Focal Segmental Glomerulosclerosis: Symptoms, Types, Causes and Treatment

Focal Segmental Glomerulosclerosis (FSGS) is a complex kidney disorder with profound impacts on patients’ health and quality of life. This article explores the key symptoms, the different types, underlying causes, and the latest approaches to treatment—providing a comprehensive guide for patients, caregivers, and anyone interested in understanding this important kidney condition.

Symptoms of Focal Segmental Glomerulosclerosis

FSGS can be a subtle disease at onset, but its symptoms can significantly disrupt daily life as the disease advances. Many patients first notice signs such as swelling or unexpected fatigue, but others may be diagnosed incidentally during routine testing. Understanding these symptoms is crucial for early detection and management.

Symptom	Description	Impact Area	Source(s)
Proteinuria	Excess protein in urine	Renal	1 3 4
Edema	Swelling in legs, ankles, abdomen	Physical	3 4
Fatigue	Persistent tiredness	Physical/Emotional	4
Hypertension	High blood pressure	Cardiovascular	3
Hematuria	Blood in urine	Renal	3
Renal Insufficiency	Reduced kidney function	Renal	3
Shortness of Breath	Difficulty breathing	Respiratory	4

Table 1: Key Symptoms of FSGS

Proteinuria: The Hallmark Sign

The most consistent and prominent symptom of FSGS is proteinuria—an abnormal loss of protein in the urine. This may be detected during routine medical tests, even before other symptoms develop. Proteinuria can be mild or severe, and when substantial, it often leads to the nephrotic syndrome, characterized by heavy proteinuria, low blood albumin, and swelling (edema) 1 3 4.

Edema and Physical Changes

Swelling (edema) is frequently seen, particularly in the legs, ankles, and feet, but may also involve the abdomen. This occurs because the kidneys lose their ability to retain essential proteins, resulting in fluid accumulation in tissues. Some patients also report swelling from the waist down or generalized body swelling 4.

Fatigue and Well-being

Living with FSGS often means coping with persistent fatigue, which can impact both physical and emotional health. Alongside this, patients may experience body pain or a general sense of pressure 4.

Blood Pressure and Urinary Changes

Hypertension (high blood pressure) and hematuria (blood in the urine) are other important features. Renal insufficiency—where kidneys fail to function adequately—can also develop, sometimes without prominent symptoms until the disease is advanced 3.

Impact on Quality of Life

FSGS doesn’t just affect the kidneys; it can disrupt all aspects of life—reducing physical activity, causing emotional distress, and limiting social engagement. Shortness of breath is less common but may occur, especially in advanced cases 4.

Types of Focal Segmental Glomerulosclerosis

FSGS isn’t a single disease but rather a pattern of injury that can occur in several distinct forms. Recognizing the different types is essential for tailoring treatment and predicting disease progression.

Type	Description	Prognosis	Source(s)
Primary (Idiopathic)	FSGS with no identifiable underlying cause	Variable	2 3 6
Secondary	FSGS due to known causes (e.g., virus, drugs, obesity)	Depends on cause	2 6
Genetic	FSGS caused by inherited gene mutations	Often early onset	5 6 9 10
Variant: NOS	Not otherwise specified; classic FSGS appearance	Intermediate	2
Variant: Tip	Lesion at tubular pole of glomerulus	Best prognosis	2 5
Variant: Perihilar	Sclerosis near vascular pole of glomerulus	Intermediate	2
Variant: Cellular	Proliferation of cells in glomerular segment	Intermediate	2
Variant: Collapsing	Segmental or global collapse of capillary tufts	Worst prognosis	2 5
APOL1-Associated	Linked to APOL1 gene variants (mainly in African ancestry)	Variable	5 6

Table 2: Types and Variants of FSGS

Primary (Idiopathic) FSGS

Primary FSGS is diagnosed when no obvious cause can be identified. It is thought to involve circulating factors that damage the kidney’s filtering units (podocytes) and is often responsive to immunosuppressive therapy. This form carries a risk of recurrence after kidney transplantation 2 6.

Secondary FSGS

Secondary FSGS arises as a result of identifiable causes, such as:

• Viral infections (e.g., HIV)
• Drug toxicities (e.g., heroin, certain medications)
• Obesity or reduced kidney mass (leading to hyperfiltration)
• Other systemic diseases

Secondary forms tend to have a slower progression, and treatment focuses on addressing the underlying cause 2 6.

Genetic FSGS

Mutations in genes important for podocyte function can cause FSGS, often manifesting early in life. Over 40 gene mutations have been linked, including INF2 and APOL1 risk alleles (the latter most common in individuals of African descent) 5 6 9 10.

Morphologic Variants

Pathologists recognize several variants of FSGS based on the appearance of kidney tissue under the microscope:

• NOS (Not Otherwise Specified): The default category; classic features without specific distinguishing characteristics.
• Tip Variant: Affects the tubular pole of the glomerulus; best response to therapy and prognosis.
• Perihilar Variant: Sclerosis near the vascular pole; often seen with adaptive (secondary) FSGS.
• Cellular Variant: Features cell proliferation and inflammation.
• Collapsing Variant: Collapse of capillary tufts and rapid loss of kidney function; worst prognosis 2 5.

APOL1-Associated FSGS

A unique form relates to APOL1 gene variants, primarily in individuals of sub-Saharan African ancestry. These genetic changes increase susceptibility to FSGS and influence response to treatment 5 6.

Causes of Focal Segmental Glomerulosclerosis

Understanding what triggers FSGS is critical for prevention and targeted therapy. The underlying causes are diverse, ranging from immune system dysfunction to inherited genetic mutations.

