Focal Segmental Glomerulosclerosis
Vivette D. D’Agati
M. Barry Stokes
Focal segmental glomerulosclerosis (FSGS) refers to a pattern of glomerular scarring that affects a subset of glomeruli (i.e., focal) and involves only a portion of the glomerular tuft (i.e., segmental) (Fig. 6.1) (1). FSGS is not a single disease but encompasses a group of distinct clinical-pathologic syndromes with diverse etiologies and disease associations. Most cases of FSGS are primary or idiopathic; these are generally characterized by
heavy proteinuria and frequent progression to end-stage renal disease (ESRD) (1). Secondary causes of FSGS include genetic defects, viral infections, drugs, toxins, and adaptive responses mediated by altered glomerular hemodynamics (referred to as glomerular hypertension) (Table 6.1). Focal and segmental glomerular scarring also occurs as a nonspecific pattern of injury in the course of progression of diverse inflammatory, proliferative, and thrombotic glomerular diseases.
heavy proteinuria and frequent progression to end-stage renal disease (ESRD) (1). Secondary causes of FSGS include genetic defects, viral infections, drugs, toxins, and adaptive responses mediated by altered glomerular hemodynamics (referred to as glomerular hypertension) (Table 6.1). Focal and segmental glomerular scarring also occurs as a nonspecific pattern of injury in the course of progression of diverse inflammatory, proliferative, and thrombotic glomerular diseases.
 FIGURE 6.1 Primary FSGS. Focal segmental distribution of glomerulosclerosis lesions. The glomerulus at the top shows a discrete segmental scar with adhesion to the Bowman capsule. The two glomeruli at the bottom of the picture are normal. (Periodic acid-Schiff [PAS], ×150.) |
Since publication of the sixth edition of Heptinstall’s Pathology of the Kidney, our understanding of the pathogenesis of FSGS has expanded and continues to be elucidated at the cellular, molecular, and genetic levels (2,3). Data from human and experimental studies indicate that podocyte injury and depletion (podocytopenia) are pivotal events in many if not all forms of FSGS and that parietal epithelial cells also play a role in the morphogenesis of the segmental lesions (1). The presence of circulating permeability factors in primary FSGS and secondary FSGS due to genetic disorders is increasingly apparent (4,5). Finally, evidence supports that the morphologic variants of primary and secondary FSGS differ with respect to their presenting clinical and demographic features, prognoses, and associations with potential pathogenetic mechanisms.
This chapter reviews the clinical-pathologic characteristics of primary FSGS and the major secondary forms of FSGS. C1q nephropathy (C1qN), an entity that often presents with nephrotic syndrome and shows histologic features of FSGS, is also discussed (6). Congenital nephrotic syndrome (CNS) and genetic conditions typically associated with diffuse mesangial sclerosis are reviewed in Chapter 5.
BACKGROUND AND HISTORY
The first morphologic depiction of FSGS lesions in patients with nephrotic syndrome was published by Fahr in 1925 (7) (Fig. 6.2). Fahr attributed the focal segmental hyalinization to capillary degeneration in patients with lipoid nephrosis. Subsequently, in a 1957 autopsy study of children with the nephrotic syndrome, Rich (8) noted that children dying acutely of infectious complications, mostly within the 1st year of diagnosis, either showed no FSGS lesions or had only a few lesions involving the juxtamedullary glomeruli, whereas children dying with uremia and hypertension displayed more extensive cortical involvement by FSGS. These findings suggested that FSGS was a progressive kidney disease that initially affected the juxtamedullary glomeruli (8). In 1970, Churg et al. (9) described the pathologic features of FSGS in children with idiopathic nephrotic syndrome for the International Study of Kidney Diseases in Children (ISKDC) and noted that FSGS was usually steroid resistant and had a poor renal prognosis. Since that time, morphologic variants of FSGS have been recognized, and numerous secondary causes of FSGS, including genetic and acquired forms, have been identified. Meanwhile, the incidence
of primary FSGS has grown, and it is now the leading cause of steroid-resistant nephrotic syndrome (SRNS) in both children and adults (10) and the most common primary glomerular disease causing ESRD in the United States (11,12).
of primary FSGS has grown, and it is now the leading cause of steroid-resistant nephrotic syndrome (SRNS) in both children and adults (10) and the most common primary glomerular disease causing ESRD in the United States (11,12).
TABLE 6.1 Etiologic classification of FSGS | ||||||||||||||||||||||||||||||||||||||||||
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 FIGURE 6.2 The first illustration of focal segmental glomerulosclerosis in a patient with nephrotic syndrome (lipoid nephrosis). Two glomeruli show segmental obliteration of capillary lumina with accumulation of matrix. (From Fahr T. Pathologische Anatomie des morbus brightii. In: Henke F, Lubarsch O, eds. Handbuch der speziellen pathologischen Anatomie und Histologie. Berlin: Springer, 1925:156.) |
Relationship of FSGS to Minimal Change Disease
Because both primary FSGS and minimal change disease (MCD) manifest the nephrotic syndrome and foot process effacement, it has been suggested that these conditions might represent a spectrum of podocytopathies that differ mainly with respect to the greater reversibility of podocyte injury in MCD. In support of this hypothesis are the findings of potential circulating permeability factors in both of these conditions and the development of either MCD or FSGS lesions in the puromycin aminonucleoside (PAN) model, depending on the cumulative dose of toxin, suggesting a related pathomechanism. The nonsclerotic glomeruli in human FSGS typically exhibit podocyte foot process effacement resembling MCD. In addition, transition from MCD-like glomerular disease (extensive foot process effacement without sclerosis) to FSGS has been noted in some sequential human biopsy samples and in the setting of recurrent FSGS following kidney transplantation (13). Of note, global glomerulosclerosis is seen with increased frequency in relapsing or steroid-dependent childhood MCD, suggesting that these sclerotic glomeruli may result from involution of immature glomeruli that may be more prone to develop global, rather than segmental, sclerosis (14). By analogy, PAN given to neonatal mice leads to impaired glomerular maturation and resorption of the underdeveloped glomeruli, possibly reflecting loss of critical podocyte functions necessary for normal glomerular maturation (15). Despite these similarities, the weight of evidence from recent immunohistochemical (16), molecular (17), and permeability factor (4,5) studies favors that MCD and FSGS are distinct entities with different pathogenesis and pathobiology (3). MCD is discussed separately in Chapter 5.
