INTRODUCTION — 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 [1-7]. FSGS is characterized by the presence of sclerosis in parts (segmental) of at least one glomerulus (focal) in the entire kidney biopsy specimen, when examined by light microscopy (LM), immunofluorescence (IF), or electron microscopy (EM).

The term "FSGS" is somewhat misleading, however, since the lesions of FSGS are not as focal in distribution as the name suggests. In experimental models of FSGS, for example, nearly all glomeruli have sclerotic lesions on three-dimensional morphometric analysis, but LM examination reveals only a limited number of glomeruli with segmental sclerotic lesions. Since the average volume of a sclerotic lesion in FSGS is approximately 12.5 percent of the total glomerular volume, evaluation of kidney biopsies by conventional single sections largely underestimates the number of sclerotic glomeruli [8]. Thus, precise quantification of sclerotic glomeruli requires three-dimensional morphometric analysis of entire glomeruli and the examination of sufficient glomeruli. A biopsy specimen containing only cortical glomeruli may underestimate the frequency of FSGS lesions in the whole kidney. In order to maximize accuracy, the diagnostic set should be comprised of consecutive sections selected from 12 to 15 routinely cut serial sections and should contain a minimum of eight glomeruli [8-10]. Kidney biopsies with few glomeruli (ie, fewer than 15) cannot confidently exclude the diagnosis of FSGS, and, due to sampling error, some cases will be misclassified as minimal change disease. (See "Minimal change disease: Etiology, clinical features, and diagnosis in adults", section on 'Distinguishing MCD from primary FSGS'.)

The lesion of FSGS can be classified into primary, secondary, genetic, and unknown forms. FSGS arises as a consequence of multiple pathways either individually or collectively resulting in injury to the podocyte, hence the term "podocytopathy." In primary FSGS, a putative circulating factor that is toxic to the podocyte causes generalized podocyte dysfunction. Secondary FSGS generally occurs as an adaptive phenomenon that results from a reduction in nephron mass, or direct toxicity from drugs or viral infections. FSGS can also be caused by a number of genetic mutations in genes that code for proteins expressed in podocytes and at the slit diaphragm. Finally, in a number of patients with an FSGS lesion, clinical presentation and 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. These patients should be classified as having FSGS due to unknown cause, rather than "idiopathic" FSGS. The presence of an FSGS lesion in a kidney biopsy by itself does not establish a diagnosis but should initiate an evaluation to identify a specific etiology, since distinguishing between the different forms of FSGS has important implications for treatment and prognosis.

The lesion of FSGS must also be distinguished from the lesion of focal global glomerulosclerosis (FGGS), which is frequently a manifestation of normal aging and can be superimposed on a lesion of FSGS, particularly in older patients [11].

The epidemiology and classification of FSGS will be reviewed in this topic. The pathogenesis, genetic causes, clinical features, diagnosis, and treatment of FSGS and 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 [3]. 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 HIV), an 11-fold increase [3]. The lifetime risk of ESKD was fourfold higher in Black patients compared with White patients and Asian patients 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 [12].

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) [13]. 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 A (IgA) nephropathy (9.6 percent), and vasculitis (6.8 percent), with FSGS occurring in <5 percent of cases [14,15].

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 nephropathy, and FSGS as the most common glomerular diseases [12]. This study also separately analyzed the incidence of 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 (or undiagnosed genetic), not primary, FSGS [12]. 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 'Severe obesity'.)

CLASSIFICATION — FSGS can be classified into the following etiologies, based upon the known and/or postulated causes of this histologic pattern [9,16]:

●Primary FSGS, which most often presents with the nephrotic syndrome. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Pathogenesis of primary FSGS'.)

●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 an adaptive response to glomerular hypertrophy or hyperfiltration. This includes disorders associated with a reduced renal 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 HIV) (table 1). (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Pathogenesis of secondary FSGS'.)

●Genetic causes of FSGS, which may present early in childhood with massive proteinuria and nephrotic syndrome or in adolescence or adulthood with less severe proteinuria. (See "Focal segmental glomerulosclerosis: Genetic causes".)

●FSGS of unknown cause, in which clinical presentation and electron microscopy (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.

Differentiating primary, secondary, and genetic FSGS has important therapeutic and prognostic implications. Patients with primary FSGS are generally treated with immunosuppressive medications, whereas those with secondary and genetic FSGS are best treated with therapies directed at the underlying cause (eg, weight reduction for obesity), if possible, and those that lower the intraglomerular pressure, such as blockers of the angiotensin II system. However, in clinical practice, the distinction among the different forms of FSGS is not always straightforward, and many patients are misdiagnosed and undergo unnecessary immunosuppressive treatment. (See "Focal segmental glomerulosclerosis: Treatment and prognosis" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults", section on 'Renin-angiotensin system inhibitors'.)

