Focal segmental glomerulosclerosis: a morphologic diagnosis in evolution.
Abstract: * Context.--The diagnosis of focal segmental glomerulosclerosis (FSGS) is a descriptive pathologic diagnosis that in certain clinical situations (ie, primary or idiopathic) becomes its own disease. The clinical diversity, varied histology, and nonspecific morphologic features of FSGS all contribute to the complexity and problematic nature in making a pathologic diagnosis of FSGS. The definitions of the disease and of the morphologic features have evolved during the last century.

Objective.--To review historic and morphologic features of FSGS in order to demonstrate a practical approach in achieving a pathologic diagnosis of FSGS on kidney tissue.

Data Sources.--In 2004 a working proposal on the pathologic (morphologic) classification of FSGS was published in an attempt to unify the complexity of diagnosing FSGS, and it has shown to be both reproducible and with unique clinical implications for each defined FSGS variant.

Conclusions.--An accurate diagnosis of FSGS can be challenging. During the last few decades, numerous new scientific discoveries have enriched our knowledge of pathogenetic mechanisms of nephrotic syndrome. Thus, it is expected there will be a need for a further modification to a morphologic classification and that the pathologist's role in diagnosing FSGS will remain in evolution. This review recapitulates the history of the pathologic diagnosis of FSGS and a current morphologic classification, hopefully opening up a discussion for further modifications that reflect the status of knowledge evolving in the 21st century.
Article Type: Report
Subject: Nephrotic syndrome (Diagnosis)
Nephrotic syndrome (Genetic aspects)
Nephrotic syndrome (Development and progression)
Nephrotic syndrome (Drug therapy)
Steroids (Drugs) (Usage)
Steroids (Drugs) (Health aspects)
Pathology (Practice)
Author: Thomas, David B.
Pub Date: 02/01/2009
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165
Issue: Date: Feb, 2009 Source Volume: 133 Source Issue: 2
Topic: Event Code: 200 Management dynamics
Accession Number: 230151957
Full Text: Focal segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome (NS) in both adults and children, with up to a fifth of affected patients being at high risk for progression to end-stage renal disease. The pathologic diagnosis of FSGS on renal biopsy or resection specimens sounds straightforward--"focal," meaning a few but not all of the total sampled glomeruli have "segmental" solidification of the tuft that is an accumulation of extracellular matrix with obliteration of the capillary lumina (sclerosis). In practice the diagnosis of FSGS is often more problematic than it is straightforward, and it goes beyond a definition that is a sum of its name. As pathologists we struggle with creating definitive or encompassing definitions when, in fact, embracing the realization that our protracted limited knowledge of FSGS remains in evolution might serve us better.

The growing list of secondary forms of FSGS, novel diagnostic categorizations based around affected cells of the glomerulus or their genetic alterations, as well as a definition as a result of therapeutic intervention, such as steroid-sensitive nephrotic syndrome and steroid-resistant nephrotic syndrome, might even suggest a clinical impatience and desire to circumvent the nuance of pathologic morphology. (1)

The purpose of this review is to revisit the history of FSGS as a morphologic entity and a disease, discuss classification as it has been recognized until today, and analyze clinical implications of morphologic variants. This review will not settle ongoing debates on defining what is FSGS, but is rather an attempt to consolidate information concerning the pathologic diagnosis of FSGS.

HISTORIC BACKGROUND

Lipoid nephrosis for a pathologist historically referred predominantly to the tubular and urine abnormalities in nephrosis, whereas glomeruli had minimal lesions. The histologic features of FSGS were illustrated early in the 20th century and described as degenerative changes of glomeruli in lipoid nephrosis. (2) Given the similar clinical presentation in minimal-change disease (MCD) and FSGS, it was not until the mid-20th century that it was reported there was a different clinical course for patients with NS in those with minimal glomerular changes versus those with juxtamedullary glomerular hyaline or sclerosing glomerular lesions without cellular proliferation. (3) Rich's autopsy series3 reported the latter group of patients had progressive renal disease and uremia. Other authors began to report progressive renal disease in nephrotic patients coinciding with progressive glomerular sclerosis and increased interstitial scarring. (4) The relationship straining between the 2 pathology morphologies, MCD and FSGS--initially often considered as part of the same spectrum--were separated into unique clinicopathologic entities following a histopathologic classification of nephrotic syndrome for the International Study of Kidney Disease in Children. Also during that period, others reported comparable glomerular sclerosing lesions in renal biopsies not only from nephrotic patients, but also from patients with nonnephrotic proteinuria. (5)