PRIMARY FSGS
Epidemiology and Clinical Presentation
The incidence of FSGS is estimated at seven cases per million per year (10). However, data from renal biopsy studies and national registries of patients with nephrotic syndrome and ESRD may be subject to detection bias, as biopsy indications are influenced by the patient’s age and clinical presentation and vary among geographic regions. Most adults with idiopathic nephrotic syndrome undergo renal biopsy on first clinical presentation because the potential causes are diverse. By contrast, in the pediatric age group, most nephrotic children will have steroid-responsive MCD; thus, a biopsy is performed only in those children who fail to respond to an empiric course of glucocorticoids or who relapse after treatment. The clinical threshold for biopsy may vary, and patients with proteinuria less than 1 g/d are more likely to undergo renal biopsy in Australia and New Zealand than in the United States and Europe (10).
The majority of children (75% to 90%) (18,19) and fewer adults (50% to 60%) with primary FSGS present with the nephrotic syndrome (i.e., nephrotic-range proteinuria, edema, hypoalbuminemia, and hypercholesterolemia); the rest have subnephrotic proteinuria. The pathophysiology of the nephrotic syndrome is discussed in detail in Chapter 5. In adults, the nephrotic syndrome is defined by urine protein excretion greater than 3.5 g/d and serum albumin levels less than 3.5 g/dL. In children with the nephrotic syndrome, urine protein excretion exceeds 1 g/m2 of body surface area per day and serum albumin is less than 2.5 g/dL. In both children and adults, serum cholesterol level exceeds 200 mg/dL and peripheral edema is present. Renal insufficiency is present at the time of biopsy in approximately 20% of children and 30% of adults; hypertension is identified in 30% of children and 45% of adults; and microhematuria is seen in 57% to 68% of cases (20). Serum complement levels are normal, and the standard serologic tests for autoimmune connective tissue diseases and viral hepatitis are negative.
The proportion of childhood nephrotic syndrome due to FSGS increases with age, from less than 10% before 6 years of age up to 50% in adolescence (21). Given that as many as 20% of primary FSGS cases are steroid responsive (20), FSGS is probably underdiagnosed in patients less than 18 years of age with nephrotic syndrome, who typically receive empiric therapy without resort to biopsy (22). In the ISKDC study of children who underwent renal biopsy between 1967 and 1974, FSGS was diagnosed in 6.9% of children with primary nephrotic syndrome (20). In more recent studies, the frequency of FSGS in children with nephrotic syndrome undergoing renal biopsy has ranged from 18% to 23%, while the incidence of nephrotic syndrome in children ranged from two to four cases per 100,000 children per year (23,24). In a study of Canadian children (most of whom were Caucasian) biopsied between 1985 and 2002, the incidence of FSGS ranged from 0.37 to 0.94 new cases per 100,000 children, with a higher incidence in more recent cases (23). Male children are more commonly affected than females (20,25,26).
In adults, the renal biopsy prevalence of primary FSGS has increased from 2.5% to 4% of all biopsies in the 1970s to 12.2% to 18.7% in the 1990s (27). In patients over 60 years of age, 5.4% of those with nephrotic syndrome had FSGS (28), while in the very elderly (greater than 80 years of age), the renal biopsy prevalence of primary FSGS was 4% (29). Between 2004 and 2008 in the United States, the incidence of ESRD caused by FSGS was 2.2%, although it is likely that FSGS also accounted for some cases of ESRD that were never biopsied and classified as either glomerulonephritis or hypertensive kidney disease (11).
Among adults with nephrotic syndrome undergoing renal biopsy, the frequency of FSGS is 10% in Asia, 20% in Europe and among North American whites, and up to 78% among North American blacks (10). In Africa, the biopsy frequency of FSGS ranges from 23% to 40% (10). Both the incidence of ESRD from FSGS and rate of progression to ESRD are higher in black children than in whites (20,30,31). In all children with ESRD, the prevalence of FSGS is 14.4%, ranging from 11.7% in whites to 23.7% in blacks (31).
The incidence of FSGS and the proportion of ESRD caused by FSGS have increased over the past few decades in both children and adults and in blacks and whites (10,21,23,30,32,33,34,35,36). This increase has been reported in some (37) but not all other countries (10) and is particularly striking in African Americans, in whom FSGS is now the leading cause of nephrotic syndrome and, in children, the leading cause of ESRD (31,38,39). The incidence of ESRD due to FSGS is approximately 5 cases per million in Caucasians and 30 to 40 cases per million in African Americans (21). The incidence of FSGS as a cause of ESRD has increased nearly fivefold in African Americans since the early 1980s. The incidence in Caucasians has also increased, albeit more slowly. This rising incidence is probably due largely to a true increase in disease incidence, as well as potential detection bias (e.g., changes in renal biopsy practice or pathologic diagnostic criteria).
