Focal segmental glomerulosclerosis
Encyclopedia
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.)
Former NBA basketball players Sean Elliott
and Alonzo Mourning
have both survived bouts against FSGS. Alonzo Mourning is an Ambassador to The NephCure Foundation.
: 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.
There are many other classification schemes also.
:
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.
, 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
.
Glomerulosclerosis
Glomerulosclerosis refers to a hardening of the glomerulus in the kidney. It is a general term to describe scarring of the kidneys' tiny blood vessels, the glomeruli, the functional units in the kidney that filter urine from the blood....
(FSGS) is a cause of nephrotic syndrome
Nephrotic syndrome
Nephrotic syndrome is a nonspecific disorder in which the kidneys are damaged, causing them to leak large amounts of protein from the blood into the urine....
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
Nephrotic syndrome
Nephrotic syndrome is a nonspecific disorder in which the kidneys are damaged, causing them to leak large amounts of protein from the blood into the urine....
. (Minimal change disease
Minimal change disease
Minimal Change Disease is a disease of the kidney that causes nephrotic syndrome and usually affects children .-Epidemiology:...
(MCD) is by far the most common cause of nephrotic syndrome in children: MCD and primary FSGS may have a similar cause.)
Former NBA basketball players Sean Elliott
Sean Elliott
Sean Michael Elliott is a retired American professional basketball player in the NBA.-Early life:Elliott was born in Tucson, Arizona and was youngest of three boys. He was a very intelligent boy growing up and attended the G.A.T.E. program at Toleson Elementary School in Tucson, Arizona...
and Alonzo Mourning
Alonzo Mourning
Alonzo Harding Mourning, Jr. is a former American professional basketball player, who played most of his 15-year NBA career for the Miami Heat....
have both survived bouts against FSGS. Alonzo Mourning is an Ambassador to The NephCure Foundation.
Appearance
The individual components of the name refer to the appearance of the kidney tissue on biopsyBiopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
: focal—only some of the glomeruli
Glomerulus
A glomerulus is a capillary tuft that is involved in the first step of filtering blood to form urine.A glomerulus is surrounded by Bowman's capsule, the beginning component of nephrons in the vertebrate kidney. A glomerulus receives its blood supply from an afferent arteriole of the renal...
are involved (as opposed to diffuse), segmental—only part of each glomerulus is involved (as opposed to global), glomerulosclerosis
Glomerulosclerosis
Glomerulosclerosis refers to a hardening of the glomerulus in the kidney. It is a general term to describe scarring of the kidneys' tiny blood vessels, the glomeruli, the functional units in the kidney that filter urine from the blood....
—refers to scarring of the glomerulus
Glomerulus
A glomerulus is a capillary tuft that is involved in the first step of filtering blood to form urine.A glomerulus is surrounded by Bowman's capsule, the beginning component of nephrons in the vertebrate kidney. A glomerulus receives its blood supply from an afferent arteriole of the renal...
(a part of the nephron
Nephron
The renal tubule is the portion of the nephron containing the tubular fluid filtered through the glomerulus. After passing through the renal tubule, the filtrate continues to the collecting duct system, which is not part of the nephron....
(the functional unit of the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
)). The glomerulosclerosis is usually indicated by heavy PAS staining and findings of IgM and C3 in sclerotic segment.
Classification
Depending on the cause it is broadly classified as- Primary, when no underlying cause is found; usually presents as nephrotic syndromeNephrotic syndromeNephrotic syndrome is a nonspecific disorder in which the kidneys are damaged, causing them to leak large amounts of protein from the blood into the urine....
- Secondary, when an underlying cause is identified; usually presents with kidney failure and proteinuriaProteinuriaProteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...
