Focal segmental glomerulosclerosis
The terminology surrounding focal segmental glomerulosclerosis (FSGS) is often confusing as the term is used as a histological description, but is also used to refer to primary and secondary forms of glomerular disease where the same histological features are seen. As the name suggests, there is focal (meaning not all of the glomeruli are affected, defined as <50% within the biopsy) and segmental (meaning only part of an individual glomeruli is involved) sclerosis of glomeruli.
In later stages, the sclerosis may progress to involve the entire glomerulus (i.e. global sclerosis). The focal nature of the disease means that it is possible that a needle biopsy specimen may miss an abnormal glomerulus due to sampling error.
Correlation with the clinical features and the ancillary use of immunohistochemistry and electron microscopy are often necessary to narrow down the many causes.
The primary or idiopathic form of FSGS is a clinico-pathological syndrome of proteinuria, usually in nephrotic range, with histological focal and segmental sclerosis of glomeruli and foot process effacement. The last feature is not normally visible on light microscopy and the abnormal podocyte processes are usually seen only on electron microscopy (diffuse effacement of the foot processes and microvillous transformation).
Several forms of FSGS include are caused by inherited mutations of podocyte-associated proteins including α-actinin-4, podocin, β-integrin and the Wilms tumour protein 1 (WT1). Logically, these forms should be referred to as 'secondary' causes given that underlying mutations have been identified, but instead they are classed as 'primary' FSGS, referring that the disease is primarily in the kidney, rather than secondary to another disease process. The label primary/idiopathic FSGS is often, and arguably artifically, restricted to idiopathic FSGS, as previously defined.
Other conditions causing FSGS include HIV nephropathy, parvovirus B19 and certain drugs. Another group of secondary FSGS is seen as a result of the burden placed on previously normal glomeruli when the total population is reduced below a certain threshold, as occurs in the end stages of several renal diseases (regardless of aetiology), in renal aplasia/dysplasia or following surgical ablation. Indeed, FSGS can be induced experimentally in animal by nephrectomy or surgical ablation.
There is a further group of secondary FSGS where histological FSGS is seen as a non-specific finding following various other renal diseases, but not specifically related to a depletion glomerular numbers.
A mouse model of doxorubicin-induced FSGS has revealed that the susceptibility gene responsible in some strains of mice acts due to the podocyte longevity being impaired due to mitochodrial DNA depletion due to failure of DNA repair after doxorubicin DNA intercalation.
The final diagnosis often relies on correlation with the clinical picture as the histological picture alone cannot separate the causes.
Certain histological features permits sub-division of FSGS into specific sub-types, some carrying a different prognosis:
- Perihilar variant
- Cellular variant
- Tip variant
- Collapsing variant
If none of these specific features are found, it is designated primary FSGS NOS (not otherwise specified; also known as 'classic' or 'usual type').
- Associated in those of African descent with APOL1 G1 and G2 variants. MYH9 (which is a nearby gene on chromosome 22) causes a rare autosomal dominant form in Epstein‐Fechtner syndrome.
The same variants seen in primary FSGS can also be seen in secondary forms.
Susceptibility genetic mutations are multiple and associated with variants in multiple podocyte proteins, in particular nephrin and podocin. They include a large number of rare syndromes such as MELAS with maternal inheritance and more classic inheritance :
- Autosomal dominant
- Autosomal recessive
- Impure heroin (first reported association with a drug)
- Calcineurin inhibitors
- Probably causes severe vasoconstriction
C1q + IgG immunostaining.
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