Pathologic Features of FSGS
Gross Pathology
In early studies of children dying of nephrosis (some of whom presumably had primary FSGS), the kidneys were described as enlarged and swollen, with fat-filled cortices (7). This fatty appearance is attributable to the abundant lipid resorption droplets seen histologically in proximal tubular epithelial cells. In cases where FSGS has progressed to ESRD, the kidneys show bilateral symmetric shrinkage.
Light Microscopy
The “classic” lesion of FSGS consists of segmental solidification of the glomerular capillary tuft by an acellular extracellular matrix that is eosinophilic, periodic acid-Schiff (PAS) reactive, and argyrophilic (Fig. 6.3). This may be accompanied by hyalinosis, the accumulation of a glassy, eosinophilic material caused by entrapment of plasma proteins (Figs. 6.4, 6.5, 6.6). Hyalinosis lesions may contain extracellular lipid vacuoles that appear as sharply delineated, round, empty spaces. FSGS lesions are often associated with adhesion to the Bowman capsule (see Fig. 6.4), and the smallest lesions may consist of a simple synechial attachment, without prominent matrix accumulation in the underlying glomerular tuft. A single lesion (Fig. 6.7) or
multiple individual lesions (Fig. 6.8) may exist in a given glomerulus, as revealed by serial sectioning and three-dimensional reconstructions (40). Juxtamedullary glomeruli appear to be more vulnerable to developing FSGS than superficial glomeruli, likely because of their greater single-nephron glomerular filtration rate (GFR) and higher glomerular capillary pressures and flow rates (41,42).
multiple individual lesions (Fig. 6.8) may exist in a given glomerulus, as revealed by serial sectioning and three-dimensional reconstructions (40). Juxtamedullary glomeruli appear to be more vulnerable to developing FSGS than superficial glomeruli, likely because of their greater single-nephron glomerular filtration rate (GFR) and higher glomerular capillary pressures and flow rates (41,42).
 FIGURE 6.3 Primary FSGS, NOS. With a silver stain, the extracellular matrix is argyrophilic (black), whereas hyaline is pink. (Jones methenamine silver [JMS] stain, ×600.) |
 FIGURE 6.4 Primary FSGS, NOS. The left half of the glomerulus shows segmental obliteration of capillary lumina by the matrix and hyalinosis with broad adhesion to the Bowman capsule. Hyaline has a glassy, more eosinophilic appearance than the adjacent matrix material. (H&E, ×400.) |
In addition to matrix and hyaline accumulation, FSGS lesions demonstrate variable degrees of cellularity. Hypercellularity can affect the extracapillary and/or the endocapillary zones. This most commonly consists of mild swelling and hyperplasia of visceral epithelial cells, forming a single layered “cap” or “cobble-stone” appearance overlying the segmental sclerosis lesion (Figs. 6.9 and 6.10). A halolike effect of a looser pale matrix between the capped visceral cells and the original glomerular basement membrane (GBM) reflects the deposition of the extracellular matrix produced by parietal cells that migrate over the sclerotic lesions (43). In other examples, the glomerular epithelial cell hyperplasia is more exuberant with confluence of the visceral and parietal cell layers. The swollen epithelial cells often display PAS-positive cytoplasmic protein resorption droplets. Intracapillary foam
cells may be seen in areas of segmental sclerosis (Figs. 6.11 and 6.12) and are sometimes numerous, leading to expansion of the glomerular tuft (Fig. 6.13). These cells express monocyte markers, such as CD68, but it is unclear if they derive from circulating macrophages or from transdifferentiation of resident glomerular endothelial or mesangial cells.
cells may be seen in areas of segmental sclerosis (Figs. 6.11 and 6.12) and are sometimes numerous, leading to expansion of the glomerular tuft (Fig. 6.13). These cells express monocyte markers, such as CD68, but it is unclear if they derive from circulating macrophages or from transdifferentiation of resident glomerular endothelial or mesangial cells.
 FIGURE 6.5 Primary FSGS. Hyalinosis and matrix both stain pink with PAS, but hyaline has a glassy appearance. (PAS, ×400.) |
 FIGURE 6.6 Primary FSGS. Hyalinosis stains bright red and extracellular matrix stains blue with trichrome stain. (Trichrome stain, ×400.) |
 FIGURE 6.7 Primary FSGS. A single segmental lesion (arrow) with endocapillary hypercellularity and mild hyalinosis involves the periphery of the glomerular tuft. (PAS, ×400.) |
 FIGURE 6.8 Primary FSGS. Three discrete lesions (arrowheads) of the matrix and/or hyaline are present in the same glomerulus. (PAS, ×400.) |
Glomerular capillaries may also show an implosive, collapsed appearance, accompanied by severe hyperplasia of epithelial cells in the Bowman space (Fig. 6.14). In some cases, capillary collapse is accompanied by endocapillary hyper-cellularity causing expansion of the glomerular tuft (see Fig. 6.13). Segmental lesions may localize to the hilar region (vascular pole), to the paratubular region (adjacent to the origin of the proximal tubule), or have an indeterminate relationship to these landmarks in the plane of section (Figs. 6.15 and 6.16) (see Morphologic Variants of FSGS below). Focal and segmental lesions of sclerosis tend to evolve into diffuse and global lesions with chronicity. The degree of global glomerulosclerosis is variable and depends on disease severity, the timing of the biopsy, and the rate of disease progression. The finding of only global glomerulosclerosis, without segmental lesions, is nonspecific and increases with age, reflecting coexistent arterionephrosclerosis related to senescence and/or hypertension. Although the nonsclerotic glomeruli may appear normal, morphometric analysis shows an increase in the glomerular area and mesangial matrix in both childhood (44) and adult primary FSGS (45); these features are more prominent in cases of secondary adaptive FSGS (see section on Adaptive FSGS below). Glomeruli unaffected by sclerosis may exhibit diffuse podocyte swelling.