In patients who are found to have an FSGS lesion by light microscopy (LM) on kidney biopsy, a combination of clinical and pathologic features can be used to distinguish among those with primary, secondary, and genetic FSGS and FSGS of unknown cause. (See 'Approach to differentiating primary, secondary, and genetic FSGS' below.)

Clinical features — Patients with primary FSGS most commonly present with the acute onset of the nephrotic syndrome and the associated features of peripheral edema, hypoalbuminemia, and, usually, high-grade (>3.5 g/day) proteinuria [17-21]. Studies evaluating the clinical characteristics of patients with primary FSGS have found that 70 to nearly 100 percent present with nephrotic syndrome [17,18,22,23]. Hematuria is common (approximately 50 percent of patients) and hypertension is present in approximately 20 percent of cases [17,18,22,23]. An elevated serum creatinine may be seen in 25 to 50 percent of patients at presentation [17,18,22,23] 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'.)

By contrast, 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 [24-27]. 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 not associated with HIV infection", section on 'Bisphosphonates and other drugs'.)

The following studies have evaluated the differences in clinical features between primary and secondary FSGS:

●The largest series evaluating the clinical differences between secondary and primary FSGS included 71 patients with obesity-related, secondary FSGS and 50 patients with idiopathic FSGS [24]. The patients with obesity-related disease had the following significant differences: a lesser degree of proteinuria (4.1 versus 6.9 g/day), lower prevalence of the nephrotic syndrome (6 versus 54 percent), a higher serum albumin (3.9 versus 2.9 g/dL), a lower serum cholesterol (229 versus 335 mg/dL [5.9 versus 8.7 mmol/L]), and a lower rate of edema (35 versus 68 percent).

●The relationships among hypoalbuminemia, peripheral edema, and primary and secondary FSGS were also evaluated in a study of 37 patients with an FSGS lesion and nephrotic-range proteinuria (>3.5 g/day), of whom 19 had a serum albumin below 3 g/dL [27]. Primary FSGS was defined as idiopathic disease (rather than by histologic criteria), while secondary FSGS was thought to result from the presence of massive obesity, vesicoureteral reflux, or renal mass reduction. Only 2 of 18 patients with a normal serum albumin concentration, compared with all with hypoalbuminemia, had primary FSGS. In addition, all patients with, but none without, hypoalbuminemia had peripheral edema.

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.

Distinguishing familial or genetic FSGS from primary FSGS can be very difficult or even impossible without the use of comprehensive genomic analysis, and familial disease may account for a significant proportion of patients with glucocorticoid-resistant FSGS, at least in children [28,29]. 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 patients with adult-onset genetic FSGS, and it remains unclear if patients have nephrotic-range proteinuria or nephrotic syndrome [30]. (See "Congenital and infantile nephrotic syndrome", section on 'Congenital Nephrotic Syndrome of Finnish type' and "Congenital and infantile nephrotic syndrome", section on 'Congenital Nephrotic Syndrome and NPHS2 mutations'.)

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 [31]. Thus, a detailed family history is of paramount importance in the evaluation of such patients. (See 'Evaluation of the patient with an FSGS lesion' below.)

Glucocorticoid resistance is a consistent feature among patients, particularly children, with monogenic forms of FSGS [16], although this may also been seen in patients with primary FSGS. In a large cohort study of patients with familial and sporadic steroid-resistant nephrotic syndrome (SRNS), a monogenic form of FSGS was detected in 29.5 percent of families with SRNS that manifested before 25 years of age [32]. However, the predictive value of glucocorticoid resistance for genetic FSGS in adults is uncertain, and a small proportion of adults who have FSGS-associated mutations may respond to glucocorticoid therapy [33], although lasting complete remissions are rarely seen. (See "Steroid-resistant idiopathic nephrotic syndrome in children: Management".)

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

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

●(See "Congenital and infantile nephrotic syndrome".)

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

Pathologic features — On LM, the histologic findings are indistinguishable between primary and secondary FSGS, except in patients with the collapsing variant of FSGS. 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 [12,24,34,35].

●In a study of 46 patients with an FSGS lesion, patients were divided by the degree of foot process effacement observed on kidney biopsy [12]. 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 [34]. Foot process effacement was greatest (82 to 89 percent) in the most severe form, collapsing FSGS. (See "Collapsing focal segmental glomerulosclerosis not associated with HIV infection", section on 'Pathology'.)

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 [36-39].

