What is Focal Segmental Glomerulosclerosis?
Focal Segmental Glomerular Sclerosis (FSGS) is a common condition that can often lead to a health issue called nephrotic syndrome. This syndrome is found in about 40% of adults and 20% of children with FSGS. In this disease, some parts of the kidneys, known as glomeruli, are damaged, but not all. It’s a widely seen cause of kidney damage in adults. There are two types of FSGS, primary (where the cause is unknown), or secondary, caused by infections, medications, changes in blood flow in the kidneys, and genetic aspects.
Although there are clear symptoms, FSGS is only confirmed through a process called histopathology, a microscopic examination of tissues from the body. This examination shows specific scars that affect only a part of some kidney cells. Recent research has revealed that the cause behind FSGS is damage to podocytes, a kind of kidney cell. This damage causes protein loss that leads to the development of scarring. Identifying whether FSGS is primary or secondary has important implications for prognosis and treatment.
FSGS symptoms include nephrotic syndrome (marked by swelling, fatigue, and loss of appetite) and are seen in over 70% of patients. High blood pressure is another common symptom, which can become severe, especially in people of Afro-Caribbean origin, who also have kidney insufficiency.
What Causes Focal Segmental Glomerulosclerosis?
Focal segmental glomerulosclerosis, or FSGS, is a kidney disease that can be categorized into three types: primary, genetic, or secondary.
In the primary type, also known as idiopathic, FSGS is linked to certain substances in the blood known as permeability factors or cytokines. These substances can cause the tiny cells on the kidneys’ filters, the foot processes, to flatten out and proteins to leak into the urine. This type of FSGS can occur in different forms, including with hyalinosis or because of diseases like IgM nephropathy, minimal-change disease, or mesangeal proliferative glomerulonephritis. Sometimes, it can also exist with other kidney conditions like IgA nephropathy.
The primary type has a few subtypes, such as the collapsing form, the one with many more cells than usual in certain parts of the kidneys, and the one with abnormalities at the tip of the kidney filters.
As for the genetic type, it’s often a result of mutations or abnormalities in numerous genes, which then affect different parts of the cells in our kidneys’ filters. These genes include NPHS1 and NHPS2, to name a few. If these genes get mutated, they can lead to a severe kidney issue called congenital nephrotic syndrome. Certain genetic markers, like APOL1, are more common in individuals of African descent and can significantly increase their risk for FSGS. People with the genetic form of FSGS often have a family history of this disease and are typically young.
Finally, the secondary type comes about because of a range of factors like certain drugs (such as heroin, analgesics, steroids), viruses (like Hepatitis B and C, HIV), toxins, and changes within the kidneys themselves. Depending on the cause, the kidneys can either respond by becoming larger or by partially flattening their foot processes.
For those with kidneys not functioning at full capacity, this could happen due to single kidney, kidney transplant, kidney dysplasia, kidney agenesis, and more. For those with normal kidney function, causes might include obesity, sickle cell disease, or congenital cyanotic heart disease.
In addition to these, FSGS can also be connected with cancers such as lymphomas and other conditions like high blood pressure, Alport syndrome, sarcoidosis, and radiation nephritis.
Risk Factors and Frequency for Focal Segmental Glomerulosclerosis
Focal Segmental Glomerulosclerosis, also known as FSGS, is a kidney disease that seems to be increasing in prevalence worldwide. It is most commonly seen in people between the ages of 18 and 45, although no age is exempt. The disease has an estimated incidence of about 7 per 1 million, with an overall prevalence of 4%. The disease affects various races and regions differently.
- In the United States, approximately half of all cases of a related condition, nephrotic syndrome, in African Americans are caused by FSGS.
- It’s also the leading cause of severe kidney disease in the country, a trend that’s been growing over the years.
- Australia reports one of the highest rates of FSGS, which may be due to proactive policies encouraging kidney biopsies.
- In the pediatric population, FSGS represents 7% to 10% of all kidney biopsies.
- Among adults, the disease is more common in males and is found in 20-30% of all cases of nephrotic syndrome.
- FSGS is found 3-7 times more often in young Black males than their white counterparts.
- Every year, FSGS affects 5 out of every million white people compared to 24 out of every million black people.
- In the US, severe kidney disease caused by FSGS affects 1.9 out of every million white people compared to 6.8 out of every million black people.
The disease varies a lot in how it affects people. It causes swelling, protein in urine that’s difficult to treat, increased blood pressure, and gradual kidney decline. In those who don’t respond to treatment, kidney failure usually occurs between 6 to 8 years after the first symptoms. However, the course of the disease can vary widely. If the disease can be put into remission, either naturally or through treatment, the odds for good kidney health are much higher. On the other hand, within the black population, the disease often leads to worse outcomes, including a specific, aggressive form of the disease that causes severe high blood pressure, a poor response to steroid treatment, excessive protein in the urine, and accelerated progression to kidney failure.
