Focal segmental glomerulosclerosis

What Is Focal Segmental Glomerulosclerosis?

Focal segmental glomerulosclerosis is a disease in which scar tissue develops on the glomeruli, the small parts of the kidneys that filter waste from the blood.1 Your kidneys contain about 1 million glomeruli that work like a kitchen strainer. When blood circulates through the glomeruli, they keep the important nutrients and minerals your body needs and strain out extra fluid and waste products that become your urine.2

FSGS happens when small sections of these tiny filters scar or harden. The name describes what doctors see under the microscope: "focal" means only some glomeruli are affected, "segmental" means only specific parts of the glomeruli have scarring, and "sclerosis" means hardening.2 Of the damaged glomeruli, only some show scarring. When this scarring happens, it becomes hard for your kidneys to filter properly. This can lead to kidney damage and, potentially, kidney failure.2

FSGS is one of the most common causes of nephrotic syndrome, a group of symptoms that includes high levels of protein in the urine, low levels of protein in the blood, and swelling in various parts of the body. The condition accounts for 40% of nephrotic syndrome cases in adults and 20% in children.3 Although it is a frequent glomerular kidney disease, FSGS is still considered rare, with healthcare providers diagnosing it in about 7 out of 1 million people per year.2

• Kidneys
• Glomeruli

Types of FSGS

There are several types of focal segmental glomerulosclerosis, classified based on their underlying causes.1

Primary FSGS: Many people diagnosed with FSGS have no known cause for their condition. This is called primary or idiopathic FSGS. Researchers believe that for unknown reasons, a protein in the blood damages part of the glomeruli.1 This is the most aggressive form and is caused by a defect in the immune system.4

Secondary FSGS: Several factors can cause secondary FSGS, such as viral infections (including HIV), drug toxicity, diseases including diabetes or sickle cell disease, obesity, medications, and even other kidney diseases.1 Controlling or treating the underlying cause often slows ongoing kidney damage and might lead to improved kidney function over time.1 Common causes include infections, certain medications, drug use, and conditions that alter the structure of the kidney such as systemic high blood pressure or aging kidney.5

Genetic FSGS: This is a rare form caused by genetic changes, also called familial FSGS. It is suspected when several members of a family show signs of FSGS. Familial FSGS can also occur when neither parent has the disease but each one carries a copy of an altered gene that can be passed on to the next generation.1 Genetic markers, such as APOL1 variants, are associated with treatment resistance and an increased risk of progression to end-stage renal disease.3

Unknown FSGS: In some cases, the underlying cause of FSGS cannot be determined, and the cause is not yet understood.1

Who Gets FSGS?

FSGS affects both adults and children, but it is most common in men older than 45. Healthcare providers diagnose it most often in people who are Black.2 The incidence of FSGS in the United States has risen over the last three decades in both children and adults.5 Race, ethnicity, and gender all have a significant effect on the incidence of FSGS, with the condition being more common in people of African ancestry.5

There are some notable risk factors for developing FSGS. The condition is more common among people with a family history of FSGS, African ancestry, low birth weight, obesity, premature birth, and viral infections including HIV.4

Signs and Symptoms

FSGS does not always cause symptoms you might notice on your own. Healthcare providers often find signs or symptoms during a routine exam or when testing for other medical conditions.2 The condition can present with clinical features of nephrotic or nephritic syndrome or renal insufficiency. Nephrotic syndrome is the most common clinical manifestation of FSGS, occurring in over 70% of patients.3

All forms of FSGS cause high levels of protein in the urine, a condition called proteinuria. This increased protein can cause the urine to appear frothy or foamy.4 Common signs and symptoms include:2

• Edema (swelling in your arms, legs, face, or around the eyes)
• High cholesterol
• Lower-than-average amounts of albumin (a protein in your blood)
• Abnormally high levels of protein in your urine
• Sudden weight gain caused by extra fluids in your body
• High blood pressure (hypertension)

When you have edema, proteinuria, and low albumin, your provider may call it nephrotic syndrome. This condition is characterized by generalized or dependent edema, fatigue, and appetite loss.3 Hypertension is also a common feature and can be severe, with diastolic blood pressure exceeding 120 mm Hg.3

If the overall kidney function deteriorates significantly, you may experience additional symptoms such as decreased urine output, fatigue, nausea, and poor appetite.4 Many people with FSGS report that fatigue negatively affects their ability to participate in meaningful activities.6

What Causes FSGS?

