Focal Segmental Glomerulosclerosis - An Overview

Introduction:

The human body has two kidneys. The kidneys are shaped like beans and are present on either side of the spinal cord below the rib cage on the backside. It performs several functions, including filtering the blood to remove excess fluid and waste from the body. Focal segmental glomerulosclerosis is a specific type of kidney damage.

What Is Focal Segmental Glomerulosclerosis?

Focal segmental glomerulosclerosis is a condition that occurs when the tiny filters in the kidney called glomeruli become sclerosed or hardened. Each kidney has around a million glomeruli, which are part of the basic unit of the kidneys known as the nephron. The glomeruli help in filtering excess water and waste out of the body. Due to the scarring or hardening of these tiny filters, the kidneys cannot remove the waste products from the body via urine. Eventually, these abnormalities may lead to progressive kidney damage, including decreased kidney function causing kidney failure. Focal means only some filters are damaged, and segmental means only some parts of the filters are hardened.

What Are the Different Types of Focal Segmental Glomerulosclerosis?

The various types of focal segmental glomerulosclerosis include:

• Primary Focal Segmental Glomerulosclerosis: Primary focal segmental glomerulosclerosis includes people with no known cause of their condition (idiopathic focal segmental glomerulosclerosis).

• Secondary Focal Segmental Glomerulosclerosis: Infection, drug toxicity, diabetes, sickle cell disease, obesity, and other kidney diseases can cause secondary focal segmental glomerulosclerosis. Treating or controlling these causes slows kidney damage and improves kidney function over a period of time.

• Genetic Focal Segmental Glomerulosclerosis: This is a rare form of focal segmental glomerulosclerosis caused by genetic factors. It is also known as familial focal segmental glomerulosclerosis. Different family members are affected by the disease. It can also occur when none of the parents have the disease but carry a copy of the gene responsible for it. This gene can be passed on to the next generation.

• Unknown Focal Segmental Glomerulosclerosis: The cause of focal segmental glomerulosclerosis is unclear in certain cases, despite the positive symptoms and tests.

What Are Circulating Glomerular Permeability Factors?

These are substances detected in the blood that are known to increase the permeability (increased leakiness) of glomerular filtration barriers, leading to increased protein excretion in the urine (proteinuria). Endothelial cells, glomerular basement membrane, and podocytes are the components of the glomerular filtration barrier. Podocytes are specialized cells that maintain the integrity of glomeruli. The circulating glomerular permeability factors play an important role in the occurrence of primary FSGS.

Circulating glomerular permeability factors are taken into account as the cause of primary FSGS for the following reasons:

• Around 30 percent of individuals experience proteinuria recurrence after kidney transplantation for primary FSGS. It occurs within hours after transplantation.

• When plasma from individuals affected with primary FSGS is injected into rats, it causes proteinuria in them.

• A newborn child experiences proteinuria due to the transmission of permeability factors from the mother affected with primary FSGS.

What Are the Different Types of Circulating Glomerular Permeability Factors in Primary FSGS?

• Soluble Urokinase Plasminogen Activator Receptor: The urokinase plasminogen activator receptor is a GPI-anchored protein. It is found in podocytes, immune cells, and tumor cells. By interacting with integrins, uPAR promotes migration, growth, and survival. Soluble urokinase plasminogen activator receptor (suPAR) is formed when uPAR is separated from GPI-anchor. The concentration of suPAR will be low in healthy individuals, and it plays an active role in stem cell transport. High levels of suPAR will be present in an infection or inflammatory state, indicating its role as an acute phase reactant. Increased levels of suPAR are noted in primary focal segmental glomerulosclerosis as well as in other conditions like cardiac diseases and chronic kidney disease. It binds with integrins found on podocytes, causing damage and resulting in loss of integrity. This leads to proteinuria, a main feature of primary FSGS.

• Cardiotrophin-Like Cytokine Factor-1 (CLCF-1): It is a part of the interleukin-6 (IL-6) cytokine family. It has been found in several studies that CLCF-1 plays an active role in the pathogenesis of primary focal segmental glomerulosclerosis. It binds to surface receptors on podocytes, which are the cells responsible for maintaining the integrity of glomeruli. By binding to its receptors, it causes podocyte damage, resulting in increased permeability of glomeruli. This causes proteinuria. Elevated levels of CLCF-1 are seen in individuals with primary FSGS after kidney transplantation, resulting in recurrence. However, more studies are required to confirm its role in primary focal segmental glomerulosclerosis.