Signs and Symptoms of Focal Segmental Glomerulosclerosis
Focal Segmental Glomerular Sclerosis (FSGS) is a condition that affects the kidneys. In children, it usually begins with a condition called nephrotic syndrome, which is characterized by swelling, excess protein in urine, low protein in the blood, and high cholesterol levels. Among adults, FSGS may present with either similar nephrotic symptoms or less severe symptoms like high blood pressure, tiny amounts of blood in urine, or reduced kidney function.
For a correct diagnosis, it’s necessary to know a range of details such as the patient’s birth history, family history, pre-existing kidney disease, exposure to harmful substances, recent viral illnesses, and other medical conditions. Understanding these details can help to identify the cause of FSGS.
Swelling or edema in FSGS usually develops over some weeks. But, it can also happen suddenly, even leading to sudden weight gain of about 15-20 lbs (6.8 to 9 kg). Often, swelling appears after an upper respiratory tract infection.
- Accumulation of fluids in lungs and abdominal cavity could be seen, but it’s rare to have fluid accumulation around the heart.
- Gross edema can make patients susceptible to infections and skin ulcers in the lower limbs.
- Abdominal pain could indicate inflammation of the abdominal lining, something that’s common in children.
- High cholesterol levels might cause yellow patches on skin called xanthomas, however, this is not common.
- Patients with FSGS often have normal physical examination results, with the exception of swelling. High-blood pressure is also not uncommon, particularly in Black patients with kidney dysfunction.
At times, patients might display severe kidney failure symptoms such as nausea, vomiting, seizures, bleeding, or changes in mental status. In cases when FSGS is due to conditions like reflux nephropathy, significant obesity, and kidney dysgenesis/agenesis, patients usually exhibit non-severe kidney disease symptoms. Over time, these patients may see kidney function progressively worsen over several months to years.
Testing for Focal Segmental Glomerulosclerosis
Focal segmental glomerulosclerosis (FSGS) is a kidney condition that is diagnosed through various tests. One method is a urinalysis, which checks urine for different elements. In cases of FSGS, this test might show large amounts of protein and casts (hardened cell debris). However, red blood cell casts are usually not present. In the early stages, creatinine levels in the blood (measured using Serum creatinine and creatinine clearance tests) are typically normal. Although it’s not always the case, FSGS can sometimes present features of nephrotic syndrome, a kidney disorder that causes your body to excrete too much protein in your urine. This includes high levels of protein in the urine, low levels of protein in the blood, and potentially swelling in the legs, ankles, and around the eyes.
In cases where FSGS has no apparent cause (idiopathic FSGS), additional tests might be done to rule out potential underlying conditions such as lupus, hepatitis B and C, and vasculitis. If FSGS might be secondary to other conditions, further tests can be done for conditions such as HIV, hepatitis, and parvovirus.
For individuals who are extremely overweight, FSGS is usually diagnosed by ruling out other potential causes. In these cases, signs of FSGS can include overworking of the kidneys and an overactive renin-angiotensin-aldosterone system, which regulates blood pressure and fluid balance. FSGS might be suspected in individuals with high levels of protein in their urine. But if a younger patient doesn’t have red blood cell casts and all other tests are negative, a definitive diagnosis comes from a kidney biopsy.
A kidney biopsy helps doctors identify conditions affecting the kidneys. Characteristic findings for FSGS include partial blockage of the glomeruli (tiny blood vessels in the kidneys), typically near the hilum area, and sometimes in the areas around the glomeruli such as the tubular pole. In the affected glomeruli, a buildup of cellless tissue matrix and hyaline (a glassy substance) block the capillaries partially. The blocking often contains granular deposits of C3 and IgM proteins. Another key finding is the abnormal fusion of foot processes (projections of cells) predominantly in the blocked segments and partial fusion over normal-looking lobules.
In FSGS associated with HIV, a special kind of microscopy of the kidney can reveal inclusions (foreign substance) in mesangial and endothelial cells which indicate viral disease.
Ultrasonography, a type of imaging that uses sound waves to create images of organs, is another tool that can help in diagnosing FSGS. In the earlier stages of the illness, it will generally show kidneys that look normal or enlarged with increased echogenicity, indicating widespread internal kidney disease. If the kidney disease is advanced, the kidneys may appear shrunken and small, indicating severe interstitial fibrosis (scarring) and glomerular scarring. In cases of FSGS associated with HIV infection, ultrasound typically shows large echogenic kidneys.
Treatment Options for Focal Segmental Glomerulosclerosis
In simpler terms, when a person has a kidney condition known as focal segmental glomerular sclerosis, the first treatment tried is often a type of medication known as glucocorticoids, often taken daily or every other day. If glucocorticoids (commonly known as steroids) don’t work or cause bad side effects, health professionals may then prescribe a type of medication to suppress the immune system, such as calcineurin inhibitors or other drugs like mycophenolate mofetil or rituximab.
Prednisolone, a type of glucocorticoid, is usually prescribed in high doses. It’s generally given for a minimum of four weeks, and stopped once the condition improves or after a maximum of 16 weeks. If the medication starts to lead to a decrease in protein in the urine (a symptom of this kidney condition) before the 16 weeks are up, it may not be necessary to continue the high dose. This is especially important if the patient is experiencing side effects from the steroids.