Over the years, the number of synonyms used for diseases presenting as idiopathic NS in the absence of immune complex deposition evolved. In the mid 1980s other similar glomerular diseases became part of the FSGS spectrum, including collapsing, cellular, and tip lesions. During the early 1980s with the human immunodeficiency virus (HIV) epidemic, FSGS was considered the major glomerular injury occurring in patients infected with the virus. However, it was also recognized that often these lesions were slightly morphologically different from the originally described FSGS and characterized by collapse of the glomerular basement membranes and accumulation of epithelial cells (podocytes) in the urinary space. This lesion was first known as HIV-associated nephropathy or HIV-FSGS. (6-8) In the late 1970s/mid-1980s it also became clear that the clinical presentation of FSGS could vary from mild proteinuria to very severe proteinuria or NS with rapid progression; these more aggressive forms were initially named malignant FSGS. (9) In 1986 FSGS with a "malignant" course was reported that was morphologically comparable with HIV-associated nephropathy, despite negative serology for HIV infection in these patients. (10) In their study, Weiss et al (10) used for the first time the term collapsing to identify this form of idiopathic NS and suggested that "collasping glomerulopathy" was a new clinicopathologic entity. Following this initial description of 5 HIV-negative African American patients with aggressive renal disease, approximately a decade later 2 additional studies confirmed the presence of a new form of NS, suggesting that collapsing damage of the glomerular tuft was part of the FSGS spectrum (collapsing FSGS). (11,12)

In addition to the term collapsing, a second term was also introduced in the mid 1980s: the cellular lesion. (13) The recognition in this study of the heterogeneity of clinical presentation, degree of proteinuria, and morphology has been a critical step in the history of FSGS, although it had created some controversy among pathologists. The cellular lesion as described by Schwartz and Lewis13 included a group of glomerular lesions characterized by hypercellularity. In their definition the increased cellularity was either due to an increased number of visceral epithelial cells in the urinary space and accompanied by collapse of the glomerular basement membranes, or by an increased number of endocapillary cells, without significant collapse but, rather, obliteration of the capillary lumina by swollen endothelial cells. In the years to come, some authors accepted and used the term cellular lesion for all forms of severe NS with increased cellularity, whereas others made a distinction between those with extracapillary proliferation and collapse versus those with endocapillary proliferation; the term collapsing FSGS was used for the former, and the term cellular lesion was restricted to the latter. (14)

Simultaneously with the appearance in the literature of the terms collapsing and cellular lesion, a third entity was introduced by Howie and Brewer (15): the tip lesion. According to the initial description and definition of the disease, the tip lesion had a more favorable prognosis, comparable to MCD, although it was recognized that there were morphologic differences between the two. Whereas by definition MCD has no abnormalities on light microscopy, tip lesion consists of a combination of changes at the tip of glomerulus, including collection of endocapillary foam cells with overlying hypertrophic podocytes bridging toward parietal and proximal tubular cells at its origin from the glomerulus, and on some occasions with herniation into the proximal tubule.15 Although the authors recognized that the tip lesion may have been included previously within the FSGS spectrum, they suggested that tip lesion was a well-defined and specific pathologic entity or in combination with other non-FSGS-like lesions (eg, membranous glomerulopathy). This observation may suggest a more parallel entity to FSGS rather than one for inclusion.

Given the heterogeneity of morphologic presentation, the term classic FSGS was introduced to identify what was originally described as FSGS. (14) In 2004 an editorial on the pathologic classification of FSGS was published to address a standardized approach in diagnosis of the heterogeneous lesions being called FSGS. (16)

THE COLUMBIA CLASSIFICATION

The working proposal for a histologic classification of FSGS is an attempt to unify a diagnosis of FSGS that was spawning as many subtypes as there are heterogeneous etiologies of the lesions. (16) A collection of expert renal pathologists convened at Columbia University to begin this arduous task, and since that time the classification scheme has been affectively referred to as the Columbia classification of FSGS. The value of this collaboration to define the lesions of FSGS is meritorious but not without its detractors. The classification is exclusively based on morphology. Stated within the editorial, the defining characteristic of a specific subtype may be present in either idiopathic or secondary etiologies. Therefore, the Columbia classification of FSGS should not be confused with accounting for etiology or pathogenetic mechanisms in the development of that defined lesion. However, neither should this undermine the utility of the morphologic classification in stratifying unique clinical characteristics within each subtype. (17)

Also, characteristic ultrastructural podocyte foot process effacement, a major pathologic feature common to all forms of proteinuria and NS, unfortunately is not defined or addressed. This again leaves electron microscopy features forlorn and uncharacterized in a system to differentiate variants of FSGS, let alone in idiopathic versus secondary etiologies.

