Morphologic Variants of Focal Segmental Glomerulosclerosis and Their Significance

Morphologic Variants of Focal Segmental Glomerulosclerosis and Their Significance Michael B. Stokes and Vivette D. D’Agati Focal segmental glomerulosclerosis (FSGS) comprises a group of clinical-pathologic syndromes characterized by heavy proteinuria and segmental obliteration of glomerular capillaries by extracellular matrix. FSGS lesions display morphologic heterogeneity with respect to their relationship to the glomerular vascular and tubular poles, the presence of capillary collapse, and endocapillary and extracapillary hypercellularity. A working proposal, commonly referred to as the Columbia Classification, distinguishes 5 mutually exclusive morphologic variants: collapsing, tip, cellular, perihilar, and not otherwise specified (NOS), which can be applied to primary and secondary forms of FSGS. Several studies have documented significant differences in baseline clinical characteristics and outcomes between morphologic variants of primary FSGS, supporting that this classification may provide useful prognostic information. The association of certain variants with particular secondary causes of FSGS suggests pathogenetic relevance. Q 2014 by the National Kidney Foundation, Inc. All rights reserved. Key Words: Focal segmental glomerulosclerosis, Morphologic classification

Background

The “classic” or prototypical focal segmental glomerulosclerosis (FSGS) lesion is segmental obliteration of glomerular capillaries by extracellular matrix, often accompanied by hyalinosis.1 In addition, FSGS lesions have variable cellular features, ranging from mild prominence of overlying epithelial cells to marked hyperplasia mimicking crescent formation, with or without implosive collapse of underlying glomerular capillaries. FSGS lesions occasionally display intracapillary foam cells and rarely show expansion of the glomerular tuft by endocapillary hypercellularity, resembling a proliferative glomerulonephritis. Segmental lesions may involve any portion of the glomerular globe, including the vascular pole (adjacent to the hilar region) and the tubular pole (adjacent to the proximal tubule). Depending on the plane of section in routine histologic sections, the lesions may have an indeterminate relationship to these anatomic landmarks. Only by serial sectioning the entire glomerulus followed by 3-dimensional reconstruction is it possible to determine the number, size, and geography of the segmental lesions.2 Because such studies are too laborintensive for routine use, pathologists must work within the limitations of practical histology. In 1984, Howie and Brewer3 were the first to use 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 (ie, the glomerular “tip”), which either prolapsed into the proximal tubule or adhered to Bowman's capsule at the tubular outlet, associated with tubular cell reactivity. Tip From Department of Pathology, Columbia University, College of Physicians and Surgeons, New York, NY. Financial Disclosure: The authors declare that they have no relevant financial interests. Address correspondence to Vivette D. D'Agati, MD, Department of Pathology, Columbia University, College of Physicians and Surgeons, Renal Pathology Laboratory, Room VC14-224, 630 West 168th Street, New York, NY 10032. E-mail: [email protected] Ó 2014 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/$36.00 http://dx.doi.org/10.1053/j.ackd.2014.02.010

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lesions showed prominent swelling of the overlying visceral epithelial cells and contained endocapillary foam cells (and less commonly hyaline); other glomeruli had no pathologic alterations other than foot process effacement. These cases typically had an excellent response to steroids and favorable outcome, similar to minimal change disease (MCD) and distinct from FSGS.3 It was subsequently suggested that glomerular tip lesion might also represent an early stage in the evolution of FSGS.4 In 1985, Schwartz and Lewis coined the term “cellular lesion” for cases of FSGS that were characterized by prominent visceral epithelial cell abnormalities, including swelling and hyperplasia.5 These lesions could display endocapillary hypercellularity with foam cells and infiltrating leukocytes or collapse of the underlying capillaries. The cellular lesion was associated with heavier proteinuria, more frequent nephrotic syndrome, and a shorter time from onset of symptoms to biopsy, suggesting a possible early stage in the development of FSGS.5 However, it did not correlate with the initial serum creatinine or the rate of ESRD.6 In 1986, Weiss and colleagues described FSGS with features of implosive glomerular collapse and glomerular epithelial hypercellularity in patients who had severe nephrotic syndrome and rapid progression to ESRD.7 This entity was subsequently called collapsing glomerulopathy (or collapsing FSGS), and its aggressive clinical course was confirmed by other investigators.8-10 Thus, collapsing FSGS may be considered a subset of the “cellular lesion” originally described by Schwartz and Lewis. It is important to note that more than 1 of these morphologic lesions may coexist in a given biopsy. Because of this inherent diversity of phenotypic expression, FSGS poses a particular challenge to classification.