 FIGURE 6.9 Primary FSGS. There is a monolayer of podocytes overlying a sclerotic portion of a glomerulus (“cobblestone pattern”). The podocytes are cuboidal with abundant cytoplasm, vesicular nuclei, and prominent nucleoli. (PAS, ×330.) |
 FIGURE 6.10 Primary FSGS. A segmental sclerosis lesion with “capping” of overlying visceral epithelial cells. (PAS, ×400.) |
Proximal tubules often display PAS-positive protein resorption droplets and clear lipid vacuoles (Fig. 6.17). Tubular atrophy and interstitial fibrosis are often present, ranging from
mild to severe, but are generally commensurate with the degree of glomerulosclerosis (Fig. 6.18). Interstitial foam cells may be seen, either singly or in aggregates, in cases with long-standing proteinuria. In the setting of severe unremitting nephrotic syndrome and marked hypoalbuminemia, proximal tubules may exhibit degenerative and regenerative changes resembling acute tubular necrosis (Fig. 6.19). Arterial vessels show changes related to hypertension and/or aging.
mild to severe, but are generally commensurate with the degree of glomerulosclerosis (Fig. 6.18). Interstitial foam cells may be seen, either singly or in aggregates, in cases with long-standing proteinuria. In the setting of severe unremitting nephrotic syndrome and marked hypoalbuminemia, proximal tubules may exhibit degenerative and regenerative changes resembling acute tubular necrosis (Fig. 6.19). Arterial vessels show changes related to hypertension and/or aging.
 FIGURE 6.11 Primary FSGS. A segmental lesion contains endocapillary foam cells (arrowhead). (PAS, ×400.) |
 FIGURE 6.12 Primary FSGS. A segmental sclerosis lesion contains endocapillary foam cells, as well as some infiltrating leukocytes (arrows) (H&E, ×400) |
 FIGURE 6.13 Primary FSGS with cellular and collapsing features. A: Several glomerular capillaries at the top of the glomerulus are expanded and occluded by foam cells (arrow). The overlying podocytes are hyperplastic. Adjacent capillaries display segmental collapse. (PAS, ×330.) B: The same glomerulus illustrated in (A) is stained for the endothelial marker, CD31. The glomerular capillaries are stained everywhere except in the segmental lesion, indicating that the capillary endothelium has been obliterated. (CD31 immunoperoxidase, ×330.) C: The endocapillary foam cells stain with the macrophage marker, CD68. (CD68 immunoperoxidase, ×330.) |
Importantly, the likelihood of identifying a diagnostic glomerular lesion in a biopsy sample is determined by both the proportion of glomeruli affected by the disease and by the sample size, and FSGS lesions may be missed in small biopsy samples (46). FSGS lesions may also be missed in early disease if only the superficial renal cortex is sampled, or if the glomerular scarring has become diffuse and global, in the later stages of disease. It has been estimated that a sample of at least 20 glomeruli is required to confidently exclude the presence of disease affecting 10% of glomeruli (46). While the percentage of glomerular involvement by FSGS lesions is difficult to ascertain in small biopsies, one study showed frequencies of 11.7% in children and 31.5% in adults, increasing to 23.2% and 48%, respectively, after serial sectioning (47). In adults with primary FSGS, the prevalence of glomeruli with segmental lesions increased from 31.5% to 71.8% after exhaustive serial sectioning (48). Therefore, additional tissue sections should be performed if there is a high clinical suspicion of FSGS. Biopsy findings of focal tubular atrophy and interstitial fibrosis without sclerosing glomerular lesions should also prompt a more exhaustive search for unsampled FSGS. In such cases, the portions of the biopsy allocated for immunofluorescence and electron microscopy should be examined carefully by light microscopy for possible FSGS lesions.
 FIGURE 6.14 Primary FSGS, collapsing variant. There is global implosive collapse of capillaries with wrinkling of the glomerular basement membranes, accompanied by swelling and proliferation of glomerular epithelial cells that contain cytoplasmic vacuoles and PAS-positive cytoplasmic droplets. One epithelial cell (inset) displays a mitotic figure. (PAS, ×330.) |
 FIGURE 6.15 Primary FSGS, NOS. A segmental sclerosis lesion with a small adhesion involves neither the hilum (asterisk) nor the tubular pole of the glomerulus (arrow). (JMS stain, ×330.) |
 FIGURE 6.16 Primary FSGS, perihilar variant. Segmental sclerosis and hyalinosis located in the perihilar region (vascular pole). (PAS, ×600.) |
 FIGURE 6.17 Proximal tubules display cytoplasmic protein and lipid droplets. (PAS, ×600.) |
 FIGURE 6.18 Primary FSGS. One glomerulus shows segmental sclerosis, and the other two are globally sclerotic, consistent with advanced chronicity. There are prominent tubular atrophy and interstitial fibrosis. (Trichrome stain, ×100.) |
 FIGURE 6.19 Primary FSGS, with severe acute tubular injury. Proximal tubules display epithelial simplification with loss of brush border. (PAS, ×200.) |
Immunofluorescence Microscopy
There is often segmental glomerular staining for IgM and C3 (and to a lesser extent C1q), consistent with nonspecific trapping in areas of sclerosis and/or hyalinosis (Fig. 6.20). Less intense and more delicate mesangial staining for IgM and C3 may also be observed involving the mesangium of nonsclerotic segments (Fig. 6.21). Protein resorption droplets in podocytes and proximal tubular cells commonly stain for albumin and IgG, as well as IgA. Tubular epithelial cytoplasmic staining for C3 may also be observed. Staining for other immune reactants is negative.