Cause	Mechanism/Trigger	Population Most Affected	Source(s)
Podocyte Injury	Direct damage to glomerular podocytes	All	1 7
Circulating Factors	Blood factors damaging the kidney filter	Primary FSGS; transplant	6 8
Genetic Mutations	Mutations in podocyte-related genes (e.g., INF2)	Children, families	5 9 10
APOL1 Risk Alleles	Genetic risk allele in APOL1 gene	African ancestry	5 6
Infections	HIV, other viruses	Immunocompromised	2 5 6
Drugs	Heroin, certain medications	Drug users, prescribed	2 5 6
Adaptive/Secondary	Increased kidney workload (obesity, loss of nephrons)	Obese, single kidney, aging	2 5 6
Unknown	No identifiable trigger (idiopathic)	General	2 6

Table 3: Causes and Risk Factors of FSGS

Podocyte Injury at the Core

FSGS invariably involves injury to specialized kidney cells called podocytes. These cells are critical for filtering blood, and their loss or dysfunction sets off a cascade leading to scarring and loss of kidney function 1 7.

Circulating Permeability Factors

Some forms—especially primary FSGS—appear to be driven by circulating factors in the blood, such as soluble urokinase receptor (suPAR), which can damage podocytes and trigger disease. The precise identity of these factors remains an area of active research 6 8.

Genetic and Familial Causes

Genetic forms result from inherited mutations in genes crucial for podocyte structure and function. These mutations can cause early-onset, severe, or recurrent disease. Notably, APOL1 gene variants are a major risk factor in people of African descent, influencing both susceptibility and the severity of FSGS 5 6 9 10.

Infections and Drugs

Certain infections, like HIV, and drugs, including heroin and some medications, can trigger secondary FSGS through direct toxicity or immune-mediated mechanisms 2 5 6.

Adaptive/Secondary Forms

Conditions that force the remaining nephrons (kidney units) to work harder—such as obesity, reduced kidney mass, or chronic overwork—can lead to maladaptive changes and secondary FSGS 2 5 6.

Other and Unknown Causes

In many cases, no specific cause can be identified, and the disease is labeled idiopathic. Ongoing research aims to clarify these triggers to improve prevention and treatment strategies 2 6.

Treatment of Focal Segmental Glomerulosclerosis

Managing FSGS is challenging—requiring a tailored approach based on the type, cause, and patient characteristics. While treatments can reduce symptoms and slow progression, not all patients respond in the same way.

Treatment	Indication/Use	Limitation/Concern	Source(s)
Corticosteroids	First-line for primary FSGS	Steroid resistance, side effects	11 12 13 14
Calcineurin Inhibitors (e.g., Cyclosporine A, Tacrolimus)	Steroid-resistant/dependent FSGS	Nephrotoxicity, dependency	11 13 14
Cytotoxic Agents	Some steroid-resistant cases	Limited efficacy, toxicity	11 13 14
Plasmapheresis	Recurrent FSGS post-transplant, resistant cases	Variable efficacy, invasive	11 13 14 15
Rituximab	Recurrent FSGS, some resistant cases	Variable response, limited data	15
Mycophenolate Mofetil	Alternative/adjunct in resistant cases	Limited data	13 14
Supportive Care	Blood pressure, cholesterol, edema management	Symptomatic only	13 14
Genetic Counseling	Genetic/Familial forms	No direct therapy	10 13

Table 4: Treatment Options for FSGS

Corticosteroids

Corticosteroids are the cornerstone of treatment for primary FSGS. Many patients respond to prolonged courses, but steroid resistance is a significant problem, particularly in adults. The main goal is to achieve remission of proteinuria, which is linked to a better prognosis 11 12 13 14.

Calcineurin Inhibitors

Drugs like cyclosporine A and tacrolimus are effective in many steroid-resistant or -dependent cases. They can be combined with steroids for better outcomes. However, these drugs carry a risk for nephrotoxicity and dependency, requiring careful monitoring 11 13 14.

Cytotoxic Agents and Other Immunosuppressives

Cytotoxic agents (such as cyclophosphamide) are sometimes used, but their efficacy is limited. Mycophenolate mofetil is an emerging alternative with some promising results, but more studies are needed 11 13 14.

Plasmapheresis and Rituximab

For patients with recurrent FSGS after kidney transplantation, or those unresponsive to other therapies, plasmapheresis (blood plasma exchange) and rituximab (an antibody therapy) may be employed. Responses are variable and more robust evidence is needed to define their roles, especially in adults 15.

Supportive and Symptomatic Care

Supportive care addresses the complications of FSGS—such as high blood pressure, high cholesterol, and edema—using standard medications like ACE inhibitors, diuretics, and statins. These measures are critical for all patients, regardless of the underlying form 13 14.

Genetic Counseling

For familial and genetic FSGS, genetic counseling provides information for families and guides decisions regarding transplantation and testing of relatives. However, immunosuppression is generally not effective for purely genetic forms 10 13.

Conclusion

Focal Segmental Glomerulosclerosis is a multifaceted kidney disease affecting diverse populations in different ways. Early recognition, accurate classification, and tailored therapy are crucial for improving outcomes.

Key Takeaways:

• FSGS often presents with proteinuria, edema, and fatigue, but symptoms can be variable and subtle at first.
• There are several types and morphologic variants of FSGS, each with different causes and prognoses.
• Causes range from genetic mutations and immune factors to infections, drugs, and adaptive changes.
• Treatment is individualized, with options including corticosteroids, immunosuppressants, plasmapheresis, and supportive care. Response to therapy varies significantly, especially in genetic and recurrent cases.
• Ongoing research aims to clarify the causes and optimize treatment, especially for resistant and recurrent forms.

By understanding the spectrum of FSGS, patients and clinicians can work together to improve quality of life and long-term kidney health.