Morphologic Variants of FSGS: The Columbia Classification For years, it was evident that FSGS is morphologically heterogeneous and that the differences observed by pathologists might be relevant to clinical presentation, outcome, and pathogenesis. The Columbia Classification is a working proposal devised by a group of kidney pathologists on

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the basis of their collective experience and evidence from viruses (including HIV15 and parvovirus B1916); hemophathe literature.11 The classification requires the recognition gocytic syndrome17; pamidronate therapy18; interferon a, of 1 of 4 defining lesions (collapsing, cellular, tip, and perib, or g therapy19; and acute vaso-occlusive disease.20 In African Americans with HIV infection21 and systemic lupus erhilar), determination of the proportion of segmentally ythematosus,22 collapsing variant has been associated with affected glomeruli with the defining lesion (in the case of apolipoprotein-L1 risk alleles. Endothelial tubuloreticular perihilar variant), and the simultaneous application of a hiinclusions (“interferon footprints”) are a helpful ultrastrucerarchical system of exclusions (Table 1). The frequencies tural finding in collapsing glomerulopathy related to interof these variants and their outcomes in primary FSGS are feron therapy,19 untreated HIV infection,15 or lupus presented in Tables 2-4. Although the classification was podocytopathy.23 heuristic and not derived from analysis of a specific disease cohort, it has subsequently been applied by Tip Variant many investigators to diverse pediatric and adult Excluding collapsing and perihilar lesions, the finding of populations with primary FSGS (mediated by 1 or more possible permeability factors) and secondary FSGS a single segmental lesion involving the tip domain (the outer (mediated by genetic mutations in specific podocyte 25% of the tuft next to the proximal tubule origin) where the tubular pole is identified, with either adhesion or conflugenes, viruses, drugs, or adaptive responses to ence of podocytes with parietal or tubular cells at the tubular glomerular hypertension).1 All forms of FSGS are thought to involve podocyte injury, lumen or neck, is diagnostic leading to podocyte depleof the tip variant (Fig 2). CLINICAL SUMMARY tion through detachment or The outer 25% of the tuft cell death. was chosen to identify  A working classification recognizes 5 morphologic variants lesions originating in the tip of FSGS: collapsing, tip, cellular, perihilar, and NOS. Collapsing Variant domain and exclude  Cohort studies of primary FSGS have identified significant The finding of segmental or segmental lesions origiclinical differences among these variants, including a global implosive collapse of nating elsewhere that higher incidence of full nephrotic syndrome at presentation glomerular capillaries with impinge on the tip as they in the collapsing and tip variants than in the NOS variant overlying visceral epithelial enlarge. Tip lesions are typiand the highest Black racial association in the collapsing cell hypertrophy and hypercally cellular (81% in 1 variant. plasia in at least 1 glomerulus series)24 and contain promi Remission rates are generally lowest for the collapsing nent endocapillary foam defines the collapsing variant variant, intermediate for the NOS variant, and highest for cells, but they may be scleof FSGS, irrespective of the the tip variant. On the other hand, the reported rates of rosing and contain hyaline. findings in other glomeruli ESRD are highest in the collapsing variant, intermediate Perihilar FSGS lesions are (Fig 1). Thus, the finding of a in NOS, and lowest in the tip variant. not permitted in this variant; single collapsing lesion  Morphologic variants can be applied to primary and indeed, none were identified trumps all other variants. secondary forms of FSGS and may provide clues to in the initial review of cases Collapsing lesions are more underlying etiologies and pathogenetic mechanisms. For with tip lesions in the largest commonly global than example, secondary FSGS related to viruses (such as study of the primary tip segmental. Capillary collapse untreated HIV and parvovirus B19) and drugs (such as variant.24 However, in the is accompanied by prominent interferon and pamidronate) often presents with the same study, most biopsies glomerular epithelial cell hycollapsing variant. The perihilar variant, particularly if (74%) also contained nontip pertrophy and hyperplasia accompanied by glomerulomegaly and relatively mild segmental lesions involving within Bowman's space, podocyte effacement, is common in secondary adaptive the periphery of the tuft. sometimes forming a “pseuFSGS. Thus, the glomerular tip docrescent.” As distinct from variant differs from the true inflammatory crescents, original description3 by the extracapillary cells are including nontip lesions. Foot process effacement is typitypically plump rather than spindled and lack pericellular cally severe and diffuse. Morphogenesis of this lesion probmatrix, extracapillary fibrin, intermingled leukocytes, or ably involves higher shear stress and turbulence at the ruptures of either the glomerular basement membrane or tubular pole, promoting detachment of podocytes for which Bowman's capsule. Mitotic figures or binucleated cells attachment to the glomerular basement membrane has been may be present.9 The swollen epithelial cells often contain large cytoplasmic protein droplets and clear transport vesiweakened by effacement. Most cases of tip variant are pricles. Although dysregulated, dedifferentiated podocytes mary. Of note, tip lesions may also develop in other proteimay contribute to the extracapillary hypercellularity,12 nuric glomerular diseases, such as diabetic nephropathy, studies support proliferation of activated parietal cells and preeclampsia, and membranous glomerulonephritis, in stem cells lining Bowman's capsule.13,14 Proximal tubules which they likely represent a common consequence of pofrequently show degenerative and regenerative changes. docyte injury and depletion at the tubular pole. Tubular microcysts containing proteinaceous casts are a In each of 2 studies of primary adult FSGS using common feature. Tubular atrophy and interstitial fibrosis the Columbia Classification,24,25 tip lesions were identified in 12% of glomeruli, whereas in an autopsy are often severe. Foot process effacement is usually study of children dying with nephrosis before 1950, diffuse. Collapsing FSGS may be primary or secondary to

