NORD gratefully acknowledges Jonathan J. Hogan, MD, Assistant Professor of Medicine, Hospital of the University of Pennsylvania, and NephCure Kidney International, for assistance in the preparation of this report.
Focal segmental glomerulosclerosis (FSGS) is a term for a specific pattern of damage to the kidneys. The kidneys are two bean-shaped organs in the body, one on each side of the body just below the rib cage in the back. The kidney has multiple functions including filtering the blood of waste products and other substances and producing urine to carrying waste from the body. FSGS occurs when the filters of the kidney, which are made of clusters of tiny blood vessels (capillaries) and known as renal glomeruli, become scarred or hardened (sclerosis). Each kidney has about a million glomeruli, which are part of a larger structure called the nephron; the nephron is the basic unit of the kidneys. The glomeruli help to filter out waste products and extra fluid from the blood. Scarring or damage to the glomeruli can lead to an inability of the kidneys to process waste products and eliminate those waste products from the body through the urine. Ultimately, these abnormalities lead to progressive kidney damage including decreased function and efficiency of the kidneys, and potentially kidney failure. There are different causes of FSGS and, in some instances, the cause is unknown. Depending on the cause, FSGS may be treated with certain medications, but sometimes despite treatment affected individuals will eventually require dialysis or a kidney transplant.
FSGS is a varied, complex pattern of kidney damage that has several different causes and numerous names and terminology, as well as different proposed classification systems. There is disagreement in the medical literature regarding which classification system is most effective in grouping FSGS. This can be extremely confusing to patients and caregivers.
The term ‘focal segmental glomerulosclerosis’ is defined as scarring or hardening (sclerosis) of parts (segmental) of some (focal) glomeruli while other glomeruli remain unaffected. These changes can be seen in kidney tissue when studied under a microscope. However, many times sclerosis progresses to affect a more widespread and global glomeruli population and the term focal segmental glomerulosclerosis, technically, does not remain accurate.
There have been several different attempts to classify FSGS, with the most straightforward being – secondary, genetic, and primary (or idiopathic) – which classifies the condition based on the underlying cause. Secondary forms include adaptive (or postadaptive) FSGS, which results from conditions that cause overactivity (hyperfiltration), stress, or high blood pressure affecting the glomeruli. This also includes reduced mass of the kidneys; as a result of the healing process from a previous kidney injury; or direct toxic effect of certain drugs or viruses. The genetic forms of FSGS are caused by an abnormal version in a gene, which causes damage to the glomeruli, or in a gene that leads to a predisposition to developing kidney damage. Some families have multiple family members who have FSGS because of one of these genetic abnormalities. Recently, researchers have established a strong connection between abnormal variants in the APOL1 gene, which is found in individuals of sub-Saharan African ancestry, and the development of FSGS. Primary (or idiopathic) FSGS is the most common form of FSGS, and is diagnosed when no secondary or genetic cause can be identified.
Another classification system, called the Columbia Classification, breaks down FSGS into five subtypes based on the appearance (morphology) of the FSGS lesions affecting the glomeruli as seen under a microscope. These five variants are: perihilar, cellular, tip, collapsing, and FSGS not otherwise specified. These distinctions are important when physicians decide how to treat a patient with FSGS.
The signs and symptoms of focal segmental glomerulosclerosis are related to progressive damage to the kidneys. Some people may not have any noticeable symptoms (asymptomatic), while others may have progressive disease that can, often rapidly, result in kidney failure.
In primary FSGS, the nephrotic syndrome is often the presenting complication associated with the disorder. The nephrotic syndrome is not a disease but rather a general term for symptoms that develop when the glomeruli (filters) of the kidneys are damaged, which results in loss of large amounts of protein in the urine (proteinuria). Patients experience swelling due to abnormal fluid accumulation (edema), particularly in the feet and ankles and sometimes as puffiness around the eyes when a person first gets up in the morning. Swelling of the feet or ankles may be persistent and affected individuals may find that their shoes no longer fit. Nephrotic syndrome can cause foamy urine due to the presence of excess protein in the urine, fatigue, high blood pressure (hypertension), loss of appetite, unintended weight gain, high cholesterol levels, and an increased tendency to form blood clots.
