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Pathologic Classification of Focal Segmental Glomerulosclerosis

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Pathologic Classification of Focal Segmental Glomerulosclerosis Pathologic Classification of Focal Segmental Glomerulosclerosis By Vivette D’Agati Focal segmental glomerulosclerosis (FSGS) is defined as a clinical-pathologic syndrome manifesting proteinuria and focal and segmental glomerular sclerosis with foot process effacement. The pathologic approach to the classification of FSGS is complicated by the existence of primary (idiopathic) forms and multiple subcategories with etiologic associations, including human immunodeficiency virus (HIV)-associated nephropathy, heroin ne- phropathy, familial forms, drug toxicities, and a large group of secondary FSGS mediated by structural-functional adaptations to glomerular hyperfiltration. A number of morphologic variants of primary and secondary focal sclerosis are now recognized, including FSGS not otherwise specified (NOS), perihilar, cellular, tip, and collapsing variants. The defining features of these morphologic variants and of the major subcategories of FSGS are discussed with emphasis on distinguishing light microscopic patterns and clinical-pathologic correlations. © 2003 Elsevier Inc. All rights reserved. HE FIRST IMAGE of focal segmental glo- tern of sclerosis evolves. Alterations of the podo- Tmerulosclerosis (FSGS) was published in cyte cytoarchitecture constitute the major ultra- 1925 in a remarkably accurate drawing by Fahr1 structural findings. from an atlas of human pathology. Even at that The approach to a diagnosis of FSGS is prob- early time, Fahr1 recognized the relatedness of this lematic because the morphologic features are non- novel lesion to minimal change disease when he specific and can occur in a variety of other condi- aptly entitled it lipoid nephrosis with degeneration. tions or superimposed on other glomerular It would be another 32 years before Rich2 provided processes.6 In addition, because the defining glo- a more detailed pathologic description of focal merular lesion is focal, it may not be adequately sclerosis in autopsy specimens of children dying sampled in small needle biopsies. with nephrotic syndrome caused by apparent lipoid The diagnosis of FSGS is further complicated by nephrosis. Rich2 was the first to observe the pref- the existence of a primary (or idiopathic) form and erential distribution of the segmental sclerosing many secondary forms (Table 1).6,7 Before a diag- lesions in juxtamedullary glomeruli early in the nosis of primary FSGS can be reached, secondary disease, indicating the focality of the sclerosing forms must be carefully excluded. Idiopathic FSGS process. He postulated that the development of must be distinguished from human immunodefi- sclerosis probably accounted for the progression to ciency virus (HIV)-associated nephropathy and renal failure seen in a subset of children with heroin nephropathy, as well as the large group of secondary FSGS caused by structural-functional idiopathic nephrotic syndrome. However, it was adaptations mediated by intrarenal vasodilatation not until the 1970s, in a report by the International and by increased glomerular capillary pressures Study of Kidney Diseases in Children, that focal and plasma flow rates.7 Such maladaptive glomer- segmental glomerulosclerosis emerged as a sepa- ular hemodynamic alterations can arise through: rate clinical-pathologic entity that was distin- (1) a reduction in the number of functioning guished from minimal change disease by its greater nephrons (such as after unilateral renal agenesis, steroid resistance and progression to renal failure.3 surgical ablation, oligomeganephronia, or any ad- Over the past 30 years, concepts of FSGS have vanced primary renal disease), or (2) mechanisms been refined in more detailed clinical-pathologic that place hemodynamic stress on an initially nor- studies from many centers. FSGS is defined as a mal nephron population (as in morbid obesity, clinical-pathologic syndrome manifesting protein- cyanotic congenital heart disease, and sickle cell uria, usually of nephrotic range, associated with lesions of focal and segmental glomerular sclerosis From the Department of Pathology, Columbia University, 4,5 and foot process effacement. Although hyaline College of Physicians and Surgeons, New York, NY. insudation is common, the condition lacks glomer- Address reprint requests to Vivette D’Agati, MD, Department ular immune complex deposits. Early in the disease of Pathology, Columbia University, College of Physicians and process, the pattern of glomerular sclerosis is focal, Surgeons, 630 West 168th St, New York, NY 10032. involving a subset of glomeruli, and segmental, E-mail: [email protected] © 2003 Elsevier Inc. All rights reserved. involving a portion of the glomerular tuft. As the 0270-9295/03/2302-0002$30.00/0 