• Anti-CD40 Antibodies: CD40 is a member of the tumor necrosis factor (TNF) family. It plays an important role in infection and immune processes. It is present on various cell surfaces, including dendritic cells, macrophages, monocytes, and podocytes. The CD40 ligand activates the endothelium, leading to increased secretion of uPAR, suPAR, metalloproteases, and chemokines. According to several studies, anti-CD40 antibodies are considered permeability factors in primary FSGS. These bind to CD40 receptors present on cell surfaces, including podocytes, causing damage to their function and structure. This leads to increased permeability of the glomerular barrier membrane, resulting in reduced protein filtering capacity.

What Are the Symptoms of Focal Segmental Glomerulosclerosis?

The symptoms of focal segmental glomerulosclerosis include the following:

• Swelling in legs, ankles, and around the eyes.

• Fluid buildup results in excess weight gain.

• Foamy urine due to high protein.

• Increased lipid level in blood.

Primary focal segmental glomerulosclerosis is the primary cause of nephrotic syndrome. It often leads to end-stage renal disease. It accounts for 40 percent of idiopathic nephrotic syndrome. A nephrotic syndrome is a group of symptoms that occur together and impact the kidneys. The symptoms include

• High blood pressure (hypertension).

• High protein content in the blood.

• Proteinuria.

• High cholesterol.

• Edema.

How to Diagnose FSGS?

The following tests are performed to diagnose focal segmental glomerulosclerosis.

• Urine Test: A 24-hour urine collection is done to determine the presence of protein or any other substance in the urine.

• Blood Test: This test calculates the glomerular filtration rate, which shows how effective the kidneys are in filtering waste from the body.

• Kidney Imaging: This helps to detect any change in the shape or structure of the kidney.

• Kidney Biopsy: Biopsy is the procedure where a little part of the diseased part is scraped off and evaluated under the microscope. Sometimes, genetic testing is done to validate the diagnosis of focal segmental glomerulosclerosis.

• Glomerular Filtration Test: This test measures how well the kidneys are working.

How Is Focal Segmental Glomerulosclerosis Treated?

Treatment of focal segmental glomerulosclerosis depends on the type and cause of the disease. Individuals’ overall health and age too determine the treatment modality. The main aim of the treatment is to control the symptoms and slow the progressive scarring of the glomeruli so that kidney failure does not occur. In Individuals with secondary focal segmental glomerulosclerosis, treating the underlying cause of the disease might prevent kidney failure. Glomeruli cannot be repaired, but kidney function might improve. Other treatment modalities include:

• Angiotensin Converting Enzyme (ACE) Inhibitors: These drugs treat high blood pressure.

• Antibiotics: Antibiotics are prescribed to treat infections.

• Diuretics: These medications are used to lower blood pressure and remove excess body fluids.

• Immunosuppressive Drugs: These drugs suppress the immune system.

• Plasmapheresis: This is a procedure that decreases the number of antibodies by removing the fluid part or plasma from the blood.

• Prednisone: This drug lowers the level of protein in the urine.

What Are the Complications Associated With Focal Segmental Glomerulosclerosis?

If left untreated, focal segmental glomerulosclerosis can lead to high blood pressure and eventually cause kidney failure. This could be life-threatening, requiring medical treatment. Complications include:

• Chronic kidney failure.

• End-stage kidney disease:It is a medical condition where the kidneys stop working.

• Infection.

• Malnutrition.

• Nephrotic syndrome: This kidney disorder causes the body to pass too much protein in the urine.

How Is the Prognosis of Focal Segmental Glomerulosclerosis?

Focal segmental glomerulosclerosis has no definite cure. The prognosis varies from person to person. In some individuals, the disease goes away on its own without treatment. For others, the disease persists over the years without much change. Kidney failure occurs in certain individuals. Such people need a kidney transplant or dialysis.

Conclusion:

Circulating glomerular permeability factors are substances that play an important role in the pathogenesis of focal segmental glomerulosclerosis. They increase the permeability of the glomerular membrane by damaging the podocytes. This results in decreased protein filtration, which leads to proteinuria. More studies are required to confirm the significance of circulating glomerular permeability factors in primary FSGS and to provide efficient treatment.