Electron Microscopy
Electron microscopy typically demonstrates effacement of podocyte foot processes overlying areas of segmental sclerosis and in more than 50% of the capillary surface area in the nonsclerotic glomeruli (Fig. 6.22). The effacement process is thought to involve retraction of podocyte foot processes (or pedicels) into the cell body or primary processes. Foot process effacement is also seen in other proteinuric diseases and is thus a nonspecific podocyte response. However, the finding of effacement involving patent glomerular capillaries in the absence of immune deposits or other ultrastructural abnormalities of the GBM should suggest a podocytopathy. A recent morphometric study showed that the mean foot process width was significantly greater in primary FSGS compared to MCD and secondary (adaptive) FSGS (49), suggesting that the degree of foot process effacement is a helpful clue in distinguishing primary FSGS from adaptive forms. Podocytes may be swollen and show increased organellar content, microvillous surface projections, and loss of primary processes. In some cases, the podocyte cell body appears to sit directly on the GBM, without recognizable primary processes.
Many filtration slit diaphragms become displaced or lost. Podocyte actin filaments typically undergo rearrangement to form a dense cytoskeletal “mat” parallel to the direction of the GBM, in the basal cytoplasm above the effaced foot processes. Detachment and lifting of injured podocytes from the GBM may be seen (Fig. 6.23). These changes are often followed by the laying down of a lamellated neomembrane between detached visceral epithelial cells and the underlying GBM. Recent studies suggest that this looser matrix, which is less electron dense than the normal GBM, is derived from parietal cells that have replaced lost podocytes (43). Cytoplasmic electron dense protein droplets are common in cases with severe proteinuria. Hyalinosis lesions are characterized by accumulation of amorphous electron dense material, sometimes containing clear, rounded inclusions representing entrapped lipid and typically localize to the infra-membranous region (i.e., between the endothelial cell and the GBM). Endocapillary foam cells are rounded cells with electron-lucent lipid-rich cytoplasmic vacuolization (Fig. 6.24).
Many filtration slit diaphragms become displaced or lost. Podocyte actin filaments typically undergo rearrangement to form a dense cytoskeletal “mat” parallel to the direction of the GBM, in the basal cytoplasm above the effaced foot processes. Detachment and lifting of injured podocytes from the GBM may be seen (Fig. 6.23). These changes are often followed by the laying down of a lamellated neomembrane between detached visceral epithelial cells and the underlying GBM. Recent studies suggest that this looser matrix, which is less electron dense than the normal GBM, is derived from parietal cells that have replaced lost podocytes (43). Cytoplasmic electron dense protein droplets are common in cases with severe proteinuria. Hyalinosis lesions are characterized by accumulation of amorphous electron dense material, sometimes containing clear, rounded inclusions representing entrapped lipid and typically localize to the infra-membranous region (i.e., between the endothelial cell and the GBM). Endocapillary foam cells are rounded cells with electron-lucent lipid-rich cytoplasmic vacuolization (Fig. 6.24).
 FIGURE 6.20 Immunofluorescence microscopy shows segmental glomerular tuft staining for IgM (A) and C3 (B). (FITC anti-human IgM [A] and FITC anti-human C3 [B], ×330.) |
 FIGURE 6.21 Immunofluorescence microscopy shows finely granular mesangial staining for IgM. (FITC anti-human IgM, ×330.) |
 FIGURE 6.22 Primary FSGS. Segmental solidification of the glomerular tuft with wrinkling of basement membranes and inframembranous hyaline is accompanied by diffuse effacement of the overlying podocyte foot processes. (Electron photomicrograph, original magnification ×6000.) |
 FIGURE 6.23 Electron micrograph shows epithelial cell (EP) detachment from the underlying glomerular capillary basement membrane (arrows). The intervening area contains finely granular material. (Original magnification, ×5000.) (Courtesy of Drs. Jacob Churg and Edith Grishman.) |
 FIGURE 6.24 Primary FSGS, tip variant. Endocapillary foam cells and extracellular matrix obliterate the glomerular capillary lumina. (Electron photomicrograph, original magnification ×3000.) |
Morphologic Variants of FSGS
Since the early descriptions of FSGS by Churg et al. (9), it was recognized that FSGS lesions were morphologically heterogeneous with respect to the degree of cellularity and their location within the glomerular globe. In 1984, Howie and Brewer (50) coined the term “glomerular tip lesion” for a distinctive finding in some patients with idiopathic nephrotic syndrome. This lesion consisted of small segmental lesions at the tubular pole (i.e., the glomerular “tip”), which either prolapsed into the proximal tubule or adhered to the Bowman capsule at the tubular outlet, accompanied by signs of injury in the adjacent proximal tubular epithelium. Tip lesions showed prominent swelling of overlying visceral epithelial cells and contained endocapillary foam cells (and less commonly hyaline); other glomeruli showed no pathologic alterations other than foot process effacement. Cases of glomerular tip lesion had an excellent response to steroids and favorable outcome, similar to MCD and distinct from FSGS (50). Subsequently, it was suggested that glomerular tip lesion might also represent an early stage in the evolution of FSGS, not otherwise specified (NOS) (51).
In 1985, Schwartz and Lewis used the term “cellular lesion” for cases of FSGS that were characterized by prominent visceral epithelial cell abnormalities, including swelling and hyperplasia. Cellular lesions might also display endocapillary hypercellularity with foam cells and infiltrating leukocytes or collapse of the underlying capillaries (52). The cellular lesion was associated with heavier proteinuria, more frequent nephrotic syndrome, and a shorter time from onset of symptoms to biopsy, suggesting that it might represent an early stage in the development of FSGS (52). However, it did not correlate with initial serum creatinine or rate of ESRD (53).
