Circulating Glomerular Permeability Factors in Primary FSGS

Introduction

Focal segmental glomerulosclerosis is a word used to describe a particular form of kidney disease. The kidneys are bean-shaped structures. They are situated one on each side below the rib cage. The kidneys' main function is to remove waste products from the blood and to excrete them in urine. FSGS is scarring (fibrosis) or hardening of filtering units of the kidney, which are groups of small blood vessels known as renal glomeruli. Glomeruli are a part of the nephron. Nephrons are the basic component of the kidney. There are more than a million glomeruli in the kidneys. Glomeruli help filter the waste from the body and eliminate it through urine. Any damage or change in the glomeruli will affect kidney function and efficiency, leading to kidney failure. FSGS is of various types depending on the cause. Based on the cause, treatment is given.

What Are the Different Types of FSGS?

• Primary Focal Segmental Glomerulosclerosis: If FSGS is identified without any recognized cause, it is classified as primary FSGS. This is the most prevalent form of FSGS, and it is diagnosed when no other secondary cause or gene mutation is detected.

• Secondary Focal Segmental Glomerulosclerosis: FSGS is caused by several factors, including obesity, diabetes, infections, and other kidney diseases. If the underlying disease is treated, kidney function improves with time.

• Genetic Focal Segmental Glomerulosclerosis: Familial FSGS is another name for this condition, which occurs due to genetic changes. This type is suspected if family members experience the symptoms associated with this condition.

What Are the Symptoms of FSGS?

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.

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.

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: In this procedure, a fine needle is inserted into the kidney, and a small tissue sample is obtained. It is then examined under a microscope.

How to Treat Focal Segmental Glomerulosclerosis?

The treatment for FSGS depends on the cause of the condition. The following are the medications used to treat the condition:

• Corticosteroids help to prevent the immune system from attacking the kidney cells.

• Diuretics help eliminate excess fluid and salt buildup in the body.

• ACE (angiotensin-converting enzyme) inhibitors and ARBs (angiotensin receptor blockers) help lower blood pressure and reduce protein loss.

• Diet modifications include reduced intake of sodium and protein.

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.