its unique pathology, some investigators feel that this variant should be called collapsing glomerulopathy and not be considered a form of FSGS. (See "HIV-associated nephropathy (HIVAN)" and "Collapsing focal segmental glomerulosclerosis (collapsing glomerulopathy)".)

Collapsing FSGS often presents with more severe nephrotic syndrome and greater kidney function impairment than FSGS NOS. However, some patients with collapsing FSGS, despite having massive proteinuria, do not present with edema, which may be due to the rapid loss in glomerular filtration rate in these patients. Affected patients are frequently resistant to therapy and often have a rapid progression to end-stage kidney disease (ESKD). Collapsing FSGS is most commonly seen in patients with HIV infection (HIV-associated nephropathy) and those of African ancestry, which may contribute to the worse prognosis. (See "Focal segmental glomerulosclerosis: Genetic causes", section on 'FSGS in Black patients'.)

Tip variant – The tip variant is characterized by epithelial cell injury and foam cell accumulation that occur at the "tip" of the glomerulus near the origin of the proximal tubule (picture 5) [25]. IF microscopy may show positive staining for IgM and C3 in the sclerotic lesion and in the mesangium.

The tip lesion may identify a subset of patients who are more likely to present abruptly with the nephrotic syndrome and are more likely to respond to glucocorticoid therapy than patients with the other FSGS variants [13,32-34]. In a report of 47 patients with tip lesions, glucocorticoid therapy led to complete remission in 59 percent and partial remission in 14 percent [34]. (See "Minimal change disease: Treatment in adults", section on 'Initial therapy for primary MCD'.)

Perihilar variant – The perihilar variant consists of perihilar sclerosis and hyalinosis in more than 50 percent of segmentally sclerotic glomeruli [25]. IF and EM findings with the perihilar variant are similar to those observed with FSGS NOS.

Although the perihilar form can occur with primary FSGS, it is much more frequently observed with secondary FSGS, due to processes associated with increased glomerular capillary pressure, such as renal agenesis or other causes of reduced nephron number. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Reduced kidney mass'.)

Cellular variant – The cellular variant is characterized by the presence of at least one glomerulus with segmental endocapillary hypercellularity that occludes the capillary lumen. Other glomeruli may exhibit findings consistent with FSGS NOS. Diffuse foot process effacement is typically seen on EM. The tip and collapsing variants must be excluded histologically to make a diagnosis of the cellular variant [25].

Some claim that the cellular variant is characterized by severe proteinuria. At least some such cases may represent collapsing FSGS in which sampling limitations result in an inability to detect at least one glomerulus with collapsing changes. The combination of severe nephrotic syndrome and acute kidney injury would strongly suggest collapsing FSGS. Some pathologists think that the cellular and collapsing variants are the same lesion.

Distinguishing FSGS from focal global glomerulosclerosis — The lesion of FSGS must be distinguished from the lesion of focal global glomerulosclerosis (FGGS), or more appropriately named "global glomerulosclerosis," which is frequently a manifestation of normal aging and/or hypertension and can be superimposed on a lesion of FSGS, particularly in older patients [35]. In contrast with FSGS, in which sclerosis is limited to only portions of involved glomeruli, the sclerosis of FGGS involves entire glomerular tufts. Tubulointerstitial fibrosis and vascular sclerosis are often present in the kidney biopsy. Glomerulomegaly, which can be seen in patients with FSGS, is usually absent. There is minimal or no foot process effacement in unaffected glomeruli [21].

Patients with FGGS have variable degrees of proteinuria and are typically non-nephrotic, although nephrotic-range proteinuria, but not nephrotic syndrome, has been reported [36]. Similar to FSGS, FGGS is a histopathologic lesion and not a disease and can be also seen superimposed in a number of other glomerular diseases, such as membranous nephropathy [37].

Distinguishing FSGS from minimal change disease — The lesion of FSGS must be distinguished from that of minimal change disease since both can present similarly with massive proteinuria, widespread podocyte foot process effacement, and minimal or no complement or immunoglobulin deposits. It has been hypothesized that minimal change disease and primary FSGS are part of the same disease spectrum, where both are associated with circulating permeability factors, but primary FSGS represents a more advanced and often more therapy-resistant phenotype [38]. This is discussed in more detail elsewhere. (See "Minimal change disease: Etiology, clinical features, and diagnosis in adults", section on 'Distinguishing MCD from primary FSGS'.)

