The individual components of the name refer to the appearance of the kidney tissue on biopsy: focal—only some of the glomeruli are involved (as opposed to diffuse), segmental—only part of each glomerulus is involved (as opposed to global),glomerulosclerosis—refers to scarring of the glomerulus (a part of the nephron (the functional unit of the kidney)). The glomerulosclerosis is usually indicated by heavy PAS staining and findings of immunoglobulin M (IgM) and C3-convertase (C3) in the sclerotic segment.
Depending on the cause it is broadly classified as:
Five mutually exclusive variants of focal segmental glomerulosclerosis may be distinguished by the pathologic findings seen on renal biopsy:
Glomerular tip lesion variant
Not otherwise specified (NOS) variant.
Recognition of these variants may have prognostic value in individuals with primary focal segmental glomerulosclerosis (i.e. where no underlying cause is identified). 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 (i.e. unsampled collapsing variant or glomerular tip variant). 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.
Some general secondary causes are listed below:
Unilateral renal agenesis
Scarring due to previous injury
Focal proliferative glomerulonephritis
Human immunodeficiency virus-associated nephropathy
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 (nephritic range <3.0gm/24hr) or nephritic range.
There are currently several known genetic causes of the hereditary forms of FSGS.
The 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.
A 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 calciuminflux. 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.
Another gene that may be involved in hereditary forms of FSGS is the gene known as CD2AP (CD2 associated protein) or CMS (Cas binding protein with multiple SH3 domains). 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.
In 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.
Another 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.
Mutations 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.
Bijou Phillips, an American actress known for her roles in the movies Almost Famous and Bully, underwent a kidney transplant for FSGS in April 2017.
Ivan Klasnić, Former Croatian footballer who played as a striker In 2007, Klasnić underwent a kidney transplant, and became the first player to participate in a major tournament (UEFA Euro 2008) after a transplant.
^Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler MC, Niaudet P, Antignac C (May 2000). "NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome". Nature Genetics. 24 (4): 349–354. doi:10.1038/74166. PMID10742096.
^Zhang J, Yang J, Hu Z (2017) Study of a family affected with focal segmental glomerulosclerosis due to mutation of COL4A5 gene. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 34(3):373-376 doi: 10.3760/cma.j.issn.1003-9406.2017.03.013
NephCure Foundation Only organization solely committed to support research seeking the cause of Nephrotic Syndrome and FSGS, improve treatment and find the cure.
Kidcomm An online resource for parents dealing with childhood kidney diseases (FSGS, Nephrotic Syndrome and others)
FSGS Research A team of kidney doctors and scientists from Brigham and Women's Hospital / Harvard Medical School working to learn more about the cause of FSGS and Nephrotic Syndrome in children and adults, with an emphasis on the genetic basis of these diseases.