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Table 1. Columbia Classification of FSGS Variants Variant FSGS (NOS)

Perihilar variant

Cellular variant

Tip variant

Collapsing variant

Inclusion Criteria

Exclusion Criteria

At least 1 glomerulus with segmental increase in matrix obliterating the capillary lumina. There may be segmental glomerular capillary wall collapse without overlying podocyte hyperplasia. At least 1 glomerulus with perihilar hyalinosis, with or without sclerosis. .50% of glomeruli with segmental lesions must have perihilar sclerosis and/or hyalinosis. At least 1 glomerulus with segmental endocapillary hypercellularity occluding lumina, with or without foam cells and karyorrhexis. At least 1 segmental lesion involving the tip domain (outer 25% of tuft next to origin of proximal tubule). The tubular pole must be identified in the defining lesion. The lesion must have either an adhesion or confluence of podocytes with parietal or tubular cells at the tubular lumen or neck. The tip lesion may be cellular or sclerosing. At least 1 glomerulus with segmental or global collapse and overlying podocyte hypertrophy and hyperplasia.

Exclude perihilar, cellular, tip, and collapsing variants

Exclude cellular, tip, and collapsing variants

Exclude tip and collapsing variants

Exclude collapsing variant Exclude any perihilar sclerosis

None

Abbreviations: FSGS, focal segmental glomerulosclerosis; NOS, not otherwise specified. Reprinted from D’Agati VD, Fogo AB, Bruijn JA, Jennette JC. Am J Kidney Dis. 2004;43(2):368-382.11

Haas and Yousefzadeh identified tip lesions in 0.3% to 4.4% of glomeruli.26 In a recent report from Howie and colleagues, tip lesions involved more than 50% of glomeruli in only 2 of 15 cases, neither of which showed 100% glomerular involvement.4 Thus, tip lesions are typically focal and may be missed subject to sampling error, particularly in limited biopsy specimens. Tip lesions were identified retrospectively in 10% of children initially diagnosed with MCD27 and in 5 of 8 autopsies of children dying with nephrosis before 1950.26 These findings suggest that the tip variant may be under-recognized in children with steroid-responsive nephrotic syndrome, in whom kidney

biopsy is typically not performed. The tip variant typically shows only mild chronic tubulointerstitial injury24,28-31 and arteriosclerosis.29

Cellular Variant

After excluding collapsing and tip lesions, the finding in at least 1 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 the cellular variant (Fig 3). Such cases may lack any evidence of segmental scars, mimicking a focal proliferative