EVALUATION OF THE PATIENT WITH AN FSGS LESION — FSGS is a histologic lesion and not a specific disease entity. The identification of an FSGS lesion in a kidney biopsy of a patient with proteinuria does not establish a specific diagnosis; rather, it should prompt the clinician to pursue a thorough evaluation to determine the underlying cause of the FSGS lesion. We use a systematic approach that takes into account clinical and pathologic features of the patient to differentiate between primary, secondary, and genetic forms of FSGS (algorithm 1) [14,21,39].

Differentiating between primary, secondary, and genetic forms of FSGS has important therapeutic and prognostic implications. Historically, approximately 50 to 60 percent of patients with presumed primary FSGS responded to immunosuppressive agents such as glucocorticoids or calcineurin inhibitors (CNIs). However, as discussed above, many of the patients initially "labelled" as having primary FSGS were likely misclassified as such since in many instances, the presence of nephrotic syndrome was not a prerequisite for the diagnosis and results of electron microscopic (EM) examination were not provided. In addition, some patients who were resistant to immunosuppression may have had genetic forms of FSGS [40].

Clinical assessment — In all patients with an FSGS lesion on kidney biopsy, we perform a history and physical examination to assess for the following clinical features:

Presence or absence of the nephrotic syndrome (ie, proteinuria >3.5 g/day, hypoalbuminemia, edema)

Risk factors for secondary FSGS, including the following:

Potential factors associated with a reduction in nephron mass (eg, history of reflux nephropathy, congenital absence or surgical removal of a kidney, low birth weight or premature birth). (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Reduced kidney mass'.)

Exposure to drugs and/or toxins associated with FSGS (eg, heroin, interferon, bisphosphonates [particularly pamidronate], anabolic steroids). (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Drugs and toxins'.)

History of viral infections (HIV, SARS-CoV-2, parvovirus B19, cytomegalovirus, Epstein-Barr virus, simian virus 40, hepatitis C). (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Viruses'.)

Prior history of inflammatory glomerular diseases (eg, IgA nephropathy, small vessel vasculitis, lupus nephritis), which can produce a nonspecific pattern of FSGS during the healing phase of focal glomerular injury.

Family history of FSGS or kidney failure of unclear etiology.

Body mass index. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Obesity'.)

Physical findings suggestive of a syndromic presentation (eg, skin lesions, deafness, neurologic abnormalities, ocular abnormalities, skeletal abnormalities, maturity onset diabetes of the young, hepatosplenomegaly, metabolic acidosis). (See "Focal segmental glomerulosclerosis: Genetic causes".)

Pathologic assessment — In all patients with an FSGS lesion on kidney biopsy, we review the findings on EM examination of the kidney biopsy to determine the degree of podocyte foot process effacement. (See 'Characteristic histologic features' above.)

EM examination of the kidney biopsy with assessment of the extent of podocyte foot process effacement has been shown to help differentiate primary from secondary FSGS. Primary FSGS is associated with diffuse foot process effacement (picture 1); by comparison, this abnormality tends to be segmental in the secondary forms [3,15,25,26].

In a study of 46 patients with an FSGS lesion, patients were divided by the degree of foot process effacement observed on kidney biopsy [3]. Patients were categorized as having diffuse (≥80 percent) or limited (<80 percent) foot process effacement. Compared with patients with limited foot process effacement, those with diffuse foot process effacement without an identifiable cause had lower serum albumin levels and higher proteinuria and were more likely to have nephrotic syndrome on presentation (100 versus 4 percent). Based upon these results, patients who presented with diffuse foot process effacement without an identifiable cause and nephrotic syndrome were classified as primary FSGS. Patients with segmental foot process effacement, with or without an identifiable cause, or diffuse foot process effacement due to an identifiable cause were classified as secondary FSGS.

In a systematic histologic study, the mean percentage of the glomerular surface area affected by foot process effacement was 65 percent in primary FSGS versus 25 percent in FSGS due to reflux nephropathy and 20 percent in obesity-related disease [25]. Foot process effacement was greatest (82 to 89 percent) in the most severe form, collapsing FSGS. (See "Collapsing focal segmental glomerulosclerosis (collapsing glomerulopathy)", section on 'Pathology'.)