. This is actually a heterogeneous group including numerous causes such as- Infections such as HIVHIVHuman immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
(known as HIV-Associated Nephropathy) - Toxins and drugs such as heroin and pamidronate
- Familial forms
- Secondary to nephronNephronThe renal tubule is the portion of the nephron containing the tubular fluid filtered through the glomerulus. After passing through the renal tubule, the filtrate continues to the collecting duct system, which is not part of the nephron....
loss and hyperfiltration, such as with chronic pyelonephritisPyelonephritisPyelonephritis is an ascending urinary tract infection that has reached the pyelum or pelvis of the kidney. It is a form of nephritis that is also referred to as pyelitis...
and refluxRefluxReflux is a technique involving the condensation of vapors and the return of this condensate to the system from which it originated. It is used in industrial and laboratory distillations...
, morbid obesityObesityObesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
, diabetes mellitusDiabetes mellitusDiabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
- Infections such as HIV
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 biopsyRenal biopsy
A renal biopsy is a procedure in which a sample of kidney tissue is obtained. Microscopic examination of the tissue can provide information needed to diagnose, monitor or treat a renal disorder.-Indications:...
:
- 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.
Causes
There are currently several known genetic causes of the hereditary forms of FSGS.| Gene | OMIM | Description |
|---|---|---|
| FSGS1: ACTN4 | 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 Podocyte Podocytes are cells in the Bowman's capsule in the kidneys that wrap around the capillaries of the glomerulus... . 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 TRPC6 Transient receptor potential cation channel, subfamily C, member 6, also known as TRPC6, is a human gene encoding a protein of the same name. TRPC6 is a transient receptor potential ion channel... |
A second gene associated with FSGS is TRPC6 TRPC6 Transient receptor potential cation channel, subfamily C, member 6, also known as TRPC6, is a human gene encoding a protein of the same name. TRPC6 is a transient receptor potential ion channel... , which encodes a member of the canonical family of TRP channel Transient receptor potential Transient receptor potential channels are a group of ion channels located mostly on the plasma membrane of numerous human and animal cell types. There are about 28 TRP channels that share some structural similarity to each other... s. This family of ion channels conduct cations in a largely non-selective manner. As with ACTN4, TRPC6 is expressed in podocyte Podocyte Podocytes are cells in the Bowman's capsule in the kidneys that wrap around the capillaries of the glomerulus... s. While TRP channels can be activated through a variety of methods, TRPC6 is known to be activated by phospholipase C Phospholipase C Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in... 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 Calcium Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust... 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 CD2AP CD2-associated protein is a protein that in humans is encoded by the CD2AP gene.-Interactions:CD2AP has been shown to interact with NPHS2, Nephrin, Cbl gene and RAB4A.-Further reading:... |
Another gene that may be involved in hereditary forms of FSGS is the gene known as CD2AP CD2AP CD2-associated protein is a protein that in humans is encoded by the CD2AP gene.-Interactions:CD2AP has been shown to interact with NPHS2, Nephrin, Cbl gene and RAB4A.-Further reading:... (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 FYN Proto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.This gene is a member of the protein-tyrosine kinase oncogene family. It encodes a membrane-associated tyrosine kinase that has been implicated in the control of cell growth... 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 APOL1 APOL1 is the gene, which in humans encodes the Apolipoprotein L1 protein.APOL1 is the gene, which in humans encodes the Apolipoprotein L1 protein.... |
In people of African descent, two common variants in APOL1 APOL1 APOL1 is the gene, which in humans encodes the Apolipoprotein L1 protein.APOL1 is the gene, which in humans encodes the Apolipoprotein L1 protein.... 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 INF2 Inverted formin-2 is a protein that in humans is encoded by the INF2 gene.... |
Another gene associated with FSGS is INF2 INF2 Inverted formin-2 is a protein that in humans is encoded by the INF2 gene.... , 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 NPHS2 Podocin is a protein that in humans is encoded by the NPHS2 gene.-Interactions:NPHS2 has been shown to interact with Nephrin and CD2AP.-Further reading:... |
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 syndromeNephrotic syndrome
Nephrotic syndrome is a nonspecific disorder in which the kidneys are damaged, causing them to leak large amounts of protein from the blood into the urine....
