Focal segmental glomerulosclerosis
|Focal segmental glomerulosclerosis|
|Classification and external resources|
|ICD-10||N00-N08 (with .1 suffix)|
|OMIM||603278 603965 607832 612551 613237 600995|
Focal segmental glomerulosclerosis (FSGS) is a cause of nephrotic syndrome in children and adolescents, as well as an important 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. (Minimal change disease (MCD) is by far the most common cause of nephrotic syndrome in children: MCD and primary FSGS may have a similar cause.)
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 IgM and C3 in sclerotic segment.
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 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 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.
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.|
Symptoms and signs
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. Some researchers found SuPAR as cause of FSGS.
- Minimal change disease, especially in children
- Several others
|This section needs additional citations for verification. (February 2013)|
- Salt restriction and diuretics, such as furosemide, for edema
- Antihypertensives (especially ACEIs) — if the blood pressure is too high
- treat present hyperlipidemia (e.g. statins, fibrates; although fibrates are contraindicated in renal failure)
- Aldosterone antagonist to decrease proteinuria and thus offer a degree of reno-protection
- Angiotensin II receptor antagonist
- Corticosteroids, such as prednisone — based on the clinical judgment of physician (no broad consensus/guideline)
- Cytotoxics, such as cyclophosphamide may be used to induce remission in patients presenting with FSGS refractory to corticosteroids, or in patients who do not tolerate steroids.
- Plasmapheresis — blood cleansing using a machine to remove the patient's blood plasma and replacing it with donor plasma.
- Vitamin E
- Fish oil
- Immunosuppressive drugs
- None — sometimes none of the above works and the patient will require dialysis with possibly later transplantation of a new kidney.
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.
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- 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.
- A general overview of Renal Pathology
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