In 1986, Weiss et al. (54) described FSGS with features of glomerular collapse and epithelial hypercellularity in patients who had severe nephrotic syndrome and rapid progression to ESRD. This entity was subsequently called collapsing glomerulopathy (or collapsing FSGS), and its aggressive clinical course was confirmed by other investigators (55,56,57). Thus, collapsing FSGS can be considered a subset of the “cellular lesion” originally described by Schwartz and Lewis. Lesions of collapsing FSGS were noted in patients with human immunodeficiency virus type 1 (HIV-1) infection who presented with severe nephrotic syndrome and rapid-progression renal failure (58), and this secondary form of collapsing FSGS was subsequently termed HIV-associated nephropathy (HIVAN) (59,60). Other secondary viral and drug-induced causes of collapsing glomerulopathy have since been described.
The prognostic significance of FSGS variants and their relationship to each other have been controversial (61). Indeed, some investigators have questioned whether collapsing glomerulopathy and glomerular tip lesion should even be considered as forms of FSGS, given their frequent lack of bona fide extracellular matrix accumulation (i.e., sclerosis). However, as both of these entities usually present with nephrotic syndrome and often coexist with “classic” FSGS lesions, either within the same biopsy or in sequential biopsies (56), they can be considered within the spectrum of FSGS.
The lack of a standardized approach to definition and classification has hindered study of these morphologic variants. With the goal of providing a framework to study the morphologic variants of FSGS, a working classification (hereafter referred to as the “Columbia Classification”) was proposed in 2004 (62). This classification sets forth defining criteria and a stepwise, hierarchical approach to distinguish five mutually exclusive morphologic variants of FSGS: collapsing, tip lesion, cellular, perihilar variant, and NOS variant (62). Importantly, this classification is applicable to primary and secondary forms of FSGS and does not imply that these variants per se represent specific disease entities.
A summary of the Columbia Classification is provided in Table 6.2 and drawings of four of the variants are provided in Figure 6.25. In this schema, a segmental lesion is defined as “less than 100% of the glomerular tuft involvement with
some residual patent capillaries,” whereas a global lesion affects the entire glomerular tuft (62). The finding of segmental (Fig. 6.26A) or global (Fig. 6.26B) glomerular capillary collapse with overlying visceral epithelial cell hypertrophy and hyperplasia in at least one glomerulus warrants a diagnosis of the collapsing variant of FSGS, irrespective of the findings in other glomeruli. Excluding collapsing lesions, the finding of a single segmental lesion involving the tip domain (outer 25% of the tuft next to the proximal tubule origin) where the tubular pole is identified is diagnostic of the tip variant (Fig. 6.27). After excluding collapsing and tip lesions, the finding of one glomerulus with segmental expansile endocapillary hypercellularity obliterating capillary lumina (with or without foam cells, hyalinosis, infiltrating leukocytes, karyorrhexis, and epithelial cell hyperplasia) is classified as cellular variant (Figs. 6.13 and 6.28). Perihilar variant is defined as segmental hyalinosis and sclerosis contiguous with the glomerular hilum affecting the majority (≥50%) of glomeruli with segmental lesions, excluding collapsing, cellular, and tip lesions (Fig. 6.29). All other cases are classified as FSGS NOS variant, which by default represents the common, “classic” or generic lesion of segmental sclerosis.
some residual patent capillaries,” whereas a global lesion affects the entire glomerular tuft (62). The finding of segmental (Fig. 6.26A) or global (Fig. 6.26B) glomerular capillary collapse with overlying visceral epithelial cell hypertrophy and hyperplasia in at least one glomerulus warrants a diagnosis of the collapsing variant of FSGS, irrespective of the findings in other glomeruli. Excluding collapsing lesions, the finding of a single segmental lesion involving the tip domain (outer 25% of the tuft next to the proximal tubule origin) where the tubular pole is identified is diagnostic of the tip variant (Fig. 6.27). After excluding collapsing and tip lesions, the finding of one glomerulus with segmental expansile endocapillary hypercellularity obliterating capillary lumina (with or without foam cells, hyalinosis, infiltrating leukocytes, karyorrhexis, and epithelial cell hyperplasia) is classified as cellular variant (Figs. 6.13 and 6.28). Perihilar variant is defined as segmental hyalinosis and sclerosis contiguous with the glomerular hilum affecting the majority (≥50%) of glomeruli with segmental lesions, excluding collapsing, cellular, and tip lesions (Fig. 6.29). All other cases are classified as FSGS NOS variant, which by default represents the common, “classic” or generic lesion of segmental sclerosis.
TABLE 6.2 Histologic variants of FSGS | ||||||||||||||||||||||||||||
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Although the Columbia Classification is essentially heuristic, reflecting the collective experience of the participating pathologists and evidence from the literature, subsequent studies have confirmed significant differences in presenting clinical and demographic features and patient outcomes among the FSGS variants (see Clinical-Pathologic Correlation of Histologic Variants of Primary FSGS and Tables 6.3 and 6.4).