EM examination is required for proper evaluation of a lesion of FSGS revealed by light microscopy (LM). In regions of the world where EM is not routinely performed or available and the degree of podocyte foot process effacement cannot be assessed, our suggested approach would be to classify patients clinically, based upon the presence or absence of full nephrotic syndrome (nephrotic-range proteinuria is not enough). Patients with nephrotic syndrome who achieve remission with immunosuppressive treatment can be given a presumed diagnosis of primary FSGS. In patients with nephrotic syndrome who fail to respond to immunosuppressive therapy, it is more difficult to make a diagnosis because such patients could have primary FSGS, genetic FSGS, or another underlying condition (eg, fibrillary glomerulonephritis or amyloidosis), the diagnosis of which would benefit from EM examination or selective additional staining (eg, DnaJ heat shock protein family member B9 [DNAJB9] if fibrillary glomerulonephritis is suspected or Congo red if amyloidosis is suspected).

In patients with nephrotic syndrome, if EM is available, but there are no glomeruli in the initial biopsy specimen for EM examination, and the patient does not respond to immunosuppressive therapy, then a repeat kidney biopsy is indicated.

Differentiating between primary, secondary, and genetic FSGS — Most patients with primary or secondary FSGS can be distinguished by the presence or absence of the nephrotic syndrome, the presence of identifiable risk factors for secondary FSGS, and the degree of podocyte foot process effacement visualized by EM examination of the kidney biopsy (algorithm 1). (See 'Clinical assessment' above and 'Pathologic assessment' above.)

However, these clinicopathologic features do not always identify patients with genetic causes of FSGS. Thus, in patients who cannot be classified by clinicopathologic assessment, genetic testing, if available, should be considered to screen for monogenic forms of FSGS. In addition, in patients with an FSGS lesion, the presence of a family history of chronic kidney disease (CKD) or end-stage kidney disease (ESKD) or physical findings suggestive of a syndromic presentation (eg, skin lesions, deafness, neurologic abnormalities, ocular abnormalities, skeletal abnormalities, maturity onset diabetes of the young, hepatosplenomegaly, metabolic acidosis) should prompt genetic testing. (See "Focal segmental glomerulosclerosis: Genetic causes", section on 'Indications for genetic testing'.)

As discussed above, patients with an FSGS lesion and no clear etiology despite extensive evaluation are considered to have FSGS of undetermined cause (FSGS-UC). (See 'FSGS of undetermined cause' above.)

Patients with nephrotic syndrome — Patients with an FSGS lesion who present with the nephrotic syndrome (ie, urine protein excretion >3.5 g/day and hypoalbuminemia) and have no identifiable risk factors for secondary FSGS (eg, drugs, viruses) most likely have presumed primary (permeability factor–related) FSGS. Our approach to establishing the diagnosis is based upon the EM examination of the kidney biopsy:

If the patient has diffuse (≥80 percent) foot process effacement on EM examination (picture 1), a diagnosis of primary FSGS is most likely since most patients with secondary FSGS have segmental (<80 percent) foot process effacement. However, genetic forms of FSGS lesions cannot be excluded with confidence. Thus, in such patients, we distinguish between primary and genetic FSGS based upon the patient's response to initial immunosuppressive therapy with glucocorticoids or a CNI. (See "Focal segmental glomerulosclerosis: Treatment and prognosis".)

In patients who respond to initial immunosuppressive therapy with glucocorticoids or a CNI, a diagnosis of primary FSGS can be established since patients with genetic forms of FSGS rarely respond to treatment with immunosuppressive agents [21]. In such patients, we do not perform genetic testing for FSGS.

In patients who do not respond to initial immunosuppressive therapy with glucocorticoids or a CNI, a diagnosis of primary FSGS or genetic FSGS may be possible. In such patients, we suggest genetic testing, if available, to screen for monogenic forms of FSGS. (See "Focal segmental glomerulosclerosis: Genetic causes".)

If the patient has segmental (<80 percent) foot process effacement on EM examination (picture 6), a secondary or genetic cause of FSGS should be suspected [41]. In patients with identifiable risk factors for secondary FSGS (eg, obesity, reflux nephropathy, reduced kidney mass, drugs, viruses), a diagnosis of secondary FSGS can be established, and we do not perform genetic testing for FSGS. In patients with no identifiable risk factors for secondary FSGS, a genetic form of FSGS may be possible, and we suggest genetic testing, if available, to screen for monogenic forms of FSGS. (See "Focal segmental glomerulosclerosis: Genetic causes".)