●(See "Focal segmental glomerulosclerosis: Genetic causes", section on 'NPHS1 gene'.)

●(See "Focal segmental glomerulosclerosis: Genetic causes", section on 'Actinin alpha 4 gene'.)

●(See "Fabry disease: Kidney manifestations", section on 'Pathology'.)

●(See "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 [40].

The histologic variants of FSGS include [9]:

●FSGS not otherwise specified (NOS), formerly called classic FSGS, is the most common form.

●Collapsing variant, although some argue that this should be considered a separate entity rather than a variant of FSGS.

●Tip variant.

●Perihilar variant.

●Cellular variant.

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.

The histologic variants of FSGS based on LM alone cannot reliably differentiate between primary versus secondary or genetic FSGS. This was shown in a retrospective analysis of 41 patients with an FSGS lesion, 18 (44 percent) of whom had evidence of nephrotic syndrome [23]. All of the patients with nephrotic syndrome had diffuse foot process effacement ranging from 80 to 100 percent (mean of 96 percent), whereas 22 of the 23 patients without nephrotic syndrome had segmental foot process effacement ranging from 20 to 60 percent (mean of 48 percent). Patients with nephrotic syndrome and diffuse foot process effacement who did not have a secondary cause of FSGS (such as viral infection or drugs) were classified as having primary FSGS; those without nephrotic syndrome and with segmental foot process effacement were classified as having secondary FSGS. There was no correlation between the histologic variant of FSGS by LM and the presence or absence of nephrotic syndrome. While the majority of patients had FSGS NOS, the presence of an FSGS NOS lesion did not discriminate patients with or without nephrotic syndrome. Similarly, there were no significant differences in the frequency of the perihilar or tip variants among patients with or without nephrotic syndrome. Although glomerulomegaly was more frequent among patients without nephrotic syndrome (70 percent), it was detected in 33 percent of those with nephrotic syndrome, indicating that glomerulomegaly is not limited to secondary FSGS.

Prognostic relevance of histologic variants — The prognosis in all histologic variants of FSGS is primarily determined by the response to immunosuppressive therapy [41,42]. If patients respond to immunosuppressive treatment and achieve remission, the long-term renal prognosis is excellent. If they do not respond to treatment, then the prognosis is generally poor, regardless of the FSGS variant.

Some studies suggest that the histologic classification can predict outcomes. This was illustrated in a retrospective analysis of 197 patients with an FSGS lesion [22]. Three percent had the cellular variant, 11 percent collapsing, 17 percent tip lesion, 26 percent perihilar, and 42 percent FSGS NOS. At a median of 1.8 years, 23 percent were on dialysis. Compared with the overall cohort, patients with collapsing FSGS had worse one- and three-year renal survival (74 versus 86 percent and 33 versus 67 percent, respectively), while patients with the tip, perihilar, and FSGS NOS variants had a three-year survival of 76, 75, and 65 percent, respectively.

The following additional observations were reported:

●Patients with the collapsing and tip variants had higher levels of proteinuria.

●Patients with the tip lesion had the least tubulointerstitial injury and best kidney function, and almost 50 percent achieved complete remission with glucocorticoid therapy.

●Patients with the collapsing variant had the worst outcomes, with lower rates of renal survival at both one year (74 versus 86 percent for the remaining patients) and three years (33 versus 67 percent).

This study supports a more favorable prognosis associated with the tip variant and a more unfavorable prognosis associated with the collapsing variant. However, it is important to emphasize again that prognosis is dependent upon the response to immunosuppressive therapy. Patients with collapsing FSGS that achieve remission with treatment typically have an excellent prognosis. On the other hand, patients with a tip lesion that do not respond to therapy have a poor prognosis and inevitably progress to end-stage kidney disease (ESKD). (See 'Tip variant' below and 'Collapsing variant' below.)

FSGS not otherwise specified (NOS) — To make the histologic diagnosis of FSGS NOS, the collapsing, tip, perihilar, and cellular variants must be excluded [34].

On LM, FSGS NOS is characterized by segmental areas of mesangial collapse and sclerosis in some, but not all, glomeruli (picture 2A-B) [34]. 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 [34,35].

Immunofluorescence (IF) microscopy usually reveals no immune deposits, except for what may represent nonspecific binding of immunoglobulin M (IgM) and complement (C3 and variably C1) in sclerotic lesions (picture 3). Very weak mesangial deposition of IgM may also be observed [34]. (See "Minimal change variants: Mesangial proliferation, IgM nephropathy, C1q nephropathy".)