On the other hand, in the Columbia classification each variant of FSGS is rigorously defined by specific criteria, reducing tremendously the confusion about the terminology that characterized the last 2 decades of the 20th century. The classification is based on an algorithmic approach to segregate the lesions into 5 categories, with the final goal to unify terminology to identify each of the specific forms of glomerular injury identified particularly since the 1980s. (16)

Collapsing Variant. Since the early descriptions of collapsing forms of glomerular lesion, it has not been clear how much collapse was required to be termed collapsing. Pathologists have used different terms in their reports, sometimes with the intention of reflecting the extension of the lesion; for example, FSGS with collapsing features has been used in cases where segmental sclerosis with accumulation of extracellular matrix was the predominant lesion in a given biopsy specimen, and collapse was only focally present. If collapse was the predominant lesion, collapsing glomerulopathy or collapsing FSGS were more often used. Glomerular collapse may be accompanied by glomerular epithelial cell hypertrophy with or without hyperplasia.

[FIGURES 1-2 OMITTED]

In the Columbia classification, collapsing FSGS or collapsing variant of FSGS is defined by collapse of at least 1 capillary loop with obliteration of the lumen with proliferation (hyperplasia) and hypertrophy of the overlying podocytes (Figure 1), regardless of the presence of other lesions resembling the other 4 variants of FSGS (Figure 2).

Collapsing forms of glomerular lesions are often accompanied by severe tubulointerstitial injury with microcysts and hypertrophic tubular epithelial cells swollen with hyaline protein reabsorption droplets. One point of question among some pathologists is whether in the absence of tubulointerstitial damage we should still consider the disease "collapsing." The Columbia classification does not mandate tubulointerstitial changes for a collapsing variant diagnosis. The status of the tubulointerstitium is not critical to the working proposal definition of any FSGS subtype. However, future renditions and directions in definition will hopefully use similar rigorously defined specific criteria of the glomerular abnormalities outside the glomerulus in an effort to recognize additional prognostic and clinical parameters.

Tip Variant. The Columbia classification diagnosis of the FSGS tip variant requires the exclusion of FSGS "collapsing variant" and at least one glomerulus with the defining feature of a segmental lesion involving the tip domain of the glomerular capillary tuft (Figure 3). In this scenario the definition of a segmental lesion is defined as foam cells, endocapillary hypercellularity (involving <50% of the tuft), or sclerosis (involving <25% of the tuft). Also, the tip domain is additionally defined as the outer 25% of the glomerulus next to the origin of the proximal tubule. Although the tip domain is typically opposite the vascular pole of an individual glomerulus, the classification additionally demands the identification of the origin of the proximal tubule with the confluent or adherent segmental lesion for the diagnosis FSGS tip variant. A perihilar lesion precludes the diagnosis of FSGS tip variant in the Columbia classification of FSGS. This somewhat awkward definition with curious restrictions in defining the segmental lesion yet exclusion based on the presence of perihilar abnormalities appears to be a nod to the early description of the glomerular tip lesion presented by Howie and Brewer. (15) This early description of the glomerular tip lesion was not restricted to FSGS, but rather a novel report of a curious glomerular abnormality seen independently in patients with proteinuria as well as being found in other heterogeneous renal abnormalities with associated proteinuria, including membranous glomerulopathy and diabetic glomerulosclerosis.

Cellular Variant.--The FSGS cellular variant diagnosis mandates the exclusion of a diagnosis of FSGS collapsing variant and exclusion of FSGS tip variant. The cellular variant is defined by the presence of at least one glomerulus with segmental endocapillary proliferation occluding lumina, with or without karyorrhexis (Figures 4 and 5). In contrast with the original description of a cellular lesion, (13) the Columbia classification restricts the hypercellularity to the endocapillary compartment of the glomerulus and does not (as originally reported) occur with collapse of the glomerular basement membranes. Therefore, application of the Columbia classification in practice by its defining features would place any such lesion with basement membrane collapse in the FSGS collapsing variant described previously. Podocyte abnormalities are not a defining feature for the cellular variant.

