Focal segmental glomerulosclerosis
|Focal segmental glomerulosclerosis|
|Other names: Segmental glomerulosclerosis, focal sclerosis with hyalinosis, familial idiopathic nephrotic syndrome|
|Light micrograph of focal segmental glomerulosclerosis, hilar variant. Kidney biopsy. PAS stain.|
|Symptoms||Foamy urine, swelling|
|Complications||High blood pressure, kidney failure|
|Causes||Unknown, genetics, certain medications, vesicoureteral reflux, obesity, obstructive sleep apnea, HIV/AIDS|
|Diagnostic method||Kidney biopsy|
|Differential diagnosis||Membranoproliferative glomerulonephritis, lupus, other causes of nephrotic syndrome|
|Treatment||Immunosuppressants, blood pressure control|
|Frequency||7 per million people|
Focal segmental glomerulosclerosis (FSGS) is term for a specific pattern of damage in the kidneys. Symptoms may include protein in the urine and swelling. Complications may include high blood pressure and kidney failure.
The cause is often unclear. Other cases may occur due to genetics, certain medications, vesicoureteral reflux, obesity, obstructive sleep apnea, or HIV/AIDS. The underlying mechanism involves scaring of parts of the glomerulus due to injury of podocytes. A kidney biopsy may confirm the diagnosis, but early in the disease a normal biopsy may not exclude it.
Treatment involves the use of immunosuppressants such as steroids, tacrolimus, or rituximab. Blood pressure may be managed with ACE inhibitors and swelling may be treated with diuretics. If kidney failure occurs, dialysis or kidney transplant may be requires.
FSGS affects about 7 per million people. It is the cause of about 40% of cases of nephrotic syndrome (high levels of protein in the urine) in adults and 20% in children. The condition was first described in 1925 by Fahr.
Depending on the cause it is broadly classified as:
- Primary, when no underlying cause is found; usually presents as nephrotic syndrome
- Secondary, when an underlying cause is identified; usually presents with kidney failure and proteinuria. This is actually a heterogeneous group including numerous causes such as
There are many other classification schemes also.
- Collapsing variant
- Glomerular tip lesion variant
- Cellular variant
- Perihilar 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:
- Glomerular hypertrophy/hyperfiltration
- Unilateral renal agenesis
- Morbid obesity
- Scarring due to previous injury
- Focal proliferative glomerulonephritis
- Toxins (pamidronate)
- Human immunodeficiency virus-associated nephropathy
- Heroin 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.
|FSGS1: ACTN4||603278||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.|
|FSGS2: TRPC6||603965||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 calcium influx. 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: CD2AP||607832||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.|
|FSGS4: APOL1||612551||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.|
|FSGS5: INF2||613237||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.|
|SRN1: NPHS2||600995||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.|
In children and some adults, FSGS presents as a nephrotic syndrome, which is characterized by edema (associated with weight gain), hypoalbuminemia (low serum albumin, a protein in the blood), hyperlipidemia and hypertension (high blood pressure). In adults, it may also present as kidney failure and proteinuria, without a full-blown nephrotic syndrome.
- Minimal change disease (MCD), especially in children
- Membranous glomerulonephritis
- Several other
MCD is a more common cause of nephrotic syndrome in children: MCD and primary FSGS may have a similar cause.
Corticosteroids and other immunosuppressive drugs
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.
- Former NBA basketball players Sean Elliott and Alonzo Mourning have both survived bouts with FSGS. Mourning is an Ambassador to the NephCure Foundation. Pro bodybuilder Flex Wheeler was diagnosed with FSGS and had a kidney transplant. Former MLS player Clyde Simms retired from professional soccer in 2014 due to FSGS.
- Gary Coleman American actor, known for his childhood role as Arnold Jackson in the American sitcom Diff'rent Strokes.
- Andy Cole, former Newcastle Utd, Manchester United and England international football player
- Ed Hearn, former Major League Baseball player for the New York Mets and Kansas City Royals
- Aries Merritt, 110 metres hurdles world record holder and 2012 Olympic champion, had a kidney transplant for collapsing FSGS days after coming third in the 2015 World Championships.
- Natalie Cole, American singer
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- "Kidney disease forces former New England Revolution, DC United M Clyde Simms to retire". 2014-02-13.
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- Clarey, Christopher (28 August 2015). "Days Before Kidney Transplant, Aries Merritt Wins Bronze in Hurdles". The New York Times. Retrieved 17 May 2016.
- "Autopsy: The Last Hours of Natalie Cole." Autopsy. Nar. Eric Meyers. Exec. Prod. Ed Taylor and Michael Kelpie. Reelz, 27 May 2017. Television.