Once the condition improves or protein disappears from the urine, the dose of prednisolone is reduced gradually over several weeks, until the total treatment period reaches six months. If partial improvement is seen within eight to twelve weeks, the medication is continued for the full 16 weeks to ensure the condition fully improves.
When glucocorticoids aren’t effective or cause too many side effects, other medications like calcineurin inhibitors might be used. Two such medications are cyclosporine and tacrolimus. Usage and effectiveness of these medications need to be monitored to avoid drug toxicity. This treatment should be tried for at least six months, and if it works, it must be continued for at least a year while the dose is reduced gradually over half a year or longer to help prevent the condition from coming back.
In some cases, other drugs or approaches might be used if patients are intolerant or resistant to the glucocorticoid or the calcineurin inhibitors. These can include Mycophenolate mofetil, high-dose dexamethasone, rituximab, adrenocorticotropic hormone, mTOR inhibitors, and for select patients, plasmapheresis.
For less severe cases, lifestyle changes like reduced salt intake and certain medications can be tried. It’s also important to manage other conditions like high blood pressure, manage symptoms like swelling with water pills (diuretics), use cholesterol-lowering drugs for high cholesterol, and in some cases, use blood thinners to prevent blood clots.
The effectiveness of treatment can vary based on age. Children often respond to treatment within a few weeks, while adults may take months to see improvement. About 30% of patients show improvements through glucocorticoids, while around half show improvement with calcineurin inhibitors.
What else can Focal Segmental Glomerulosclerosis be?
For patients showing signs of nephrotic syndrome, it can be tough for doctors to tell the difference between focal segmental glomerulosclerosis and other kidney conditions. These other conditions can include diseases like minimal change disease, membranoproliferative glomerulonephritis, mesangial proliferative glomerulonephritis, or membranous glomerulonephritis. As such, doctors may consider the following conditions when working to diagnose the problem:
- Mesangial proliferative glomerulonephritis
- Membranoproliferative glomerulonephritis
- Nephrotic syndrome
- Systemic lupus erythematosus
- Diabetes mellitus
- IgA nephropathy
- Amyloidosis
What to expect with Focal Segmental Glomerulosclerosis
Several characteristics can predict the outcome of FSGS (Focal Segmental Glomerulosclerosis), a disease that damages the kidneys’ filtering system. These include the patient’s race, with Black individuals often having worse outcomes. Other factors include the amount of protein leaking into the urine (proteinuria), whether there’s already an existing decrease in kidney function (renal insufficiency), and the exact type of FSGS (histological variant). Those who have the ‘tip variant’ often have the best outcome, while the ‘collapsing variant’ tends to have the worst.
In addition, patients with a significant amount of damage to the kidney tissue (IFTA – interstitial fibrosis/tubular atrophy) and their response to treatment can also dictate the outcome. Those who have partial or complete remission after treatment usually have a better prognosis. Finally, patients diagnosed with primary FSGS, where the cause is unknown and seems to originate in the kidney itself, tend to fare worse than those with adaptive or secondary FSGS, which is caused by another condition or factor.
Possible Complications When Diagnosed with Focal Segmental Glomerulosclerosis
Focal segmental glomerulosclerosis, a kidney disease, could lead to several potential complications. Here are some of them:
- Uncontrolled high blood pressure
- Anemia
- Advanced kidney failure
- Blood clots in a vein
- Frequent infections
- A condition that results in the formation of blood clots in small blood vessels
Additionally, medications used to manage this disease can also cause complications. Prednisone therapy, for example, could lead to complications such as:
- Infections
- High blood pressure
- High blood sugar levels
Meanwhile, the complications of a medication called cyclophosphamide might include:
- Infections
- Low white blood cell count
- A condition that causes bleeding in the bladder
Lastly, cyclosporine therapy could potentially lead to complications including:
- Kidney insufficiency
- Overgrowth of the gums
- Infections
Preventing Focal Segmental Glomerulosclerosis
Doctors should teach patients how to manage high blood pressure and cholesterol levels, as well as chronic kidney disease. They should also explain the various options for kidney replacement therapy. These options include hemodialysis (a procedure that uses a machine to clean the blood when the kidneys can’t), peritoneal dialysis (a procedure which uses the lining of the abdomen to filter the blood), and kidney transplantation (surgery to replace a damaged kidney with a healthy one).
Patients should be informed about the warning signs and symptoms of these conditions, and when they should seek medical help. Doctors will also likely recommend changes to the patients’ diets. For instance, they should limit their salt intake. The recommended amounts are 2 grams of sodium (which is about 5 grams of salt) per day.
Patients who are treated with diuretics (medicines that help remove excess water from the body) and develop hypokalemia (low potassium levels), may need to take potassium supplements.
High protein intake can make proteinuria (presence of excess proteins in the urine) worse, which could further harm kidney function. This is why the current guidelines recommend a daily protein intake of 1 to 1.3 grams per kilogram of a person’s body weight. The protein should be from high-quality sources. Reducing fat intake can also help manage dyslipidemia (abnormally high levels of fats in the blood).