Definition

 • Characterized histologically by sclerosis involving some but not all glomeruli (focal) and affecting only a portion of the glomerular tuft (segmental).

• As a primary glomerular disease, focal and segmental glomerulosclerosis (FSGS) is, like MCD, characterized clinically by the nephrotic syndrome and histologically by podocyte injury. However, in FSGS there is focal and segmental glomerular scarring on light microscopy.

• FSGS can also occur as a pattern of scarring secondary to glomerular injury of any type and cause; therefore, segmental glomerular scarring can be seen in many clinical contexts and does not always indicate primary FSGS.

* Careful exclusion of other underlying diseases through histological examination and clinical correlation is essential before making a diagnosis of primary FSGS.

Epidemiology

 • Primary FSGS is a common cause of nephrotic syndrome in adults.

• Patients of African origin or ancestry are at increased risk of FSGS; this is related to more frequent risk alleles of APO-L1 in these populations.

Aetiology

• Idiopathic primary FSGS: unknown; rapid recurrence of the disease after kidney transplantation suggests a circulating factor.

 • Rare cases are due to genetic mutations, particularly in podocyte proteins involved in the slit diaphragm, cytoskeleton, and signalling pathways. Genetic causes are more frequently seen in children then adults (e.g. congenital nephrotic syndrome of Finnish type due to mutations of NPHS1, or diffuse mesangial sclerosis/ Dennis Drash syndrome/ Frasier syndrome related to mutations of WT-1).

• Podocyte injury and FSGS can also develop in association with viral infections (e.g. HIV), drugs (e.g. pamidronate) and tumours (in particular lymphoid).

• Haemodynamic stress to the glomerulus can also cause podocyte injury leading to secondary FSGS, either through increased workload on a normal- size nephron population (e.g. obesity, anabolic steroids, sickle- cell anaemia), or through reduced nephron mass of any cause with related increased work in remaining nephrons.

• APO- L1 risk allele associated FSGS: in patients with African ancestry, risk alleles confer an increased risk of FSGS of any aetiology.

Pathogenesis

 • Podocyte injury and loss cause heavy proteinuria and segmental glomerular scarring.

Presentation

 • Primary FSGS, genetic FSGS, FSGS related to viral infections, drugs and tumours: nephrotic syndrome.

• Secondary FSGS: heavy proteinuria without the nephrotic syndrome; variable degree of renal failure depending on cause.

Light microscopy

 • Involved glomeruli show replacement of a segment of the glomerular tuft by sclerosis (Fig. 1).

• The sclerotic segment often shows adhesion to Bowman’s capsule.

 • Glomerulosclerosis is usually accompanied by tubulointerstitial fibrosis around the involved glomerulus.

• There are five morphological patterns of FSGS: not otherwise specified (NOS), tip variant, cellular variant, collapsing variant, and perihilar variant. The collapsing variant is most often seen in association with drugs (e.g. pamidronate) and viruses (e.g. HIV). The perihilar variant is usually seen in secondary FSGS related to haemodynamic stress (e.g. obesity).

Fig1. Focal and segmental glomerulosclerosis, not otherwise specified (NOS). Haematoxylin and eosin. A portion of the tuft between 1 and 2 o’clock is replaced by fibrous stroma, with closure of the capillary lumens. This part of the glomerulus also adheres to Bowman’s capsule (arrow) (see Plate 21).

Table1. Classification of FSGS by cause with histological findings

Immunofluorescence

• Non- specific entrapment of IgM and C3 may be seen in areas of sclerosis.

Electron microscopy

• Primary FSGS: extensive podocyte foot process effacement, often with microvillous change, as for MCD. There are no electron- dense deposits.

• Secondary FSGS: segmental podocyte foot process effacement; there may also be evidence of an underlying disease causing the scarring, such as immune complex glomerulonephritis (in which case, electron- dense deposits may be seen).

Prognosis

• Depends on whether primary or secondary FSGS, and on the histological variant: tip variant has a better outcome, and collapsing variant has a worse outcome.

 • Commonly leads to progressive renal insufficiency.

 • Primary FSGS has a high rate of recurrence in kidney transplants and without appropriate pre- emptive treatment often leads to rapid loss of the graft function.