The causes of FSGS can be classified as primary (idiopathic), genetic, or secondary, with secondary causes including infections, drugs, and hemodynamic maladaptations.3 Accurate identification of the underlying cause is crucial for guiding treatment decisions, predicting prognosis, and assessing transplant risks.3

Understanding the physiopathology of FSGS is still unclear. Recent research has highlighted that the pathogenesis involves podocyte injury and damage. Podocytes are critical cells in the glomeruli that are part of the barrier between blood vessels and urine. When podocytes are damaged, this barrier becomes permeable, causing proteins to leak into the urine.5 The condition leads to protein loss and the development of focal sclerosis.3

People who have primary FSGS often do not have an obvious cause. Researchers believe that for unknown reasons, a protein in their blood damages part of the glomeruli.2 In some cases, FSGS can recur on a graft after kidney transplantation, and an unidentified circulating factor may be implicated.7

Diagnosis

For possible focal segmental glomerulosclerosis, your healthcare professional reviews your medical history and orders lab tests to see how well your kidneys work.8 Although clinical signs may suggest FSGS, the diagnosis can only be confirmed through histopathological findings obtained from a kidney biopsy.3

Testing may include:8

• Urine tests: These include a 24-hour urine collection that measures the amount of protein and other substances in the urine
• Blood tests: A blood test called glomerular filtration rate measures how well the kidneys are getting rid of waste from the body
• Kidney imaging: These tests are used to show kidney shape and size and might include ultrasound and CT or MRI scans
• Kidney biopsy: A biopsy usually involves placing a needle through the skin to take a tiny sample from the kidney

The results of the kidney biopsy can confirm a diagnosis of FSGS. During the procedure, your doctor removes a sample of kidney tissue and studies it under a microscope, looking for tissue scarring on some but not all (focal) glomeruli, with scarring affecting only a portion (segmental) of the affected glomeruli.4 Proteinuria, low serum albumin, and casts on urinalysis can support clinical suspicion, but histopathological confirmation is required for diagnosis.3

Treatment Options

Treatment for focal segmental glomerulosclerosis depends on the type and the cause of the condition.8 Your doctor recommends treatment based on your kidney function, protein in the urine, and type of FSGS.4 Treatment can be divided into nonspecific and specific therapy.9

Medications: Depending on symptoms, medicines to treat FSGS might include:8

• An angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) to lower blood pressure and reduce protein in the urine
• Medicines to lower cholesterol levels, as people with FSGS often have high cholesterol
• Medicines to help the body get rid of salt and water, called diuretics, which can improve blood pressure and swelling
• Medicines to lower the body's immune response, including corticosteroids, which may stop the immune system from damaging the kidneys in primary FSGS

In patients with primary or secondary FSGS and proteinuria, the initial approach consists of optimal blood pressure control and the use of ACE inhibitors or ARBs. For patients who remain non-nephrotic or become non-nephrotic after 6 months of therapy, this remains the primary therapeutic approach.9 Patients who are persistently nephrotic after a course of conservative therapy or who present with complications from nephrotic syndrome require more aggressive treatment with prednisone or immunosuppressive agents.9

If you have primary FSGS, your doctor is likely to prescribe medicines that modify your immune system, including steroids and medicines that target T and B cell function.4 The first-line treatment for idiopathic FSGS with nephrotic syndrome is a prolonged course of corticosteroids. However, steroid resistance or steroid dependence is frequent, and despite intensified immunosuppressive treatment, FSGS can lead to end-stage renal failure.7

Supportive Treatment: In patients with secondary FSGS and nephrotic-range proteinuria, the mainstay of therapy remains blood pressure control with ACE inhibitors and ARBs, along with disease-specific treatment if available (for example, antiretroviral therapy in HIV-associated nephropathy).9 Patients with FSGS benefit from supportive measures including regular, moderate exercise to help manage blood pressure and weight, following your doctor's instructions and taking medicines as prescribed, and seeing your doctor as scheduled to monitor kidney function.4

Clinical Trials: Clinical trials are another treatment option. Your doctor helps you find the right study for you. These trials test more targeted treatments with potentially lower risks of side effects. Some clinical trials enroll patients based on their genetic testing results to test the effectiveness of precision-based therapies targeted to specific genetic changes.4

Treatment for Kidney Failure: FSGS is a serious condition that can lead to kidney failure, which can only be treated with dialysis or kidney transplant.1 If kidney function deteriorates to the point of kidney failure, these treatments become necessary to sustain life.