Table 2. Frequency of Morphologic Variants in Primary FSGS

Reference

N

Age*

Ethnicity or Race

Paik et al Silverstein et al43

92† 41

80.4 6 42.4 mo (12-171) 10.9 6 0.9 y

El-Rafaey et al50 Thomas et al29 Deegens et al41 Nada et al51 Taneda et al42 Gipson et al52

72 197 93 210 85 138†

6.3 y (1-16) 49 6 15 y 49 6 16 y .17 y 39.4 6 1.7 y (18-77) ,18 y, 67%; .18 y, 33%

Korean Black, 80.5%; White, 19.5% Egyptian Black, 40% White, 96% Indian Japanese Black, 38%; White, 57%; Other, 5%

77‡

,16 y, 73%; .16 y, 27%

40

Canaud et al53

Unknown

FSGS Variant Frequency (%)

Nephrotic Syndrome (%)

Collapsing

Tip

Cellular

Perihilar

NOS

92 63.4

10.6 29

6.1 0

1.5 27

9.1 0

72.7 44

100 70 63 Unknown 44.7 UPC .2: 76 1-1.99: 24 100

6 11 5 2 16 12

2 17 37 13.5 30 10

0 3 0 8 14 3

7 26 26 4 16 7

13

8

22

8

85 42 32 72.5 24 68

49

Abbreviations: FSGS, focal segmental glomerulosclerosis; N, number of cases; NOS, not otherwise specified; UPC, urine protein-to-creatinine ratio. *Mean 6 standard error of mean (range). †All steroid resistant. ‡All with ESRD.

403

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Table 3. Comparison of Presenting Features in Collapsing, Tip Lesion, and NOS Variants of Primary FSGS Variant

Number of Cases*

Black Race* (%)

Urine Protein Excretion† (g/d)

Nephrotic Syndrome* (%)

Collapsing Tip NOS

94 108 264

69.2 14.3 37.0

8.8 7.4 4.7

88 92 63

Abbreviations: FSGS, focal segmental glomerulosclerosis; NOS, not otherwise specified. Data are expressed as total counts* or means† derived from compilation of 3 large U.S. cohorts.28,29,31

glomerulonephritis, and this variant was introduced so that pathologists could accept such purely cellular lesions within the rubric of FSGS. Cellular lesions are typically found in the peripheral tuft.28 Foot process effacement is usually severe.28

Perihilar Variant The perihilar variant is characterized by segmental hyalinosis and sclerosis lesions at the glomerular vascular pole in more than 50% of glomeruli with segmental lesions (Fig 4). Hyalinosis may extend to the adjacent afferent arteriole. Visceral epithelial cell hyperplasia is uncommon, and podocyte loss may be apparent and associated with adhesions to Bowman's capsule. There are limited pathologic descriptions of primary perihilar FSGS. However, in secondary adaptive FSGS (which typically has perihilar features), the glomeruli are usually enlarged and foot process effacement is usually focal and relatively mild. The predominance of the perihilar variant accompanied by glomerulomegaly has been reported in biopsy series of adaptive FSGS related to obesity,32 body-building,33 oligomeganephronia,34 solitary kidney,35 low nephron endowment due to prematurity,36 systemic hypertension37 and sickle cell anemia.38 In the setting of adaptive FSGS, reflex dilatation of the afferent arteriole leading to glomerular hypertension may cause particular stress on the perihilar segment.39

FSGS (NOS) Cases not meeting criteria for the other 4 variants are classified as FSGS not otherwise specified (NOS; Fig 5). The defining lesion of the NOS variant is simply segmental obliteration of the glomerular capillaries by extracellular matrix. Hyalinosis, endocapillary foam cells, capsular

adhesion, and parietal cell coverage of the sclerotic lesions are common features. Foot process effacement is variable but typically diffuse.28 The degree of tubulointerstitial scarring is not significantly worse in NOS compared with the other variants, implying that NOS is not just an advanced stage of the other variants.28,29 In most pediatric and adult series of primary FSGS, NOS is the most common variant (see Table 3). Although most examples of the NOS variant appear to occur ab initio, repeat biopsies have shown that other variants may evolve into NOS over time.24

