Focal Segmental Glomerulosclerosis Classification

Focal Segmental Glomerulosclerosis Classification

A. Brad Farris, III, MD

Light microscopy of a case of collapsing FSGS shows a glomerulus with areas of sclerosis image (silver stain).

Immunofluorescence for C3 shows a predominantly segmental pattern of staining in the mesangium and in areas of glomerular capillary loop collapse in a case of FSGS.



  • Focal segmental glomerulosclerosis (FSGS)


  • Group of podocytopathies (of varied etiology) that share the feature of focal segmental glomerulosclerosis, typically with moderate to heavy proteinuria


Morphologic Classification

  • Based on glomerular morphology categories defined by the Columbia classification

    • Collapsing variant

    • Glomerular tip lesion

    • Cellular variant

    • Perihilar variant

    • FSGS not otherwise specified (NOS)

Etiologic Classification

  • Based on identified causes of FSGS: Some correspondence with morphologic variants

  • Familial/genetic

    • Increasing number of genes identified

      • β-integrin mutations

      • α-actinin-4 mutations

      • WT-1 mutations

      • Podocin mutations

  • Drug-induced

    • Pamidronate

    • Heroin (heroin nephropathy)

    • Lithium

    • Interferon-α and -β

  • Virus

    • HIV (HIV-associated nephropathy [HIVAN])

    • Parvovirus B19

  • Adaptive, structural-functional responses

    • Secondary to congenital or acquired reduction in nephrons relative to body mass

      • Oligomeganephronia, unilateral renal agenesis, renal dysplasia, reflux nephropathy, hypertension, anabolic steroids

  • Vascular

    • Hypertension

    • Thrombotic microangiopathy

    • Atheromatous emboli

    • Calcineurin inhibitor toxicity

  • Idiopathic

    • Usual primary form, either NOS or collapsing variant

    • Plasma factor responsible, identity sought



  • Most common cause of nephrotic syndrome in adults

  • Apparent increased incidence over past 2 decades

    • ˜ 25% of adult nephropathies, compared with < 10% 20 years ago


  • Focal and segmental glomerular hyalinization and capillary loop degradation described by Fahr in 1925

  • Arnold Rich described juxtamedullary glomerulosclerosis in children dying with nephrotic syndrome in 1957

  • FSGS was recognized as a distinct entity by International Study of Kidney Diseases in Children in the 1970s

  • Collapsing variant was recognized by Mark Weiss in the 1980s and later as usual pattern of HIVAN



  • Now classified as podocytopathies

    • Familial podocyte protein defects

      • Mutations in TRPC6, a calcium-permeable cation channel, lead to abnormal podocyte function and hereditary FSGS

      • FSGS with defects in α-actinin-4 (ACTN4), podocin (NPHS2, defective in corticosteroid-resistant nephrotic syndrome), and nephrin (NPHS1, defective in congenital nephrotic syndrome of the Finnish type) are relatively rare familial forms of FSGS

      • Nephrin interacts with CD2-associated protein (CD2AP), and podocin interacts with the nephrin-CD2AP complex

      • Mutations in WT1 transcription factor, which regulates several podocyte genes, lead to FSGS syndromes (Denys-Drash and Frasier syndromes)

    • Abnormal cytokines are now thought to play major role in idiopathic FSGS development

      • Circulating factor identified in patients who have recurrent FSGS after transplant, typically occurring within months after transplantation

    • Podocyte dysregulation/dysfunction

      • Differentiation markers of podocytes (e.g., Wilms tumor WT-1 protein, podocalyxin, and synaptopodin) disappear in collapsing FSGS and HIVAN

    • Loss of podocytes leads to adhesions

    • Risk factor in African descent is APOL1 gene

  • Relationship with minimal change disease (MCD) unclear

    • Dystroglycan, an integral component of the GBM, is decreased in MCD but maintained in nonsclerotic segments in FSGS



  • Generally poor with substantial fraction progressing to end-stage renal disease

Clinical Presentation

  • Proteinuria

  • Nephrotic syndrome

  • Azotemia


  • Plasmapheresis has been used to induce remission in some patients with recurrent FSGS


General Features

  • Pale yellow kidneys due to lipid in tubules


General Features

  • Glomeruli

    • Sclerosis involves some glomeruli (focal) and only a portion of glomerular tuft (segmental)

      • Diagnosed even when only 1 glomerulus involved

      • Global sclerosis may be an incidental finding and is not particularly useful in making diagnosis of FSGS

    • Adhesions (synechiae) of glomerular tuft to Bowman space often accompany segmental sclerosis and are often seen early in sclerosis process

    • Hyalinosis

      • Portion of glomerular involvement has a smooth, glassy (hyaline) appearance

      • Typically thought to occur from insudation of plasma proteins

    • Increased matrix with obliteration of glomerular capillary lumen

    • FSGS has zonal distribution, beginning in corticomedullary (juxtamedullary) junction (CMJ)

      • Important to note whether sampling of CMJ is included

    • Glomerular hypertrophy often accompanies FSGS

      • Potential surrogate marker in cases without sampled segmental sclerosis

  • Tubules

    • Tubular epithelial cells contain PAS(+) reabsorption droplets due to glomerular proteinuria

    • Tubular atrophy is typically only focal early in course of FSGS

      • TBM thickened in areas of atrophy

      • Tubular atrophy may be more prominent late in course of the disease

    • Tubulointerstitial changes pronounced in collapsing variants of FSGS and in HIVAN

      • Cystic dilatation and more prominent lymphoid infiltrate

  • Interstitium

Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Focal Segmental Glomerulosclerosis Classification

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