FSGS stands for Focal Segmental Glomerulosclerosis, a type of autoimmune kidney disease (glomerulonephritis). It is characterized by scarring of the tiny filtering units in the kidney (glomeruli) and leads to a progressive decline in kidney function. In this blog, I will discuss what causes FSGS.


what causes fsgs


What Causes FSGS?

By Majd Isreb, MD, FACP, FASN, IFMCP

FSGS is one of the common glomerulonephrites. The symptoms may include swelling, foamy urine, and high blood pressure. Early diagnosis and treatment can help slow the progression of FSGS and prevent kidney failure.

The pathology of FSGS

As in almost all glomerulonephritis, FSGS is described according to the kidney biopsy findings. In FSGS, sclerotic lesions affect parts (focal) of some (segmental) glomeruli.

Based on pathology, FSGS can be divided into several types:

  1. Tip lesion involves the end or “tip” of the glomeruli. This seems to be the most benign and responsive to therapy.
  2. The perihilar lesion affects the glomeruli near the renal arterioles.
  3. Cellular, which presents in the early stages of the evolution of FSGS and is the least common variant.
  4. Classic (NOS), which is the most common subtype.
  5. Collapsing FSGS is characterized by severe scarring and damage to the glomeruli, resulting in abrupt proteinuria (excessive protein in the urine) and progressive kidney function decline. This carries the worst prognosis with poor response to conventional treatments.

What causes FSGS?

As you can see, the name FSGS is defined by the histological pattern of glomerular injury. At the root cause, FSGS is not a single disease entity. FSGS, for example, can be caused by various factors, including genetics, infections, drug use, and obesity.

Genetics of FSGS

FSGS can have a genetic component, as some forms of the disease are inherited and run in families. More than 50 genes have been described as potentially responsible for FSGS.

Mutations in genes such as NPHS1 or NHPS2 are associated with the rapid onset of massive protein loss in the urine in early childhood. While mutations or SNPS in other genes have been linked to inherited cases of FSGS that appear later in life. These includes ACTN4, INF2, and TRPC6 genes.

Even genetic variants in the COQ2 gene, which provide instructions for making an enzyme that produces coenzyme Q10 (CoQ10), have been associated with FSGS. Affected individuals were treated successfully with CoQ10 supplementation.

In some cases, the genetic basis of FSGS is still unknown, and further research is needed to fully understand the genetics of the disease. In addition, other environmental, genetic, or epigenetic modifiers could explain the development of FSGS in certain families.

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Infections that are associated with FSGS

Various infections have been associated with the development of FSGS. These include:

  1. HIV/AIDS: Human Immunodeficiency Virus (HIV) can lead to FSGS in some individuals with AIDS.
  2. Hepatitis B and hepatitis C: Chronic Hepatitis B and C infections can increase the risk of FSGS.
  3. Other viruses, such as parvovirus B19 and Cytomegalovirus, can cause FSGS.
  4. Streptococcal infections: Repeat streptococcal infections, such as strep throat, have been linked to FSGS in some cases.
  5. Lyme disease: The bacterium that causes Lyme disease, Borrelia burgdorferi, can trigger a disease called minimal change disease (MCD) in some individuals. MCD is another glomerulonephritis, and it could be argued that it is part of the FSGS spectrum of diseases. However, I could not find any case report or review in the literature showing a clear association between Lyme disease and FSGS. If you know of any, could you send them my way?

It’s important to note that while infections can trigger FSGS in some cases, not all individuals with these infections will develop FSGS.


Clearly filtered glass bottle


Medications and FSGS

Certain medicine has been linked to the development of FSGS, these includes:

  1. Nonsteroidal anti-inflammatory drugs (NSAIDs): Long-term use of NSAIDs, such as ibuprofen, have sometimes been linked to FSGS.
  2. Interferon
  3. Bisphosphonates
  4. Anabolic steroids
  5. Lithium
  6. Sirolimus
  7. Tyrosine kinase inhibitors
  8. Immune checkpoint inhibitors (Nivolumab, Pembrolizumab, and Ipilimumab)
  9. Street drugs: Illegal street drugs, such as cocaine and heroin, have been associated with FSGS.
  10. Supplement?
  11. Herbs?

It’s important to note that while drug use can trigger FSGS in some cases, not all individuals who take these drugs will develop FSGS. The exact mechanisms behind the association between drug use and FSGS are still being studied. Additionally, the benefits of taking these drugs to treat medical conditions may outweigh the potential risks in some cases.


Maladaptive FSGS

Maladaptive FSGS is usually the result of a “mismatch” between the load on the filtering units of the kidneys and their capacity. This can be seen in situations where the kidney mass is decreased or where there is an increase in waste production. Therefore, any kidney disease that leads to a decrease in the number of filtering units (nephrons) can ultimately cause some form of maladaptive FSGS.

Decreased kidney mass (reduced nephron numbers)

This can be seen in these conditions:

  1. Reflux nephropathy, in which the urine backs up into the kidneys, causing damage and fewer nephrons.
  2. Surgical resection of part of the kidneys or one of the kidneys.
  3. Renal dysplasia is usually congenital and leads to a small kidney.
  4. The congenital absence of one of the kidneys.
  5. A decrease in the number of nephrons at birth (nephron endowment)

Normal kidneys but excessive waste production

As in individuals with:

  1. Obesity
  2. High intake of protein

The bottom line

FSGS is not a single disease entity. It is defined by the histological pattern of glomerular injury. Various causes can lead to FSGS, including genetics, infections, drug use, and obesity. It is, therefore, essential to look for the root cause of this disease through an Integrative approach. This approach can be made in conjunction with conventional medical therapy, especially in the aggressive forms of this disease.