Pathologic classification of focal segmental glomerulosclerosis: a working proposal  Vivette D D'Agati, MD, Agnes B Fogo, MD, Jan A Bruijn, MD, J.Charles Jennette, MD  American Journal of Kidney Diseases  Volume 43, Issue 2, Pages 368-382 (February 2004) DOI: 10.1053/j.ajkd.2003.10.024 Copyright © 2004 National Kidney Foundation, Inc. Terms and Conditions

Fig 1 FSGS (NOS) and FSGS perihilar variant. (A) FSGS (NOS). A low-power view shows segmental lesions of sclerosis in all 4 glomeruli pictured. Lesions of sclerosis are characterized by increased matrix, causing obliteration of the capillary lumina. Distribution of lesions within the tuft is variable, affecting both peripheral and perihilar segments. In some glomeruli, the location of the sclerosis cannot be ascertained because of the plane of section. (JMS; original magnification ×100.) (B) FSGS (NOS). High-power view of a glomerulus shows a discrete segmental lesion of sclerosis with wrinkling and collapse of glomerular basement membranes (stained blue) and hyaline deposits (stained red). Overlying the wrinkled capillaries, there is detachment of podocytes, which form a “cap,” with intervening deposition of looser neomembrane that is weakly trichrome-blue positive. Although the capped podocytes appear hypertrophied, there is no podocyte hyperplasia. (Masson trichrome; original magnification ×400.) (C) FSGS (NOS). There is segmental obliteration of the glomerular tuft by increased matrix and hyaline material. Sclerosed segments form adhesions to Bowman's capsule. There is no obvious podocyte hypertrophy or hyperplasia. The location of the sclerotic lesion within the glomerular tuft cannot be determined because neither the tubular nor the vascular pole are represented in the plane of section. (PAS; original magnification ×250.) (D) FSGS perihilar variant. On low-power examination, 1 of the 3 glomeruli pictured contains a discrete lesion of segmental sclerosis affecting the vascular pole region. The lesion shows both increased matrix (sclerosis) and hyalinosis. There is adhesion of the sclerotic segment to Bowman's capsule in the vascular pole region. Perihilar lesions were identified in more than 50% of glomeruli with segmental sclerosis. Both the glomerulus with segmental sclerosis and the 2 nonsclerotic glomeruli are hypertrophied in this patient with morbid obesity. (PAS; original magnification ×100.) (E) FSGS perihilar variant. High-power view of the perihilar lesion in (D) shows both the increased matrix (sclerosis) and glassy hyalinosis deposited in the vascular pole segment of the tuft, identified by the incoming arteriole and macula densa. There is no obvious podocyte hypertrophy or hyperplasia. (PAS; original magnification ×250.) (F) FSGS perihilar variant. A very early lesion illustrates the mild increase in matrix and hyaline surrounding the glomerular hilus. There also is hyalinosis of the adjacent preglomerular arteriole. The glomerulus is hypertrophied in this patient with a solitary functioning kidney. (PAS; original magnification ×250.) American Journal of Kidney Diseases 2004 43, 368-382DOI: (10.1053/j.ajkd.2003.10.024) Copyright © 2004 National Kidney Foundation, Inc. Terms and Conditions