Collapsing Variant (Also Known as Collapsing Glomerulopathy)
Collapsing lesions of sclerosis may be focal and segmental but are more typically diffuse and global in distribution. Capillary collapse is best appreciated with silver or PAS stains, which demonstrate wrinkling of the GBMs, leading to luminal obliteration (Fig. 6.30). There is usually little if any extracellular
matrix accumulation in the acute collapsing lesions, but this may be present in other glomeruli. Hyalinosis lesions are rare in this variant. Capillary collapse is accompanied by prominent epithelial cell hypertrophy and hyperplasia within the Bowman space. The epithelial cells typically line the external surface of the glomerular tuft but may fill the Bowman space, forming a “pseudocrescent” (Fig. 6.31). Serial sections have shown that these lesions are often continuous with the parietal epithelial cell layer; however, these cells usually lack the spindled morphology, intercellular matrix, and pericellular
fibrin seen in true inflammatory crescents. Features of fibrinoid necrosis and ruptures of the GBM or Bowman capsule, which are often identified in crescentic glomerulonephritis, are absent. Visceral epithelial cell nuclei are typically enlarged and show vesicular chromatin and prominent nucleoli; rarely, mitotic figures or binucleated cells are evident (see Fig. 6.25) (56). The swollen epithelial cells often contain large cytoplasmic protein droplets, coarse cytoplasmic vacuoles, and lipid droplets; they may have prominent subpodocyte, tunnel-like spaces that raise the cell bodies off the underlying basement membrane (Fig. 6.32). Proximal tubules frequently show degenerative and regenerative changes (Fig. 6.33), and tubular microcysts (dilated tubules filled with proteinaceous casts) are commonly seen (Fig. 6.34). Tubular atrophy and interstitial fibrosis are often severe and disproportionate to the degree of glomerulosclerosis. Foot process effacement is usually severe. Endothelial tubuloreticular inclusions (TRIs) are not a feature of primary collapsing FSGS but may be seen in secondary collapsing glomerulopathy associated with interferon therapy (71), HIV infection (60), or the podocytopathy of systemic lupus erythematosus (SLE) (72).
matrix accumulation in the acute collapsing lesions, but this may be present in other glomeruli. Hyalinosis lesions are rare in this variant. Capillary collapse is accompanied by prominent epithelial cell hypertrophy and hyperplasia within the Bowman space. The epithelial cells typically line the external surface of the glomerular tuft but may fill the Bowman space, forming a “pseudocrescent” (Fig. 6.31). Serial sections have shown that these lesions are often continuous with the parietal epithelial cell layer; however, these cells usually lack the spindled morphology, intercellular matrix, and pericellular
fibrin seen in true inflammatory crescents. Features of fibrinoid necrosis and ruptures of the GBM or Bowman capsule, which are often identified in crescentic glomerulonephritis, are absent. Visceral epithelial cell nuclei are typically enlarged and show vesicular chromatin and prominent nucleoli; rarely, mitotic figures or binucleated cells are evident (see Fig. 6.25) (56). The swollen epithelial cells often contain large cytoplasmic protein droplets, coarse cytoplasmic vacuoles, and lipid droplets; they may have prominent subpodocyte, tunnel-like spaces that raise the cell bodies off the underlying basement membrane (Fig. 6.32). Proximal tubules frequently show degenerative and regenerative changes (Fig. 6.33), and tubular microcysts (dilated tubules filled with proteinaceous casts) are commonly seen (Fig. 6.34). Tubular atrophy and interstitial fibrosis are often severe and disproportionate to the degree of glomerulosclerosis. Foot process effacement is usually severe. Endothelial tubuloreticular inclusions (TRIs) are not a feature of primary collapsing FSGS but may be seen in secondary collapsing glomerulopathy associated with interferon therapy (71), HIV infection (60), or the podocytopathy of systemic lupus erythematosus (SLE) (72).
 FIGURE 6.25 Drawings of the histologic features of the Columbia Classification variants of FSGS (NOS not shown). Top Row: Normal glomerulus for comparison with epithelial cells green, endothelial cells yellow, mesangial and smooth muscle cells orange, foam cells yellow with clear vacuoles, and basement membranes gray. Tip lesion variant FSGS with segmental lesion involving the tubular pole, confluence of podocytes, and tubular epithelial cells, an endocapillary foam cell (yellow with clear vacuoles) and slight increase in the extracellular matrix. Perihilar variant FSGS with segmental hyalinosis (red) and sclerosis (dark gray) involving the vascular pole (perihilar region). Bottom Row: Collapsing variant FSGS with segmental collapse of capillaries, separation of podocytes from the glomerular basement membrane, accumulation of subepithelial extracellular matrix and hyperplasia and swelling of overlying epithelial cells that have abundant cytoplasmic protein droplets. Cellular variant FSGS with segmental obliteration of capillary lumens by endocapillary hypercellularity caused by foam cells (yellow with vacuoles) and adjacent epithelial hypertrophy and mild hyperplasia. |
 FIGURE 6.26 A: Primary FSGS, collapsing variant. A glomerulus shows segmental collapse of capillaries, associated with marked hyperplasia and swelling of overlying epithelial cells, one of which is undergoing mitosis (arrow). (PAS, ×400.) B: Primary FSGS, collapsing variant. There is global collapse of capillaries, associated with hyperplasia and swelling of overlying epithelial cells, many of which display abundant cytoplasmic protein droplets and vacuoles. (JMS stain, ×400.) |
 FIGURE 6.27 Primary FSGS, tip variant. Segmental endocapillary foam cell accumulation is seen at the origin of the proximal tubule. The affected segment has prolapsed into the tubular orifice with confluence of overlying podocytes with proximal tubular epithelium. The remainder of the glomerular tuft appears normal in cellularity. (JMS stain, ×400.) |
 FIGURE 6.28 Primary FSGS, cellular variant. There is segmental expansion of the glomerular tuft by endocapillary foam cells, occluding capillary lumina. (Jones stain, ×600.) |
 FIGURE 6.29 FSGS, perihilar variant. A glomerulus shows segmental perihilar sclerosis and hyalinosis. (PAS, ×600.) |
Tip Variant
As originally described by Howie and Brewer in 1984 (50), the glomerular tip lesion consists of a small segmental lesion in the glomerular tuft adjacent to the origin of the proximal tubule with intracapillary foam cells and/or PAS-positive hyaline, hyperplasia and vacuolization of overlying podocytes, tuft adhesion to the Bowman capsule, and confluence of podocytes with proximal tubular epithelial cells (50). The remaining glomeruli showed no pathologic alteration, except diffuse foot process effacement on electron microscopy. In the Columbia Classification, tip lesion is defined as a segmental lesion in the tip domain (the outer 25% of the glomerular tuft adjacent to the tubular orifice) and where the tubular pole is identified, with either adhesion or confluence of podocytes with parietal or tubular cells at the tubular lumen or neck (Figs. 6.35, 6.36, 6.37). The outer 25% of the tuft was chosen to identify lesions originating in the tip domain and exclude segmental lesions originating elsewhere that impinge on the tip as they enlarge. Glomerular tip lesions are typically cellular (81% in one series) (73) and contain prominent endocapillary foam cells, but they may also be sclerosing and contain hyaline (see Fig. 6.36). “Classic”/NOS lesions are more common in repeat biopsies, suggesting evolution from tip lesions (73). In the largest study of primary tip variant using the Columbia Classification, most biopsies (74%) also contained nontip segmental lesions involving the periphery of the tuft, but none showed perihilar segmental sclerosis or diffuse mesangial hypercellularity (73).