Perihilar Variant.--In FSGS perihilar variant the segmental sclerotic lesion is located at the vascular pole and often accompanied by hyalinosis (Figure 6). Such diagnosis can be made only if the lesion is not accompanied by tip, collapsing, or cellular lesion within the same biopsy. FSGS perihilar variant most closely resembles the lesions initially described in children with steroid-resistant nephrotic syndrome as well as lesions observed in animal models of renal ablation. (18,19) Accordingly, this variant, although a form of idiopathic FSGS, is also common in secondary forms mediated by hyperfiltration, and in that case it is often accompanied by glomerulomegaly. (20-23)

Not Otherwise Specified.--Not otherwise specified, or FSGS NOS, is a term used when none of the above definitions apply. In FSGS NOS the segmental solidification of the tuft can be present in any portion of the glomerulus. Generally, it is accompanied by adhesion of the tuft to the Bowman capsule, and on occasion hyalinosis can be observed, although these are not part of the diagnostic criteria (Figure 7). FSGS NOS is practically a diagnosis by exclusion, and its significance needs to be investigated further. For example, given the recent discoveries of genetic forms of podocyte injury leading to FSGS, it is possible that in the not-so-distant future the application of the Columbia classification to more etiology-based classification of NS may shed light on the correlation of morphologic findings and specific genetic mutations of podocyte protein, known to be the major causes of FSGS.

[FIGURE 3 OMITTED]

INCIDENCE OF FSGS VARIANTS USING THE COLUMBIA CLASSIFICATION AND CLINICAL IMPLICATIONS

Since the publication of the Columbia classification, several authors have independently studied its potential application with respect to acquiring important information regarding demographic, clinical presentation, prognosis, and response to conventional drugs or new combinations of known medications.

An analysis of 197 patients with a diagnosis of FSGS according to the Columbia classification revealed that FSGS NOS variant was the most common form (42% of cases), followed by the perihilar variant (26%), tip variant (17%), collapsing variant (11%), and cellular variant, which was the least frequent (3%). Patients with collapsing variant and tip variant had a greater amount of proteinuria than patients with perihilar variant and FSGS NOS (P < .001). The demographic was significantly different for the collapsing variant and tip variant patients--most patients (91%) with collapsing variant were African American while only 15% of patients with tip variant were African American. (17)

Stokes and colleagues (24) confirmed the demographic data previously

published that formed a high predilection of tip variant (86%) and a high level of proteinuria in tip and collapsing variant compared with perihilar and NOS variants in whites. In contrast, the predominance of African Americans with collapsing variant was only 53.6%, but the incidence of cellular variant was slightly higher (10%). Given the higher number of patients with cellular variant, more significant prognostic data were gathered, and patients with FSGS cellular variant showed an intermediate rate of remission between collapsing and tip variant (44.5% vs 13.2% and 65.3%, respectively). (24) Similarly, in the cohort followed by the Glomerular Disease Collaborative Network, when compared with other variants the patients with tip variant had a higher frequency of complete remission (1 year, P < .001), and FSGS collapsing variant had the worst renal survival (3 years). Based on these data, the authors suggested that the nature of the injury in FSGS collapsing variant may be different compared with other variants. (17,25) This concept also has been expanded in a more recent proposed classification of NS (1) (see also Barisoni et al in this issue of the ARCHIVES).

The data reported by the Glomerular Disease Collaborative Network and by the Columbia University group were confirmed recently by other studies. Deegens and colleagues (26) reported better renal function in patients with FSGS tip variant compared with FSGS NOS, with better renal survival at 5 years (78%) compared with perihilar variant and FSGS NOS (55% and 63%, respectively; P = .02). The incidence of each variant present in this series was 37% tip variant, 32% NOS, 26% perihilar variant, and 5% collapsing variant. (26)

In contrast with the above-mentioned study on a population with a high prevalence of adult whites, if the criteria of the Columbia classification are applied to a pediatric population with a high prevalence of African Americans, the ratio between the different variants changes: although NOS remains the most common diagnosis (44%), it is followed by cellular (32%) and collapsing (24%) variants. Interestingly, both the tip and perihilar variants were not represented in this pediatric series, supporting the hypothesis that the Columbia classification may correlate, to a certain degree, with demographic data. However, the probability to response of therapy remains unchanged compared with previous studies, and the collapsing variant carries the worst prognosis. (27)

In summary, the pathologic variants of FSGS are associated with demographic, clinical, and outcome differences.

ARE ALL SEGMENTAL SCLEROSIS FSGS? DIFFERENTIAL DIAGNOSIS

Segmental sclerosis is a morphologic description of a lesion that may represent a primary injury of the glomerulus or a secondary response to other injurious events, such as hyperfiltration, healed immune complex-mediated diseases, or scarring. Known examples of glomerulonephritis where segmental sclerosis is commonly part of the disease entity are immunoglobulin (Ig) A nephropathy, IgM nephropathy, and C1q nephropathy. Segmental accumulation of extracellular matrix is also not uncommon in healed crescentic necrotizing glomerulonephritis, diabetic nephropathy, or even membranous glomerulopathy. Whereas often the recognition that the segmental sclerosis is simply a secondary phenomenon, on occasion it may create confusion in the classification and final diagnosis.