Patients without nephrotic syndrome — Patients with an FSGS lesion who present without the nephrotic syndrome (ie, urine protein excretion <3.5 g/day or nephrotic-range proteinuria and a normal serum albumin concentration) should be suspected of having a secondary or genetic cause of FSGS rather than primary FSGS. Our approach to distinguishing between secondary and genetic FSGS in these patients is based upon the EM examination of the kidney biopsy:

If the patient has diffuse (≥80 percent) foot process effacement on EM examination (picture 1), a diagnosis of genetic FSGS should be suspected since most patients with secondary FSGS have segmental (<80 percent) foot process effacement. In such patients, we suggest genetic testing, if available, to screen for monogenic forms of FSGS. (See "Focal segmental glomerulosclerosis: Genetic causes".)

If the patient has segmental (<80 percent) foot process effacement on EM examination (picture 6), a diagnosis of secondary FSGS, genetic FSGS, or FSGS of undetermined cause may be possible. In patients with identifiable risk factors for secondary FSGS (eg, drugs, viruses), a diagnosis of secondary FSGS can be established, and we do not perform genetic testing for FSGS. In patients with no identifiable risk factors for secondary FSGS, genetic testing can be considered, if available, to screen for monogenic forms of FSGS. (See "Focal segmental glomerulosclerosis: Genetic causes".)

SUMMARY AND RECOMMENDATIONS

Overview – Focal segmental glomerulosclerosis (FSGS) is a histologic lesion, rather than a specific disease entity, that is commonly found to underlie the nephrotic syndrome in adults and children. FSGS is characterized by the presence of sclerosis in parts (segmental) of some (focal) glomeruli on light microscopic (LM) examination of a kidney biopsy specimen. (See 'Introduction' above.)

Classification and clinical features – FSGS can be classified into the following forms, based upon clinical presentation and pathologic findings on kidney biopsy:

Primary FSGS (also known as permeability factor–related FSGS), which most often presents with the nephrotic syndrome. (See 'Primary FSGS' above.)

Secondary FSGS, which most often presents with non-nephrotic proteinuria and, commonly, some degree of kidney function impairment. This category most commonly refers to FSGS that develops as a maladaptive response to glomerular hypertrophy or hyperfiltration. This includes disorders associated with a reduced kidney mass and/or renal vasodilation, such as unilateral renal agenesis. Other secondary causes of FSGS include drugs and toxins (including heroin, interferon, and pamidronate) and viral infections (particularly COVID-19 and HIV). (See 'Secondary FSGS' above.)

Genetic FSGS, which may present early in childhood with massive proteinuria and nephrotic syndrome or in adolescence or adulthood with less severe proteinuria. (See 'Genetic FSGS' above.)

FSGS of undetermined cause, in which clinical presentation and electron microscopic (EM) findings on biopsy are similar to those in patients with secondary FSGS, but a clear etiology cannot be determined despite extensive evaluation, including a comprehensive genetic analysis. (See 'FSGS of undetermined cause' above.)

Pathology – On LM, FSGS lesions are characterized by segmental consolidation of capillary loops with obliteration of the capillary lumen. FSGS lesions are often accompanied by hyalinosis, macrophage infiltration of the sclerosed tufts, and adhesion of the sclerosed loops to the Bowman capsule. Immunofluorescence (IF) usually reveals no immune deposits, except for what may represent nonspecific binding of IgM and complement (C3 and variably C1) in sclerotic lesions. EM of the FSGS lesions shows collapsed capillary loops often with hyaline entrapment; electron dense deposits are not present. Podocyte foot process effacement is a characteristic feature. (See 'Pathology' above.)

Evaluation of the patient with an FSGS lesion – The identification of an FSGS lesion in a kidney biopsy of a patient with proteinuria does not establish a specific diagnosis; rather, it should prompt the clinician to pursue a thorough evaluation to determine the underlying cause of the FSGS lesion. We use a systematic approach that takes into account clinical and pathologic features of the patient to differentiate between primary, secondary, and genetic forms of FSGS (algorithm 1). Most patients with primary or secondary FSGS can be distinguished by the presence or absence of the nephrotic syndrome, the presence of identifiable risk factors for secondary FSGS, and the degree of podocyte foot process effacement visualized by EM examination of the kidney biopsy. (See 'Evaluation of the patient with an FSGS lesion' above.)

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Topic 3049 Version 46.0

References

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