The clinical significance of IgM and C3 deposition was evaluated in a study of 106 patients with primary FSGS [43]. Glomerular IgM deposition (particularly within sclerotic lesions) was found in 58 patients (55 percent); C3 deposits were detected in 35 percent of patients with IgM deposition but none of the patients without IgM deposition. The response to immunosuppressive therapy was similar in patients with and without IgM deposition; however, the rate of complete or partial remission in patients with combined IgM and C3 deposition was significantly lower than that of patients with IgM without C3 deposition (59 versus 92 percent). Refractory nephrotic syndrome was also more common among patients with C3 deposition compared with those without C3 deposition. Further studies are needed to evaluate the role of IF staining in predicting prognosis in patients with the lesion of FSGS NOS.

Collapsing variant — Collapsing FSGS, which can be induced by HIV infection or other conditions (such as coronavirus disease 2019 [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 not associated with HIV infection".)

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 (GFR) in these patients. Affected patients are frequently resistant to therapy and often have a rapid progression to ESKD. Collapsing FSGS is most commonly seen in patients with HIV infection (HIV-associated nephropathy [HIVAN]) 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) [34]. 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 [22,44-46]. In a report of 47 patients with tip lesions, glucocorticoid therapy led to complete remission in 59 percent and partial remission in 14 percent [46]. (See "Minimal change disease: Treatment in adults", section on 'Initial therapy for primary MCD'.)

Insight into the pathologic and clinical evolution of the glomerular tip lesion was reported in a retrospective study of two series of patients with FSGS who had more than one kidney biopsy over time (sometimes including autopsy kidneys) [47]:

●Among 24 patients with an initial tip lesion who underwent a second biopsy for persistent or relapsing proteinuria, 17 subsequently had findings of FSGS NOS, while seven continued to only have the tip lesion.

●Among patients with an original diagnosis of FSGS prior to transplantation, recurrent nephrotic syndrome was noted in seven renal allografts; six revealed the tip lesion.

●Patients with a tip lesion at initial presentation, compared with those who had other types of FSGS, were more likely to have a complete response to glucocorticoids. However, those patients who did not respond to glucocorticoids were more likely to progress to ESKD.

Given these findings, the authors speculated that, rather than being unique, the tip lesion may be an early form of FSGS NOS in some cases and a variant of minimal change disease in others.

Perihilar variant — The perihilar variant consists of perihilar sclerosis and hyalinosis in more than 50 percent of segmentally sclerotic glomeruli [34]. 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 renal 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 [34].

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 (AKI) would strongly suggest collapsing FSGS. Some pathologists think that the cellular and collapsing variants are the same lesion.

CONFIRMATION OF AN FSGS LESION

Distinguishing FSGS from focal global glomerulosclerosis (FGGS) — 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 [11]. 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 [16].

Patients with FGGS have variable degrees of proteinuria and are typically non-nephrotic, although nephrotic-range proteinuria, but not nephrotic syndrome, has been reported [48]. 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 [49].

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 proteinuria, 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 [50].

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'.)

Distinguishing FSGS from healing of prior inflammatory injury — A nonspecific pattern of FSGS can occur during the healing phase of any focal glomerular injury due, for example, to active IgA nephropathy, small vessel vasculitis, or lupus nephritis. In these settings and perhaps in other kidney diseases as well, release of transforming growth factor (TGF)-beta from platelets and glomerular cells may play a role in progressive kidney injury [51]. TGF-beta stimulates extracellular matrix production, inhibits matrix degradation, and facilitates the adhesion of inflammatory cells to the matrix; each of these changes can promote the development of glomerulosclerosis [52].

EVALUATION OF THE PATIENT WITH AN FSGS LESION — As previously stated, 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. (See 'Classification' above.)

Differentiating between primary, secondary, and genetic forms of FSGS has important therapeutic and prognostic implications. Historically, approximately 50 to 60 percent of patients with primary FSGS responded to immunosuppressive agents such as glucocorticoids or calcineurin inhibitors. 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 [53].

In evaluating the patient with a confirmed FSGS lesion (see 'Confirmation of an FSGS lesion' above), we use a systematic approach that takes into account clinical and histologic features of the patient to differentiate between primary, secondary, and genetic forms of FSGS (algorithm 1) [16,23,54].

Initial evaluation — Patients presenting with proteinuria with or without kidney dysfunction should undergo a thorough evaluation for glomerular disease and other disorders, as discussed in more detail separately. Such an evaluation generally involves laboratory testing and, in certain patients, a kidney biopsy. (See "Glomerular disease: Evaluation and differential diagnosis in adults", section on 'Proteinuria'.)

