The pathophysiology of focal segmental glomerulosclerosis (FSGS) is based on two types of FSGS. Primary FSGS is also known as idiopathic FSGS, there is a hypothesis that suggests it occurs as a result of circulating immune activating factors interacting with the glomerular epithelium. The underlying pathogenesis of FSGS is fusion or effacement of the foot processes (podocytes) of the glomeruli and sclerosing of some parts of the glomeruli. These changes result in apoptosis and detachment of the glomerular basement membrane (GBM) resulting in subsequent loss of negative charge on podocytes and podocytopenia. Secondary FSGS is based on glomerular hypertrophy and hyperfiltration and over expression of inflammatory mediators such as, TGF-beta, PDGF and VEGF. The underlying pathogenesis can be based on multiple genetic mutations in NPHS1, NEPH1, NPHS2, WT1 and INF2 genes. Conditions associated with FSGS include, diabetes, HIV, sickle cell disease, nephrotic syndrome and minimal change disease. On microscopic histopathological analysis progressive changes seen are, foot process effacement, podocyte apoptosis, exposed GBM, capillary expansion and mesangial matrix proliferation.

There are two types of FSGS, primary FSGS and secondary FSGS, pathophysiology is discussed below:

• The pathogenesis of primary or Idiopathic FSGS is not so clear.^[1]
• Many studies had theorized that FSGS occurs as a consequence of effects of circulating immune activating factors on the glomerular epithelium.^[1]
• The damaging role of circulating factors like the soluble urokinase plasminogen activating receptor (suPAR) on the glomerular podocytes had been suggested.^[1]
• The underlying pathogenesis of FSGS is fusion or effacement of the foot processes (podocytes) of the glomeruli, with sclerosing of some parts of the glomeruli (hence the name focal segmental).
• The involvement of the permselective filtration barrier and effacement of podocyte foot processes are inevitable.
• These changes result in:^[2][3][4]
  • Apoptosis
  • Detachment from the glomerular basement membrane (GBM)
  • Subsequent podocytopenia
  • Interference with slit diaphragm and its corresponding lipid raft
  • Interference with actin cytoskeleton
  • Interference with the GBM or with the interaction of the GBM and the podocytes
  • Interference with the negative charge of podocytes
• Circulating factors implicated in the pathogenesis of primary FSGS include:
  • Soluble urokinase plasminogen activating receptor (suPAR) and MicroRNAs.^[1]
  • suPAR is a heavily glycosylated protein that can be found in several places.^[4][5][6][7]
  • Cardiotrophin-like cytokine factor-1 (CLCF1)

The pathogenesis of secondary focal segmental glomerulosclerosis (FSGS) occurs due to the following factors:

• Glomerular hypertrophy and hyperfiltration, which is due to the following:^[8][9]
  • Scarring due to the previous injury
  • Glomerular abnormality
  • Direct toxic injury to podocytes
• Various inflammatory mediators include over-expression of:^[3][10][11]
  • Tumor growth factor-beta (TGF-beta)
  • Platelet-derived growth factor (PDGF)
  • Vascular endothelial growth factor (VEGF)

The development of focal segmental glomerulosclerosis is the result of multiple genetic mutations such as:^{[12][10][13][14][15][16][17][18]}

• Nephrin gene in congenital Finnish-type nephrotic syndrome – NPHS1
• Nephrin-like transmembrane gene – NEPH1
• Podocin gene – NPHS2
• CD2-associated protein (CD2AP)
• Alpha-actinin-4 gene
• Transient receptor potential cation channel – TRPC6
• Mutation in wilms tumor gene – WT1

• Mutation in SCARB2 (LIMP2) gene

• Mutation in formin gene – INF2

• Mitochondrial cytopathies

Conditions associated with focal segmental glomerulosclerosis (FSGS):^{[19][20][21][22][23][24][25]}

• Diabetes
• Human immunodeficiency virus (HIV)
• Sickle cell disease
• Systemic lupus erythematosus (SLE)
• Nephrotic syndrome
• End stage renal disease (ESRD)
• Minimal change disease

On microscopic histopathological analysis progressive changes seen are:^[10][26]

• Foot process effacement
• Podocyte apoptosis
• Exposed glomerular basement membrane
• Capillary expansion
• Formation of synechiae
• Mesangial matrix proliferation