Clinical-Pathologic Correlations of FSGS Variants The collapsing variant of primary FSGS is strongly associated with African ancestry and is more common in males than females.28,29,31 This variant usually presents with severe nephrotic syndrome and kidney insufficiency despite a shorter duration of symptoms compared with the NOS variant, suggesting a more acute injury rather than delayed diagnosis.9,28 Adults with the collapsing variant tend to be younger, have a higher serum creatinine at presentation, and have heavier proteinuria and lower serum albumin than adults with NOS variant.28,29 In 1 pediatric study, the collapsing variant was associated with higher blood pressures than the cellular variant or NOS, but the outcomes were similar.40 The collapsing variant has the lowest percentage of remissions (complete and partial) and the highest rate of ESRD.28,29,31 The tip variant predominantly affects older adults and usually has a favorable clinical course.24,29,41 All ethnic groups may be affected, but Caucasians predominate in most North American studies; however, in 1 series most patients were African American.25 The tip variant typically presents with sudden onset of severe nephrotic syndrome,

Table 4. Outcomes in Primary FSGS Morphologic Variants Reference 29

Thomas et al

Follow-Up

Outcomes

All Cases (%)

Collapsing (%)

Tip (%)

Cellular (%)

Perihilar (%)

NOS (%)

1.8 y (0-16)

CR/PR ESRD CR/PR ESRD CR/PR† ESRD† CR/PR ESRD

24 33 44 34 14 25 38.5 30.7

18 67 50 70 NA 47 13 65

53 24 57 22 NA 7 76 6

33 NA NA NA NA NA 44 28

19 25 25 37 NA NA NA NA

16 35 38 45 NA 20 39 35

Deegens et al41

66 mo (1-273)

D’Agati et al31

3.1 (2.1, 3.7) y*

Stokes et al28

33.7 6 2.7 mo

Abbreviations: CR, complete remission; FSGS, focal segmental glomerulosclerosis; mo, months; NA, not available; NOS, not otherwise specified; PR, partial remission; y, years. Follow-up data presented as mean 6 standard deviation or median (range). Significant differences between FSGS variants in individual studies appear in bold. *Median (25th, 75th percentiles). †All steroid resistant, subsequently treated with either cyclosporine or mycophenolate and dexamethasone.

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Figure 1. Focal segmental glomerulosclerosis, collapsing variant. Global collapse of glomerular capillaries is accompanied by exuberant hyperplasia and swelling of overlying epithelial cells, many of which contain abundant cytoplasmic protein droplets and vacuoles. The extracapillary glomerular epithelial proliferation obliterates the urinary space, forming a pseudocrescent (Jones methenamine silver stain, original magnification 3400).

similar to MCD, and has better initial kidney function than the collapsing or NOS variants.24 Some cases of the tip variant demonstrate acute tubular injury and interstitial edema associated with reversible acute kidney failure, analogous to the reversible acute tubular injury occurring in adult MCD. The tip variant has the best initial and final kidney function and the highest rate of complete remission and kidney survival at 5 years.29 However, progression to ESRD and recurrence in the kidney allograft have been described.4 Factors that predict poor kidney outcome in the tip variant include failure of remission of proteinuria25 and greater number of nontip segmental lesions in the initial biopsy.4,24 Some studies have shown higher remission rates

Figure 2. Focal segmental glomerulosclerosis, 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 between overlying podocytes and the proximal tubular epithelium. The remainder of the glomerular tuft appears normal in cellularity (Jones methenamine silver stain, original magnification 3400).

Figure 3. Focal segmental glomerulosclerosis, cellular variant. Segmental expansion of the glomerular tuft by endocapillary foam cells is seen. Overlying epithelial cells are also prominent. Features of capillary collapse or tip lesion are not seen (Jones methenamine silver stain, original magnification 3400).

and less ESRD for the tip variant compared with FSGS NOS,24,29 whereas others (including 2 pediatric series) did not.25,40,42 Whether the tip variant in children is biologically different from the disease in adults is uncertain. Kidney biopsy in children with idiopathic nephrotic syndrome is usually performed only in patients who fail a 4- to 6-week course of glucocorticoid therapy, thus potentially selecting for those tip variant cases that have an inherently worse prognosis compared with adults, in whom steroid responsiveness is typical.24 On the other hand, the National Institutes of Healthsponsored FSGS clinical trial showed that, even among 138 initially steroid-resistant children and young adults, those with the tip variant had better kidney survival than patients with the NOS and collapsing variants.31 In this study, rates of progression to ESRD at 3 years were highest for the collapsing variant (47%), intermediate for NOS (20%), and lowest for the tip variant (7%). The cellular variant is rare in adults (3-4.6% of primary FSGS cases),28,29 but it has been reported in up to 37% of

Figure 4. Focal segmental glomerulosclerosis, perihilar variant. There is segmental accumulation of matrix and hyaline at the vascular pole (perihilar region); (trichrome stain, original magnification 3400).