In patients with proteinuria who undergo kidney biopsy and are found to have an FSGS lesion, we perform the following initial evaluation:

●History and physical examination, including an assessment of 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 renal 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 (eg, HIV, parvovirus B19, cytomegalovirus, Epstein-Barr virus, simian virus 40, hepatitis C) (see "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Viruses')

•Prior history of inflammatory glomerular disease (eg, IgA nephropathy, small vessel vasculitis, lupus nephritis) (see 'Distinguishing FSGS from healing of prior inflammatory injury' above)

•Family history of FSGS or kidney failure of unclear etiology (see "Focal segmental glomerulosclerosis: Genetic causes")

•Body mass index (BMI) (see "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Severe obesity')

•Blood pressure

•Edema

•Physical findings suggestive of a syndromic presentation (eg, hearing loss, skin or eye abnormalities, cardiac dysfunction, hepatosplenomegaly)

●Review of the findings on electron microscopic (EM) examination of the kidney biopsy with determination of the degree of podocyte foot process effacement. EM examination is an absolute requirement for proper evaluation of a lesion of FSGS revealed by light microscopy (LM).

Approach to differentiating primary, secondary, and genetic FSGS — Our approach to differentiating between primary, secondary, and genetic forms of FSGS is based primarily upon the clinical and pathologic assessment of the patient with an FSGS lesion (algorithm 1) (see 'Initial evaluation' above). 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. 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. Finally, it should be recognized that in many patients with an FSGS lesion a clear etiology cannot be determined despite extensive evaluation. In most of these patients clinical presentation and EM findings on biopsy are similar to patients with secondary (maladaptive) FSGS. One study found that the underlying cause remained unknown in more than 60 percent of patients with the features of secondary FSGS [12]. (See "Focal segmental glomerulosclerosis: Genetic causes", section on 'Indications for genetic testing'.)

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 nephrotic syndrome. 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.

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.

Patients with nephrotic syndrome — Patients with an FSGS lesion who present with the nephrotic syndrome (ie, urine protein excretion >3.5 g/day and serum albumin <3.5 g/dL, when measured by bromocresol green, or <3.0 g/dL, when measured by bromocresol purple) and have no identifiable risk factors for secondary FSGS (eg, drugs, viruses) most likely have primary (permeability factor-mediated) 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 calcineurin inhibitor. (See "Focal segmental glomerulosclerosis: Treatment and prognosis".)

•In patients who respond to initial immunosuppressive therapy with glucocorticoids or a calcineurin inhibitor, a diagnosis of primary FSGS can be established since patients with genetic forms of FSGS rarely respond to treatment with immunosuppressive agents [16]. 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 calcineurin inhibitor, 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. 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 distinguish 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 unknown 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

●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. The term "FSGS" is somewhat misleading, however, since the lesions of FSGS are not as focal or segmental in distribution as the name suggests. (See 'Introduction' above.)

●FSGS is a common histopathologic lesion among adults with nephrotic syndrome in the United States, accounting for 35 percent of all cases and over 50 percent among African Americans. By comparison, FSGS is a less common cause of nephrotic syndrome in other countries. 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. (See 'Epidemiology' above.)

●FSGS can be classified into the following etiologies, based upon the known and/or postulated causes of this histologic pattern (see 'Classification' above):

•Primary (permeability factor-related) FSGS, which most often presents with the nephrotic syndrome.

•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 an adaptive 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 HIV).

•Genetic causes of FSGS, which may present early in childhood with massive proteinuria and nephrotic syndrome or in adolescence or adulthood with less severe proteinuria.

•FSGS of unknown 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.

●The lesion of FSGS must be distinguished from the lesion of focal global glomerulosclerosis (FGGS), or more appropriately named "global glomerulosclerosis" (GGS), which is frequently a manifestation of normal aging and/or hypertension and can be superimposed on a lesion of FSGS, particularly in older patients. The lesion of FSGS must also be distinguished from that of minimal change disease since both can present similarly with proteinuria, podocyte foot process effacement, and minimal or no complement or immunoglobulin deposits. (See 'Confirmation of an FSGS lesion' above.)

●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. EM examination of the kidney biopsy is required for proper evaluation and classification of a lesion of FSGS revealed by LM. (See 'Evaluation of the patient with an FSGS lesion' above.)

●Differentiating between primary, secondary, and genetic forms of FSGS has important therapeutic and prognostic implications. In evaluating the patient with a confirmed FSGS lesion, we use a systematic approach that takes into account clinical and histologic features of the patient to differentiate between primary, secondary, and genetic forms of 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. (See 'Approach to differentiating primary, secondary, and genetic FSGS' above.)

However, these clinicopathologic features do not always identify patients with genetic causes of FSGS. 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 should prompt genetic testing.