, which is characterized by edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
(associated with weight gain), hypoalbuminemia
Hypoalbuminemia
Hypoalbuminemia is a medical condition where levels of albumin in blood serum are abnormally low. It is a specific form of hypoproteinemia.Albumin is a major protein in the human body, making up about 60% of total human plasma protein by mass...
(low serum albumin
Human serum albumin
Human serum albumin is the most abundant protein in human blood plasma. It is produced in the liver. Albumin constitutes about half of the blood serum protein...
, a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
in the blood), hyperlipidemia
Hyperlipidemia
Hyperlipidemia, hyperlipoproteinemia, or hyperlipidaemia is the condition of abnormally elevated levels of any or all lipids and/or lipoproteins in the blood...
and hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
(high blood pressure). In adults it may also present as kidney failure and proteinuria
Proteinuria
Proteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...
, without a full-blown nephrotic syndrome
Nephrotic syndrome
Nephrotic syndrome is a nonspecific disorder in which the kidneys are damaged, causing them to leak large amounts of protein from the blood into the urine....
.
Tests
- UrinalysisUrinalysisA urinalysis , also known as Routine and Microscopy , is an array of tests performed on urine, and one of the most common methods of medical diagnosis...
- Blood tests – cholesterol
- Kidney biopsyNeedle aspiration biopsyNeedle aspiration biopsy , may refer to fine needle aspiration cytology , fine needle aspiration biopsy and fine needle aspiration , is a diagnostic procedure sometimes used to investigate superficial lumps or masses...
Treatment
- Salt restriction and diuretics, such as furosemideFurosemideFurosemide or frusemide is a loop diuretic used in the treatment of congestive heart failure and edema. It is most commonly marketed by Sanofi-Aventis under the brand name Lasix...
, for edema - Antihypertensives (especially ACEIs) – if the blood pressure is too high
- treat present hyperlipidemiaHyperlipidemiaHyperlipidemia, hyperlipoproteinemia, or hyperlipidaemia is the condition of abnormally elevated levels of any or all lipids and/or lipoproteins in the blood...
(e.g. statinStatinStatins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
s, fibrateFibrateIn pharmacology, the fibrates are a class of amphipathic carboxylic acids. They are used for a range of metabolic disorders, mainly hypercholesterolemia , and are therefore hypolipidemic agents.- Members :...
s) - Aldosterone antagonistAldosterone antagonistAldosterone antagonist refers to diuretic drugs which antagonize the action of aldosterone at mineralocorticoid receptors. This group of drugs is often used as adjunctive therapy, in combination with other drugs, for the management of chronic heart failure...
to decrease proteinuria and thus offer a degree of reno-protection - CorticosteroidCorticosteroidCorticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
s, such as prednisonePrednisonePrednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant drug. It is used to treat certain inflammatory diseases and some types of cancer, but has significant adverse effects...
– based on the clinical judgment of physicianPhysicianA physician is a health care provider who practices the profession of medicine, which is concerned with promoting, maintaining or restoring human health through the study, diagnosis, and treatment of disease, injury and other physical and mental impairments...
(no broad consensus/guideline) - Cytotoxics, such as cyclophosphamideCyclophosphamideCyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
may be used to induce remission in patients presenting with FSGS refractory to corticosteroids, or in patients who do not tolerate steroids. - PlasmapheresisPlasmapheresisPlasmapheresis is the removal, treatment, and return of blood plasma from blood circulation. It is thus an extracorporeal therapy...
– blood cleansing using a machine to remove the patient's blood plasmaBlood plasmaBlood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
and replacing it with donor plasma. - Vitamin EVitamin EVitamin E is used to refer to a group of fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of vitamin E, of which γ-tocopherol is the most common in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine and dressings...
- Immunosuppressive drugImmunosuppressive drugImmunosuppressive drugs or immunosuppressive agents are drugs that inhibit or prevent activity of the immune system. They are used in immunosuppressive therapy to:...
s - None – sometimes none of the above works and the patient will require dialysisDialysisIn medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
with possibly later transplantationOrgan transplantOrgan transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
of a new kidney.
External links
- 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