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the study of Deegens and colleagues.41 (median followup 5 years). It is important to note that 0 of 18 pediatric patients with the NOS variant in 1 study43 developed ESRD (mean follow-up 46.8 months), whereas ESRD developed in 20% of NOS cases in the National Institutes of Health clinical trial, in which approximately 2/3 of subjects were younger than 18 years old31 (median follow up 3.1 years). This difference may reflect the fact that all subjects in the latter study had initial steroid-resistant disease, whereas the percentage of steroid-resistant cases of the NOS variant in the former study is unknown.

Limitations of Morphologic Classification Figure 5. Focal segmental glomerulosclerosis, not otherwise specified variant. A segmental lesion of sclerosis with obliteration of capillaries by extracellular matrix forms an adhesion to Bowman’s capsule with parietal cell coverage. Features of capillary collapse, tip lesion, endocapillary hypercellularity, or perihilar localization are not seen (Jones methenamine silver stain, original magnification 3400). Reprinted with permission from Ref1 (D’Agati VD et al, 2011).

pediatric FSGS cases.43 In a study of 22 patients with the cellular variant (only 1 of who was ,18 years old), patients had heavier proteinuria, more frequent nephrotic syndrome, lower serum albumin, and shorter interval from onset of symptoms to biopsy compared with the NOS variant, suggesting a more acute disease.28 In a pediatric study, the cellular variant showed less chronic injury, less hypertension, and better remission rates than the collapsing variant, and 75% entered remission.43 Although outcome data for the cellular variant are scarce, prognosis appears to be intermediate between the NOS and tip variants.28 In the Chapel Hill series of primary FSGS, Thomas and colleagues reported that the perihilar variant had the lowest frequency of nephrotic syndrome, the lowest initial serum creatinine, and the highest association with hypertension.29 Despite infrequent use of steroids and low rates of complete or partial remission (10% for each), kidney survival was good (75% at 3 years) and better than the NOS and collapsing variants.29 These outcomes may relate to inclusion of some cases with unrecognized secondary (adaptive) FSGS. In a Dutch cohort of mostly Caucasian adults with FSGS, the 5-year survival for the perihilar variant was 55%, compared with 63% for NOS and 78% for the tip variant.41 The relatively poor prognosis of the perihilar variant in this study was associated with more severe glomerular scarring, suggesting more advanced disease at diagnosis.41 There were too few cases of the perihilar and cellular variant in the FSGS clinical trial study to analyze outcomes.31 In most series of primary FSGS, the NOS variant is the most frequent, ranging from 32% to 73% of cases (Table 2). The rates of remission (complete or partial) range from 16% to 72.2%,29,43 and the rate of ESRD ranges from 0%43 to 37%,41 with median follow-up ranging from 2028 to 60 months.41 The rate of ESRD in adult patients with the NOS variant ranges from 22.2% in the study of Taneda and colleagues42 (mean follow-up 56 months) to 37% in