FSGS can potentially progress to cause severe complications as such declining kidney function and, ultimately, kidney failure. Symptoms associated with kidney failure include abnormally pale skin (pallor), drowsiness, nausea, and/or vomiting. Severe complications of renal failure include bleeding into the stomach, a decrease in the amount of circulating red blood cells (anemia), and abnormal heart rhythms due to elevated potassium levels in the blood. When the kidneys stop working, this is called end stage renal disease.
Patients with primary (idiopathic) FSGS can experience a rapid decline in their kidney function, while with secondary FSGS there is usually a slower disease progression. Secondary FSGS is usually characterized by slowly increasing amounts of protein in the urine and slowly worsening kidney function, and often, there is no swelling affecting the feet and ankles (peripheral edema).
The genetic forms of FSGS are highly variable even among individuals with the same genetic variant. Signs and symptoms can range from mild disease with little to no symptoms, to severe disease with nephrotic syndrome, eventually causing kidney failure.
There are many different causes for FSGS. Many researchers believe that FSGS is caused by damage to a specialized kidney cell in the glomerulus (filter) called the podocyte. Abnormalities in the health, function, or number of podocytes ultimately leads to the scarring (sclerosis) of the glomeruli that characterizes FSGS.
In individuals with the primary form, the specific cause is often unknown (idiopathic). Some researchers believe that affected individuals have proteins called permeability factors in their blood that damage podocytes, which causes the glomeruli (filters) to leak protein into the urine. Research is ongoing to identify these permeability factors and how they cause primary FSGS.
There are a variety of causes of secondary FSGS. Adaptive FSGS is diagnosed when a patient has a condition that causes excess stress on the glomeruli (filters), such as when the glomeruli (filters) receive increased blood flow (hyperfiltration). Conditions that can cause increased blood flow to the kidneys include obesity, diabetes, sickle cell anemia, sleep apnea, and heart disease that causes low levels of oxygen in the blood (cyanotic heart disease). In response, the glomeruli (filters) may become enlarged (hypertrophic). Adaptive FSGS is also caused by reduced mass of the kidneys which can be caused by congenital defects of the kidneys such as the absence of one kidney (unilateral renal agenesis), prematurity, or being small for gestational age as a newborn. Finally, adaptive FSGS may occur due to other types of chronic damage to the glomeruli (filters), such as when urine backs up from the bladder into the kidneys (reflux nephropathy).
Other causes of secondary FSGS include the use of certain medications or drugs that have been shown to damage podocytes, such as interferon, bisphosphonates, anabolic steroids, heroin, anthracyclines, calcineurin inhibitors, lithium, and sirolimus. Certain viruses including human immunodeficiency virus (HIV), parvovirus B19, hepatitis C virus, simian virus 40, Epstein-Barr virus, and cytomegalovirus have also been associated with FSGS.
Some individuals develop FSGS because of previous injury to the kidneys. During the healing phase of a previous inflammatory disease of the kidneys, it is believed that, as the body tries to heal the kidneys, scarring or hardening (sclerosis) of the glomeruli may occur. Kidney disorders such as IgA nephropathy, small vessel vasculitis, and lupus nephritis have been associated with the development of FSGS.
The genetic forms of FSGS occur due to an abnormal variant in a susceptibility gene, or a disease-causing variant in a gene known to cause FSGS (monogenic FSGS). More than 40 different genes have been reported to be associated with FSGS. Some of these genes create (encode) proteins that are involved in the proper health, development, and function of podocytes. An abnormal variant in a susceptibility gene means that a person is at a greater risk of developing a disorder than someone without that gene variant, but that the disorder won’t develop unless other factors (usually environmental, immunologic, or other genetic factors) also occur. People with an abnormal variant in a susceptibility gene may never develop the disorder associated with that gene. Monogenic disorders develop because of a variation in one specific gene. Most individuals with a disease-causing variation will develop symptoms of the disorder. A variation in the single gene is all that is necessary for the disorder to develop. Other factors including variations in other genes or environmental factors can influence how a monogenic disorder progresses or the specific symptoms that develop.
Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation (abnormality) of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Genes associated with FSGS affect proteins that are essential in maintaining the health, structure, development and function of the glomeruli (filters). These include genes in podocytes and the glomerular basement membrane, which is a vital component of the small blood vessels (capillaries) that make up glomeruli.
In recent years, abnormal variants in the APOL1 gene have been shown to be associated with FSGS in patients of African ancestry. This is sometimes referred to as APOL1-associated FSGS.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes (bundles of genetic material) that an individual receives from his/her father and mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to child is 50% for each pregnancy regardless of the sex of the resulting child.
Recessive genetic disorders occur when an individual inherits two abnormal genes for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not develop the disease itself. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child, is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
In rare instances, FSGS has been inherited as an X-linked trait, which are genetic disorders caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off.” A male has one X-chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers if the other X chromosome from their mother is normal. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son. In some females, known as heterozygotes, which inherit a single copy of the disease gene, disease traits on the X chromosome may not always be masked by the normal gene on the other X chromosome. As a result, these females may exhibit some of the symptoms associated with the disorder.
Focal segmental glomerulosclerosis is estimated to affect about 7 people per million people in the general population, although specific incidence rates vary in different populations. FSGS accounts for about 40% of adults with nephrotic syndrome and about 20% of children with nephrotic syndrome. In the United States, FSGS accounts for 5%-20% of all people who experience end stage renal disease. Some recent studies have found that the number of people who have FSGS is increasing each year.
FSGS affects men slightly more often than women and can affect children or adults. It most often occurs in adults about 45 years or older. FSGS occurs more commonly in African Americans than in Caucasian, and the rate of decline of kidney function is generally more rapid in African Americans
A diagnosis of focal segmental glomerulosclerosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. To confirm the diagnosis, small pieces of kidney tissue are sampled in a procedure called a kidney biopsy. These tissue samples are evaluated under a microscope to look for the signs of FSGS.
Clinical Testing and Workup
A sample of kidney tissue taken via biopsy and studied under a microscope can reveal characteristic changes in the kidney that indicate FSGS. During this procedure, a small needle is passed through the skin to the kidney to obtain a small sample of tissue. This sample is viewed under a microscope by a special doctor called a pathologist who studies the specific cells and characteristics of the tissue sample to identify disease. Sometimes, a biopsy sample is inconclusive, and multiple samples may need to be taken.
Urine and blood tests help to suspect the condition. Urine tests reveals elevated levels of protein leakage and sometimes also find blood in the urine. Blood tests may find elevated levels of cholesterol and waste products in the blood, with lower than normal blood protein (albumin) levels.
To measure kidney function, physicians order a blood test called creatinine, which allows them to calculate the glomerular filtration rate (GFR). This blood test helps to check on how well the kidneys are working. Specifically, this test will determine how well the kidneys are filtering waste products and water from the blood that passes through the kidneys. This test allows physicians to determine the rate of kidney decline and help to plan the most effective treatment.
Molecular genetic testing can confirm a diagnosis of FSGS in certain cases. Molecular genetic testing can detect an abnormal variant in one of the genes known to cause the disorder. Genetic testing can be done as part of a research study, or a diagnostic service at specialized laboratories. When performed as a diagnostic service, they are often expensive, and health insurance may not cover this testing. Because of these factors, and because there are currently no proven treatments for many genetic forms of FSGS, genetic testing is not commonly performed.
The treatment of focal segmental glomerulosclerosis is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, specialists who asses and treat kidney disorders (nephrologists), surgeons who specialize in organ transplants, social workers, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan treatment. Genetic counseling may be of benefit for affected individuals and their families for the patients with a genetic form of FSGS.