Outlook and Prognosis

FSGS is often an aggressive, progressive condition marked by a continuous adjustment by the body to survive.5 As more podocytes become damaged or lost, proteinuria can reach a nephrotic range (3 grams or more per day). More than 70% of newly diagnosed adult patients with primary FSGS have proteinuria in the nephrotic range.5 Further disease progression can cause nephrotic syndrome. In FSGS, proteinuria is a standard measure of disease activity and a predictor and contributor to disease progression.5

Despite treatment, FSGS can result in kidney failure in 12% of pediatric and 5% of adult patients.10 Data from the US Renal Data System shows the incidence rate of end-stage kidney disease caused by FSGS increased by 11 times between 1980 and 2000.5 Although rare, FSGS is one of the most common glomerular causes of end-stage kidney disease.5

Between 30% and 40% of FSGS patients experience a recurrence of FSGS after a kidney transplant, with a high incidence of recurrence in the transplanted kidney.4 This recurrence can cause the new kidney to fail, often requiring maintenance dialysis. If you are diagnosed with genetic FSGS, you have a much lower risk of post-transplant FSGS recurrence.4 Genetic testing can help you understand your risk for needing a kidney transplant and your prognosis after a transplant.4

Treatment aims to reduce proteinuria to induce a complete or partial remission, which is important for long-term preservation of kidney function.5 It remains an important challenge for the scientific community to identify a specific diagnostic biomarker and to develop specific therapeutics for this condition.7

Living With FSGS

Living with focal segmental glomerulosclerosis can be challenging, as the disease is full of surprises and can significantly impact daily life.11 Many people with FSGS experience debilitating fatigue that negatively affects their ability to participate in meaningful activities. Finding relief for FSGS fatigue can be tricky, but there are ways to cope and feel more energized.6

Coping with Symptoms: Being honest with the people in your life and yourself can help you navigate the challenges that come with fatigue. Structure your day so you can tackle tougher projects or more essential chores first thing in the morning when you have more energy. Responsibilities that require less energy can fall lower on your to-do list.6 Many people do not report their feelings because they do not feel that they have anyone to talk to who can relate. No two people with glomerular disease are the same, and the disease progresses differently in everyone.12

Support and Mental Health: Everyone benefits from a mentor or advocate, someone that they can rely on and trust. Mentors who have been living and fighting through kidney disease or are on the same journey as you can be saviors of sanity. Valuable life survival techniques can be learned from those who are on dialysis and who have had a transplant.12 Get help coping with the challenges of living with FSGS through support groups. Connect with others who understand your journey, share experiences, and find comfort in knowing you are not alone.4

For many patients, it is important to have family, faith, and love around them, as these things keep them going.11 Hope is essential and comes from a positive attitude and, for many, a profound faith. The key gatekeeper is often the nephrologist, as all support systems connect through this medical professional.12

Diet and Lifestyle: Eating a kidney-friendly diet can help manage the symptoms and progression of FSGS. Learn more about a kidney-friendly diet from healthcare providers and nutritionists.4 Current recommendations call for a protein intake of 1 to 1.3 grams of high biologic value protein per kilogram of body weight. A reduction of dietary fat intake may help with dyslipidemia. A reduction in daily salt intake to 2 grams of sodium (6 grams of salt) is also recommended.9

Physical Activity: Regular, moderate exercise helps manage blood pressure and weight and improves overall well-being.4 Some patients practice yoga and play sports to deal with the emotional stress of their condition. Yoga not only helps emotionally, but stretching can help deal with flashes of pain.11

Work and Daily Life: Many people with FSGS are able to continue working, and some are able to work from home. However, for others, going to work is no longer an option after diagnosis, especially in jobs that require being on your feet all day.11 It is important to be open with family, friends, and employers about how you feel, as many people do not know about or understand this rare condition.6