All pathologic classifications are limited by the heterogeneity of pathologic findings, sampling error, variable reproducibility, and the absence of an external standard to verify diagnoses. The likelihood of detecting a focal glomerular disease process is a function of the percentage of glomeruli affected, the size of the segmental lesions, and the number of serial sections studied. The defining features of segmental capillary collapse and tip lesions may be lost during histologic preparation, leading to underdiagnosis. Indeed, additional sectioning of biopsies of cases of apparent cellular variant sometimes reveals unsampled glomerular tip lesions or collapsing lesions.28 FSGS lesions initially affect juxtamedullary glomeruli,44 which may not be sampled in superficial cortical biopsy samples. In addition, because other variants may evolve to the NOS variant over time, such variants may be less frequent in biopsies obtained late in the disease course. In a recent study by Meehan and colleagues, the Columbia Classification showed good interobserver reproducibility among a group of 6 kidney pathologists.45 The overall agreement for 366 diagnoses was 75.2%, with a k value of 0.676, and with k values for individual variants ranging from moderate to good (0.53 for cellular, 0.60 for NOS, 0.76 for tip, 0.77 for collapsing, and 0.84 for perihilar).45 Of note, this study was performed by evaluating digital images of individual glomeruli rather than by review of glass slides under the microscope; therefore, its applicability to actual clinical practice is uncertain. Recognition of the cellular lesion is problematic because endocapillary foam cells are not a specific feature, but they may occur to some degree in other variants. What distinguishes the cellular variant is the expansile, purely cellular nature of the endocapillary lesions, which typically lack appreciable extracellular matrix. Another common pitfall is to consider any extracapillary proliferation as a de facto marker of the collapsing variant. Given the rarity of the cellular variant and the apparent difficulties in its recognition,45 it may be advisable to merge this category with the NOS variant in future iterations of the Columbia Classification after first diligently excluding the collapsing and tip variants by exhaustive sectioning. In addition, because outcomes appear much better in those tip variant cases with exclusively tip lesions compared with those with mixed tip and nontip lesions,4,24 a future approach would be to limit the tip variant to the former subgroup. An important limitation of morphologic classification is that the etiology and pathogenesis of primary FSGS are

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largely unknown, but these are likely diverse and multifactorial. Validation studies in FSGS have been mostly retrospective and may be subject to confounding bias because patients were heterogeneous in terms of age, ethnicity, duration and severity of clinical disease, and treatment before and after the diagnosis of FSGS (Tables 2-4). Regardless of etiology, the findings of different clinical characteristics in the collapsing and tip variants suggest that these morphologic variants reflect distinct biological pathways. Of note, some investigators have suggested that collapsing glomerulopathy and glomerular tip lesion should be classified separately from FSGS given the lack of extracellular matrix accumulation (ie, sclerosis) in most of these cases.46 However, because both of these entities demonstrate segmental glomerular lesions and may be accompanied by “classic” FSGS lesions, it is reasonable to include them within the spectrum of FSGS. A goal of future investigations should be to understand differences that underlie the morphogenesis of these variants. For example, does the collapsing variant involve greater rapidity and severity of podocyte injury and depletion than the NOS variant? The fact that untreated HIVinfected patients who develop FSGS typically manifest collapsing glomerulopathy whereas those on antiretroviral therapy typically develop NOS lesions supports this view.47 Is the highly steroid-responsive tip variant mediated by the same permeability factor as MCD, perhaps followed by a “second hit” to the podocyte? Greater knowledge of the chemotactic factors that stimulate parietal cell hyperplasia after podocyte injury is needed to understand why some variants incite more extracapillary proliferation and its potential for podocyte renewal.

Summary Some investigators have suggested that remission response, not morphologic variant, is the only important predictor of outcome in FSGS.26 However, multiple studies using the Columbia Classification provide evidence to the contrary (Tables 3 and 4). There is general agreement that outcomes are best in the tip variant and worst in the collapsing variant. Likewise, presenting serum creatinine values are highest in the collapsing variant and lowest in the tip variant. The collapsing variant has the highest Black racial association, whereas the tip variant predominantly affects Whites. Full nephrotic syndrome at presentation is more common in the tip and collapsing variants than in the NOS and perihilar variants. The perihilar variant, when lacking nephrotic syndrome and accompanied by glomerulomegaly and mild effacement, should prompt investigation for possible causes of secondary FSGS mediated by elevated glomerular capillary pressures and flows (“adaptive FSGS”). Ideally, a disease classification should include information about etiology and pathogenesis, but these are unknown for primary FSGS. The same argument could be made about any glomerular disease with diverse clinical manifestations for which the etiology is poorly understood, such as lupus nephritis and immunoglobulin A (IgA) nephropathy. In the latter 2 conditions, pathologic classification or scoring are considered a valuable gauge for individualizing optimal therapy in lupus nephritis48

and prognostication in IgA nephropathy.49 Pending the identification of specific etiologies and pathogenesis in individual patients with FSGS, morphologic classification is useful to identify subgroups with significantly different clinical behaviors and should be included in future therapeutic trials.

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