Psychosocial support for the entire family is essential as well. Several of the organizations listed in the Resources section provide support and information on kidney disorders.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as the underlying cause of FSGS; how far kidney function has declined; the presence or absence of certain symptoms; and an individual’s age and general health. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks of treatment, including possible side effects and long-term effects; patient preference; and other appropriate factors.
The general goal of treatment is to decrease proteinuria and either stabilize or improve kidney function. It has been shown that patients who experience improvement in their proteinuria to the normal range generally have the best kidney outcomes (i.e. no progression of kidney disease, or need for dialysis or a kidney transplant). Patients who achieve a reduction in proteinuria also have better kidney outcomes, although not as good as patients with normal amounts of proteinuria. Patients whose proteinuria does not improve have the worse kidney outcomes.
Distinguishing between primary (idiopathic) FSGS, secondary FSGS and genetic FSGS is extremely important as the treatment options and response to treatment will differ. The response to various treatments is highly individualized as well, meaning that treatments which are effective in one person may be ineffective, or poorly tolerated, in another person.
Individuals with primary FSGS and nephrotic syndrome are treated with a class of steroid drugs called glucocorticoids and/or other drugs that suppress the activity of the immune system (immunosuppressive drugs). These drugs have side effects and some individuals may not be able to tolerate these medications. Other individuals may not improve despite taking these medications. Some physicians do not use immunosuppressing drugs for people with primary FSGS if they do not have nephrotic syndrome because the disease is less aggressive. Individuals with primary FSGS without nephrotic syndrome and with lower levels of protein in the urine may be treated with drugs called renin-angiotensin-aldosterone system (RAAS) inhibitors and dietary restriction of sodium, without immunosuppression.
If the disease worsens, then they may be treated with glucocorticoids and other immunosuppressive drugs. These include medications called calcineurin inhibitors (cyclosporine and tacrolimus) and mycophenolate mofetil have been shown to improve proteinuria levels in patients with FSGS.
In individuals with virus-associated FSGS, treatment is aimed toward treating the underlying infection. In individuals with medication-associated FSGS, discontinuation of the offending medication is required.
There are several supportive therapies that are given to help manage the various symptoms associated with FSGS including water pills (diuretics) and a low sodium diet to relieve edema; blood thinning medications that help prevent blood clots (anticoagulants); drugs called statins that can help lower cholesterol levels; and RAAS inhibitors such as angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), which can help to control blood pressure and lower the amount of protein in the urine.
Physicians may also recommend exercise, smoking cessation, supplemental vitamins, and maintaining a healthy or low protein diet.
Despite treatment, some affected individuals progress to end stage renal disease, in which the kidneys no longer function. End stage renal disease cannot be reversed and requires dialysis or a kidney transplant. If a patient undergoes kidney transplant, there is a risk that FSGS will recur in the transplanted kidney; this is particularly true for individuals with primary FSGS. When FSGS recurs, additional drugs that suppress the immune system may be used. These drugs often differ from the drugs that are used to initially treat FSGS. A procedure called plasmapheresis (see below) may also be recommended.
As mentioned above, a circulating permeability factor may be present in the blood that causes primary (idiopathic) FSGS in some patients. Removing this factor may lead to improvement by reducing protein levels and, sometimes, remission of FSGS if it occurs in the transplanted kidney. The circulating permeability factor may be removed by a procedure called plasmapheresis. During plasmapheresis, blood is removed from the patient, and the blood cells are separated from plasma. The patient’s plasma is removed, replaced with other humans’ plasma, and this blood is transfused back into the patient. Studies have shown that plasmapheresis is most effective the earlier it is used to treat recurrence.
Other medications have been studied for the treatment of focal segmental glomerulosclerosis including drugs called rituximab and adrenocorticotropic hormone (ACTH). Generally, these medications are used in individuals who do not respond to other medications, or relapse after successful treatment with other medications. Additional medications that have been used to treat FSGS include cyclophosphamide, mizoribine, adalimumab, fresolimumab, abatacept and galactose, as well as a procedure called LDL-pharesis. As researchers better understand the varied mechanisms that cause damage to kidney glomeruli, newer and targeted therapies are being studied for the treatment of FSGS.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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