[FIGURES 4-6 OMITTED]

It is known that a percentage of patients with IgA nephropathy may present with proteinuria and NS and segmental sclerosis in addition to the presence of mesangial IgA and complement deposition. Although by morphologic criteria they may fall in some of the categories of FSGS variants described above, it is clear that in these cases the presence of sclerosis is a secondary phenomenon, and the primary diagnosis is IgA nephropathy. (28,29)

More controversial is the case of IgM or C1q nephropathy. Immunoglobulin M nephropathy has been considered part of the MCD spectrum as well as the FSGS spectrum. The morphologic features at light microscopy may vary from MCD-like to diffuse mesangial proliferation to segmental sclerosis. Most cases have a benign course with good response to steroid therapy. (30,31) Its etiology and significance are unknown and its incidence is very low in Western countries, but it is a relatively common disease in Asia (Taiwan, India, Thailand, and others). (30,31) Although in its clinical and morphologic presentation IgM nephropathy may resemble MCD or FSGS, the presence of electrondense deposits (IgM and complement) exclude this entity from the MDC-FSGS spectrum, as by definition FSGS and MCD are not immune complex-mediated or complement-mediated diseases.

C1q nephropathy was first described by Jennette and Hipp (32) in 15 patients with mesangial deposition of C1q and steroid-resistant nephrotic syndrome. It generally affects older children and young adults, with an average age of 17.8 years. (32) Similar to IgM nephropathy, C1q nephropathy may present with features resembling MCD, diffuse mesangial proliferation, or FSGS, but in this case patients tend to be either resistant or dependent to steroid therapy. (33) Although some authors have suggested that C1q nephropathy may represent a variant of FSGS, (34) C1q nephropathy is a complement-mediated disease and not a disease mediated by podocyte injury, and the presence of mesangial electron-dense deposits should exclude this entity from the FSGS spectrum.

[FIGURE 7 OMITTED]

Although the Columbia classification recognizes the FSGS tip variant, its significance is still controversial, and it is also clear from several studies and observations that it may occur in association with other glomerular diseases. The question among renal pathologists is whether tip lesion simply represents a protrusion of the tip of the glomerulus into the tubular pole and a nonspecific glomerular abnormality in response to proteinuria, (35-37) a variant of FSGS as suggested by the Columbia classification, (16) or a variant of MCD. (35,36) This may be irrelevant given the fact that most pure tip lesions have a very good prognosis and response to steroid therapy. (17,36)

FSGS, THE 21ST CENTURY: RECENT DISCOVERIES AND FUTURE CLASSIFICATIONS

As mentioned above, the classification of FSGS has evolved during the last several decades, and its evolution is far from being complete. As scientific discoveries rapidly change the level and depth of our knowledge about certain diseases, the new information needs to be integrated with conventional schemes to classify renal diseases. The most striking example of recent tremendous advances in discovering genetic and molecular mechanisms of renal diseases is, indeed, the case of FSGS (see the review by Barisoni et al in this issue of the ARCHIVES). Aware of the advances made in studying the molecular bases of podocyte diseases, this group of authors recently suggested a new approach to classify diseases with primary NS that integrates conventional histologic features with etiology.1 Recognizing that the common pathogenetic element among the heterogenous variety of lesions with NS is podocyte injury, they proposed that the various clinical and histologic variants are the result of podocyte response to injurious stimuli: effacement, apoptosis, arrested differentiation, or dedifferentiation. In addition, different from conventional practice, they suggest that each of the morphologic entities listed in the taxonomy represents a glomerular reaction, what pathologists know as "descriptive diagnosis," to injurious stimuli, rather than a specific disease, and that the "final diagnosis" derives from the combination of a descriptive term and etiologic factor, when applicable. (1) Although vogue and exciting to attempt to immediately integrate this taxonomy of podocytopathies with the aforementioned pure morphologic approach (the Columbia classification), it would be premature and entirely speculative without a systematic study on podocyte phenotype and genotype found within each of the morphologic variants of FSGS. Exactly when and how these new approaches will integrate with more conventional standards of practice in renal pathology is not clear, but given the rapid pace of change in medicine, molecular discoveries, and novel drug development for new therapeutic interventions, evolution from a morphologic classification would seem inevitable.

Accepted for publication October 16, 2008.

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David B. Thomas, MD

From Nephrocor, Uniondale, NY.

The author has no relevant financial interest in the products or companies described in this article.

Reprints: David B. Thomas, MD, Nephrocor, 100 Charles Lindbergh Blvd, Uniondale, NY 11553 (e-mail: dbthomas@nephrocor.com).
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