Fig 2 FSGS cellular variant. (A) The defining glomerulus in this patient with primary FSGS shows segmental endocapillary hypercellularity. Involved segments are engorged with endocapillary cells, including some infiltrating mononuclear leukocytes. (H&E; original magnification ×250.) (B) In the cellular variant, silver stain shows expansion of the involved segments by endocapillary cells (not matrix), including foam cells and some karyorrhectic leukocytes. No glomerular capillary wall collapse is seen. There is hypertrophy and hyperplasia of the overlying podocytes. (JMS; original magnification ×400.) (C) This example of the cellular lesion shows numerous endocapillary leukocytes, mimicking a segmental endocapillary proliferative glomerulonephritis. There is hypertrophy and hyperplasia of overlying podocytes. Adjacent glomerular segments have mild mesangial hypercellularity. (H&E; original magnification ×400.) (D) High-power view of a cellular lesion shows karyorrhectic nuclear debris, admixed with foam cells and hyaline material. Overlying podocytes are hyperplastic. (H&E; original magnification ×600.) (E) Electron micrograph of the cellular lesion shows engorgement of the glomerular capillary lumen by foam cells and infiltrating mononuclear cells. There is mild inframembranous hyalinosis. No collapse or rupture of the glomerular basement membrane is seen. There is overlying podocyte hypertrophy and complete foot-process effacement with loss of primary processes. (Original magnification ×2,500.) (F) Electron micrograph shows more pronounced dilatation of the glomerular capillary by endocapillary cells, including many lipid-laden foam cells. Foot processes are completely effaced, with loss of primary processes and detachment of podocytes from the glomerular basement membrane. (Original magnification ×2,500.) American Journal of Kidney Diseases 2004 43, 368-382DOI: (10.1053/j.ajkd.2003.10.024) Copyright © 2004 National Kidney Foundation, Inc. Terms and Conditions

Fig 3 FSGS tip variant. (A) Low-power view shows a segmental lesion involving the tip domain at the origin of the tubular pole. The vascular pole is not visible in this plane of section. (PAS; original magnification ×250.) (B) High-power view of the lesion in A shows the involved segment to contain endocapillary foam cells and form an adhesion to Bowman's capsule at the mouth of the proximal tubule. There is capping of the overlying podocytes, which become confluent with the adjacent tubular epithelium. (PAS; original magnification ×600.) (C) Low-power view shows the portion of the glomerular tuft involving the tip domain to be expanded by a segmental lesion with cellular features located at the tubular pole. (PAS; original magnification ×250.) (D) High-power view of the tip lesion in C shows endocapillary foam cells admixed with a few leukocytes. There is a small adhesion of the tuft to Bowman's capsule at the tubular pole. Overlying podocytes appear confluent with the adjacent tubular epithelial cells. (PAS; original magnification ×600.) (E) Opposite the vascular pole, the origin of the proximal tubule is visible. In this area, there is an early tip lesion with inframembranous hyalinosis, a few endocapillary foam cells, and confluence of swollen podocytes with the tubular epithelium. (PAS; original magnification ×250.) (F) In this glomerulus, the tip lesion appears to herniate into the tubular lumen and forms a capsular adhesion. (PAS; original magnification ×250.) (G) High-power view of a tip lesion shows its cellular character, with endocapillary foam cells. There is adhesion to the origin of the tubular pole, with capping of the overlying podocytes and confluence with the adjacent tubular epithelium. (H&E; original magnification ×600.) (H) This tip lesion has cellular features and forms an adhesion to Bowman's capsule at the origin of the proximal tubule. The segment of the tuft containing the tip lesion appears to be detached from the remainder of the tuft because of the plane of section. (PAS; original magnification ×250.) (I) In this example, the tip lesion has sclerosing, rather than cellular, features. There is segmental sclerosis involving the tip domain at the origin of the proximal tubule, with adhesion to Bowman's capsule and capping of the overlying podocytes. Brush border identifies the tubular epithelial cells. (PAS; original magnification ×250.) American Journal of Kidney Diseases 2004 43, 368-382DOI: (10.1053/j.ajkd.2003.10.024) Copyright © 2004 National Kidney Foundation, Inc. Terms and Conditions

