Several histologic variants of FSGS can be distinguished, including classic FSGS (also known as FSGS not otherwise specified), perihilar variant, glomerular tip variant, cellular variant, and collapsing variant. It is unclear if these different subtypes have different pathophysiologic bases or merely represent different degrees of glomerular damage.

The perihilar variant of FSGS is characterized by the presence of perihilar hyalinosis and sclerosis in >50% of affected glomeruli. This variant can be seen in primary disease; however, if seen in the presence of glomerulomegaly, it suggests a secondary form related to glomerular hyperfiltration. The glomerular tip variant is characterized by a focal lesion localized near the urinary pole of Bowman’s capsule, where the proximal tubule begins. The capillary lumina in this region appear obliterated secondary to the presence of foam cells and swollen endothelial cells, whereas the overlying podocytes appear hypertrophic and confluent with adjacent parietal and tubular epithelial cells. Adhesions may be seen between the glomerular tuft and the urinary pole. The cellular variant is characterized by the presence of segmental endocapillary hypercellularity in at least one glomerulus that affects at least 25% of the tuft and results in occlusion of the capillary lumina. The infiltration of leukocytes, foam cells, and other cell types may result in karyorrhexis and other evidence of active inflammation. The collapsing variant is characterized by a segmental or global collapse of glomerular capillaries with significant hypertrophy and hyperplasia of overlying podocytes, which often contain large intracytoplasmic protein resorption droplets. Unlike in other FSGS variants, hyalinosis and foam cells are generally not seen. This variant may occur as a primary phenomenon but is also the characteristic lesion of HIV-associated nephropathy (see Plate 4-55).