Focal segmental glomerulosclerosis


Focal segmental glomerulosclerosis is a cause of nephrotic syndrome in children and adolescents, as well as a leading cause of kidney failure in adults. It is also known as "focal glomerular sclerosis" or "focal nodular glomerulosclerosis." It accounts for about a sixth of the cases of nephrotic syndrome.

Classification

Depending on the cause it is broadly classified as:
There are many other classification schemes also.

Pathologic variants

Five mutually exclusive variants of focal segmental glomerulosclerosis may be distinguished by the pathologic findings seen on renal biopsy:
  1. Collapsing variant
  2. Glomerular tip lesion variant
  3. Cellular variant
  4. Perihilar variant
  5. Not otherwise specified variant.
Recognition of these variants may have prognostic value in individuals with primary focal segmental glomerulosclerosis. The collapsing variant is associated with higher rate of progression to end-stage renal disease, whereas glomerular tip lesion variant has a low rate of progression to end-stage renal disease in most patients. Cellular variant shows similar clinical presentation to collapsing and glomerular tip variant but has intermediate outcomes between these two variants. However, because collapsing and glomerular tip variant show overlapping pathologic features with cellular variant, this intermediate difference in clinical outcomes may reflect a sampling bias in cases of cellular focal segmental glomerulosclerosis. The prognostic significance of perihilar and NOS variants has not yet been determined. The NOS variant is the most common subtype. Collapsing variant is the most common type of glomerulopathy caused by HIV infection.

Causes

Some general secondary causes are listed below:
Focal segmental glomerulosclerosis may develop following acquired loss of nephrons from reflux nephropathy. Proteinuria is nonselective in most cases and may be in subnephrotic range or nephritic range.

Genetic causes

There are currently several known genetic causes of the hereditary forms of FSGS.
GeneOMIMDescription
FSGS1: ACTN4The first gene involved with this disorder is ACTN4, which encodes alpha-actinin 4. This protein crosslinks bundles of actin filaments and is present in the podocyte. Mutations in this protein associated with FSGS result in increased affinity for actin binding, formation of intracellular aggregates, and decreased protein half-life. While it is unclear how these effects might lead to FSGS there are a number of theories. Firstly, protein aggregation may have a toxic effect on the podocyte. Secondly, decreased protein half-life or increased affinity for actin binding may alter actin polymerization and thereby affect the podocytes cytoskeletal architecture.
FSGS2: TRPC6A second gene associated with FSGS is TRPC6, which encodes a member of the canonical family of TRP channels. This family of ion channels conduct cations in a largely non-selective manner. As with ACTN4, TRPC6 is expressed in podocytes. While TRP channels can be activated through a variety of methods, TRPC6 is known to be activated by phospholipase C stimulation. There are at least 6 mutations in this channel, located throughout the channel. At least one of these mutations, P112Q, leads to increased intracellular calcium. It is unclear how this might lead to FSGS, though it has been proposed that it may result in alteration of podocyte dynamics or podocytopenia.
FSGS3: CD2APAnother gene that may be involved in hereditary forms of FSGS is the gene known as CD2AP or CMS. The protein expressed by this gene is expressed in podocytes where it interacts with fyn and synaptopodin. There is a report that a splicing mutation in this gene was found in two patients with HIV associated FSGS and this led to altered protein translation. This has been theorized to result in altered actin binding and, thus, alteration of the cytoskeletal podocyte architecture.
FSGS4: APOL1In people of African descent, two common variants in APOL1 have been associated with FSGS. It is believed that these variants arose as a defensive mechanism against Trypanosoma brucei rhodesiense or some other sub-Saharan parasite despite conferring high susceptibility to FSGS when inherited from both parents.
FSGS5: INF2Another gene associated with FSGS is INF2, which encodes a member of the formin family of actin-regulating proteins. The observation that alterations in this podocyte-expressed formin cause FSGS emphasizes the importance of fine regulation of actin polymerization in podocyte function.
SRN1: NPHS2Mutations in the NPHS2 gene, which codes for the protein called podocin, can cause focal segmental glomerulosclerosis. This is a recessive form of FSGS. An affected individual has two mutant copies of the NPHS2 gene, in contrast to ACTN4 and TRPC6 mediated forms of disease, which are dominant and require only one mutant copy of the gene. NPHS2-mediated FSGS is resistant to treatment with steroids.

Some researchers found SuPAR as a cause of FSGS.
Another gene that has been associated with this syndrome is the COL4A5 gene.

Diagnosis

Symptoms and signs

In children and some adults, FSGS presents as a nephrotic syndrome, which is characterized by edema, hypoalbuminemia, hyperlipidemia and hypertension. In adults, it may also present as kidney failure and proteinuria, without a full-blown nephrotic syndrome.

Tests

Corticosteroids and other immunosuppressive drugs

Etymology

The individual components of the name refer to the appearance of the kidney tissue on biopsy: focal—only some of the glomeruli are involved, segmental—only part of each glomerulus is involved, glomerulosclerosis—refers to scarring of the glomerulus. The glomerulosclerosis is usually indicated by heavy PAS staining and findings of immunoglobulin M and C3-convertase in the sclerotic segment.

Notable patients