Fig 3 FSGS tip variant. (A) Low-power view shows a segmental lesion involving the tip domain at the origin of the tubular pole. The vascular pole is not visible in this plane of section. (PAS; original magnification ×250.) (B) High-power view of the lesion in A shows the involved segment to contain endocapillary foam cells and form an adhesion to Bowman's capsule at the mouth of the proximal tubule. There is capping of the overlying podocytes, which become confluent with the adjacent tubular epithelium. (PAS; original magnification ×600.) (C) Low-power view shows the portion of the glomerular tuft involving the tip domain to be expanded by a segmental lesion with cellular features located at the tubular pole. (PAS; original magnification ×250.) (D) High-power view of the tip lesion in C shows endocapillary foam cells admixed with a few leukocytes. There is a small adhesion of the tuft to Bowman's capsule at the tubular pole. Overlying podocytes appear confluent with the adjacent tubular epithelial cells. (PAS; original magnification ×600.) (E) Opposite the vascular pole, the origin of the proximal tubule is visible. In this area, there is an early tip lesion with inframembranous hyalinosis, a few endocapillary foam cells, and confluence of swollen podocytes with the tubular epithelium. (PAS; original magnification ×250.) (F) In this glomerulus, the tip lesion appears to herniate into the tubular lumen and forms a capsular adhesion. (PAS; original magnification ×250.) (G) High-power view of a tip lesion shows its cellular character, with endocapillary foam cells. There is adhesion to the origin of the tubular pole, with capping of the overlying podocytes and confluence with the adjacent tubular epithelium. (H&E; original magnification ×600.) (H) This tip lesion has cellular features and forms an adhesion to Bowman's capsule at the origin of the proximal tubule. The segment of the tuft containing the tip lesion appears to be detached from the remainder of the tuft because of the plane of section. (PAS; original magnification ×250.) (I) In this example, the tip lesion has sclerosing, rather than cellular, features. There is segmental sclerosis involving the tip domain at the origin of the proximal tubule, with adhesion to Bowman's capsule and capping of the overlying podocytes. Brush border identifies the tubular epithelial cells. (PAS; original magnification ×250.) American Journal of Kidney Diseases 2004 43, 368-382DOI: (10.1053/j.ajkd.2003.10.024) Copyright © 2004 National Kidney Foundation, Inc. Terms and Conditions

Fig 4 FSGS collapsing variant. (A) A low-power view shows 4 glomeruli, all of which have global collapse of the tuft and podocyte hypertrophy and hyperplasia. There are associated tubular degenerative changes. (JMS; original magnification ×100.) (B) On high-power view, the lesion of collapsing sclerosis shows global occlusion of capillary lumina by implosive collapse of glomerular basement membranes. There is no appreciable increase in intracapillary cells or matrix. Overlying podocytes form a cellular corona over the collapsed tuft. Some of the enlarged podocytes appear binucleated and have lost their cohesion to the tuft. (JMS; original magnification ×400.) (C) An example of global collapse of the glomerular tuft with marked overlying podocyte hyperplasia, forming a pseudocrescent that fills the urinary space. An apoptotic podocyte has detached from the tuft and is passing into the tubular pole. (JMS; original magnification ×400.) (D) Hyperplastic podocytes contain numerous intracytoplasmic protein resorption droplets, which appear red with trichrome stain. The collapsed tuft, shown in blue, has no patent capillary lumina. (Masson trichrome; original magnification × 400.) (E) Hyperplastic podocytes form several layers of cells over the collapsed tuft. Some of the swollen podocytes contain intracytoplasmic vacuoles. Podocyte nuclei have a vesicular chromatin pattern with prominent nucleoli. (JMS; original magnification ×400.) (F) A segmental lesion of collapsing sclerosis spares more than half the tuft. Collapsed capillaries have prominent overlying podocyte hypertrophy and hyperplasia, with abundant trichrome-red intracytoplasmic protein resorption droplets. (Masson trichrome; original magnification ×400.) (G) By electron microscopy, the collapsed loop has folded glomerular basement membranes, with complete effacement of foot processes. Overlying podocytes are detached from the glomerular basement membrane with intervening layering of neomembrane material. (Original magnification ×2,500.) American Journal of Kidney Diseases 2004 43, 368-382DOI: (10.1053/j.ajkd.2003.10.024) Copyright © 2004 National Kidney Foundation, Inc. Terms and Conditions