In two studies of primary adult FSGS using the Columbia Classification, tip lesions were identified in 12% (73) and 24% (61) of glomeruli, respectively, while in an autopsy study of children dying with nephrosis, Haas and Yousefzadeh identified tip lesions in 0.3% to 4.4% of glomeruli (74). In a recent report from Howie et al. (51), tip lesions involved more than 50% of glomeruli in only 2 of 15 cases, neither of which showed 100% glomerular involvement (51). Thus, glomerular tip lesions are typically focal and may be missed subject to sampling error, particularly in limited biopsy specimens.
Interestingly, glomerular tip lesions were identified retrospectively in 10% of children initially diagnosed with MCD (75) and in five of eight autopsies of children dying with nephrosis prior to 1950 (74). These findings suggest that tip variant may be underrecognized in children with steroid-responsive nephrotic syndrome, as renal biopsy is typically reserved for children whose nephrotic syndrome is resistant to steroid therapy.
Compared to the collapsing, cellular, and NOS variants, the tip variant shows the least amount of chronic tubulointer-stitial injury (3,64,70,76) and arteriosclerosis (64). A subset of cases demonstrate acute tubular injury, patchy interstitial edema, and mononuclear interstitial inflammatory cell infiltrates, which are associated with reversible acute renal failure, analogous to the reversible acute tubular injury occurring in adult MCD. Foot process effacement is typically severe (Figs. 6.38 and 6.39).
Cellular Variant
The cellular lesion is characterized by focal segmental expansion of the glomerular tuft by endocapillary foam cells and infiltrating leukocytes, with or without endocapillary fibrin, hyaline, karyorrhexis, pyknosis, and hyperplasia of overlying epithelial cells (Figs. 6.13, 6.28, and 6.40). As noted previously, mild prominence of visceral epithelial cells and a few intracapillary foam cells are not uncommon in cases of “typical” (i.e., NOS) FSGS (Figs. 6.11 and 6.12); the key diagnostic feature of the cellular lesion is expansion of the glomerular tuft by the endocapillary hypercellularity without an accompanying matrix (sclerosis). Such cases may lack any evidence of segmental scars, mimicking a focal proliferative glomerulonephritis. Cellular lesions are most commonly located in the peripheral tuft (70). Additional sectioning of the biopsy may reveal unsampled glomerular tip lesions or collapsing lesions, either of which would change the variant designation.
Perihilar Variant
The perihilar variant is characterized by segmental hyalinosis and sclerosis lesions contiguous with the glomerular hilum (i.e., at the vascular pole) involving the majority (at least 50%) of glomeruli with segmental lesions (Figs. 6.16, 6.29, 6.41, and 6.42). There may be extension of hyalinosis to involve the adjacent incoming afferent arteriole. Visceral epithelial cell hyperplasia is uncommon in this variant. Podocyte loss is often obvious, associated with adhesions to the Bowman capsule. There are only limited descriptions of the glomerular pathology and ultrastructural features in cases of primary perihilar FSGS. However, in adaptive FSGS (which typically shows perihilar features), the glomeruli are usually enlarged and foot process effacement is mild (Fig. 6.43).
NOS Variant
The defining lesion of NOS variant is segmental obliteration of the glomerular capillaries by the extracellular matrix. As a diagnosis of exclusion, it requires that a biopsy does not meet defining features for any of the other variants. In children and young adults in the FSGS Clinical Trial, NOS was the most common variant in all age groups (3). Of note, the degree of
tubulointerstitial scarring is not significantly worse in NOS compared to the other variants, implying that NOS is not just an advanced stage of the other variants (64). Thus, the NOS variant may occur ab initio or other variants may evolve into NOS over time.
tubulointerstitial scarring is not significantly worse in NOS compared to the other variants, implying that NOS is not just an advanced stage of the other variants (64). Thus, the NOS variant may occur ab initio or other variants may evolve into NOS over time.
TABLE 6.3 Frequency of Columbia Classification morphologic variants in primary FSGS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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TABLE 6.4 Renal outcomes in primary FSGS by histologic variant | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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