disease progresses, a more diffuse and global pat- doi:10.1053/snep.2003.50012 Seminars in Nephrology, Vol 23, No 2 (March), 2003: pp 117-134 117 118 VIVETTE D’AGATI Table 1. Etiologic Classification of FSGS scarring in the course of other primary glomerular diseases (such as chronic glomerulonephritis, dia- Primary (idiopathic) FSGS C1q nephropathy betic glomerulosclerosis, membranous glomeru- HIV-associated nephropathy lopathy, hereditary nephritis, and so forth). Five Heroin nephropathy main light microscopic patterns of FSGS have Familial FSGS been defined, including FSGS (not otherwise spec- ␣ Mutations in -actinin 4 (autosomal dominant) ified [NOS]), perihilar variant, cellular variant, tip Mutations in podocin (autosomal recessive) Mitochondrial cytopathies variant, and collapsing variant. Although the ap- Drug toxicity pearance of the glomerular tuft differs in these Pamidronate forms, all share the common feature of podocyte Lithium alterations at the ultrastructural level. At the ␣ Interferon- present time, it is unclear if these morphologic Secondary FSGS (adaptive structural-functional response likely mediated by glomerular variants reflect pathogenetic differences or whether hypertrophy/hyperfiltration) they are the consequence of different severities of Reduced renal mass podocyte injury or tempos of histopathologic evo- Oligomeganephronia lution. Future studies are needed to address these Unilateral renal agenesis questions. The pathologic features and major clin- Renal dysplasia Reflux nephropathy ical correlates of each of these morphologic vari- Sequela to cortical necrosis ants are discussed. Surgical renal ablation Any advanced renal disease with reduction in FSGS (NOS) functioning nephrons FSGS (NOS) constitutes the generic lesion of Chronic allograft nephropathy Initially normal renal mass FSGS. The synonyms classic FSGS or FSGS of the Diabetes mellitus usual type often are applied. This category requires Hypertension that other morphologic categories (perihilar, cellu- Obesity lar, tip, and collapsing) be excluded. FSGS (NOS) Cyanotic congenital heart disease is the most common morphologic pattern of FSGS. Sickle cell anemia Nonspecific pattern of FSGS caused by renal scarring Evidence from repeat biopsy examinations sug- Focal proliferative glomerulonephritis (IgA gests that other variants may evolve into this pat- nephropathy, lupus nephritis, pauci-immune focal tern in the course of disease progression and in- necrotizing and crescentic glomerulonephritis) creasing chronicity. Hereditary nephritis Diabetic nephropathy Pathologic Features Hypertensive arterionephrosclerosis Membranous glomerulopathy FSGS (NOS) is defined as a discrete segmental Thrombotic microangiopathies consolidation of the glomerular tuft by increased extracellular matrix, causing obliteration of the glomerular capillary lumen/lumina (Figs 1A–1B). anemia). Finally, primary and secondary FSGS Early in the disease, the segmental lesions have a also must be differentiated from the nonspecific predilection for the juxtamedullary glomeruli. Le- pattern of focal and segmental glomerular scarring sions of sclerosis can affect the perihilar (ie, vas- that can follow a variety of inflammatory, prolif- cular pole) region or the periphery of the tuft. In erative, thrombotic, and hereditary conditions. some glomeruli, segmental lesions may affect FSGS comprises a number of morphologic sub- more than one lobule, involving both the perihilar types that may have different prognostic and ther- and peripheral regions. According to one study apeutic implications. These morphologic variants using serial sections, peripheral lesions tend to be were defined at a recent consensus conference of more common in childhood FSGS than the adult renal pathologists in New York City (Table 2). The disease.8 Any number of glomeruli can be affected categorization outlined in Table 2 encompasses the by segmental sclerosis, with or without associated spectrum of primary FSGS, as well as some sec- global sclerosis. ondary forms. This schema presumes prior exclu- Glomerular capillaries are occluded segmentally sion of secondary FSGS caused by glomerular by relatively acellular matrix material, often asso- PATHOLOGIC CLASSIFICATION OF FSGS 119 Table 2. Morphologic Variants of FSGS Variant Positive Criteria Negative Criteria FSGS (NOS) At least one glomerulus with segmental increase in matrix Exclude perihilar, cellular, tip, and obliterating the capillary lumina collapsing variants There may be segmental glomerular basement membrane collapse without podocyte hyperplasia Perihilar variant Perihilar sclerosis and hyalinosis involving Ͼ50% of Exclude cellular, tip, and collapsing segmentally sclerotic glomeruli variants Cellular variant At least one glomerulus with segmental endocapillary Exclude tip and collapsing variants hypercellularity occluding
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