Focal segmental glomerulosclerosis

1. What is focal segmental glomerulosclerosis?

Focal segmental glomerulosclerosis (FSGS) is a class of glomerular diseases defined by focal and segmental patterns of scar in the kidney glomeruli. This disease spectrum includes primary, genetic, and secondary diseases. Primary FSGS is diagnosed in patients without a known cause. There are a number of genetic mutations that disrupt the structure and function of the glomerular podocyte and slit diaphragm that manifest as FSGS. Secondary FSGS may arise from various kidney insults that lead to a common end point of glomerular damage. These secondary insults include:

• Viral infection: HIV, parvovirus

• Drugs: heroin, pamidronate

• Postinflammatory conditions: autoimmune diseases

• Vascular issues: atheroembolic disease, hypertension, sickle cell disease

• Reflux nephropathy

The sclerosing type of C1q nephropathy may be grouped with primary or secondary FSGS with the distinguishing factor of C1q in the glomeruli revealed on kidney biopsy immunofluorescence staining and electron dense deposits with electron microscopy. The etiology of C1q nephropathy is unknown. Obesity-related glomerulopathy is also often considered a secondary FSGS that manifests with glomerular hypertrophy in addition to the sclerosis of FSGS. The common factor in these conditions is damage to the glomerular structure.

2. How common is FSGS?

FSGS is a rare condition with an estimated incidence of 1.8/100,000 per year. The lifetime risk is estimated to be more than four times higher for African Americans compared with other races. FSGS is the underlying cause of approximately 4% of patients with end-stage kidney disease (ESKD) in the United States and up to 10.8% of those younger than 24 years. In adults, FSGS is the fourth most common cause of ESKD, following diabetes, hypertension, and glomerulonephritis not otherwise specified. Among children, FSGS is the second leading cause of ESKD, following congenital kidney anomalies.

3. What is the clinical presentation of FSGS?

FSGS may present as nephrotic syndrome with edema, hypoalbuminemia, and hypercholesterolemia, or it may present in a patient with isolated proteinuria. Microscopic hematuria is found in approximately half of patients at diagnosis. However, gross hematuria is rare. Children are more likely to present with nephrotic syndrome, but the entire phenotypic spectrum of FSGS occurs in both children and adults. Kidney function as assessed by glomerular filtration rate may be normal but is impaired in up to 60% at presentation. ESKD at presentation is rare.

Clinical clues may help distinguish whether a patient has primary or secondary FSGS. Patients with primary FSGS more often have low serum albumin levels (<3 g/dL) and edema, whereas patients with secondary FSGS more often present with albumin levels >3.5 g/dL, without edema, and with some historical evidence of a predisposing primary condition or exposure.

4. What is the cause of primary FSGS?

There are likely several causes of primary FSGS. Research has focused on possible immune defects, such as T-cell dysregulation, and the presence of a circulating permeability factor, such as cardiotrophin-like cytokine 1, that induces changes in the glomerular filtration barrier with resultant proteinuria. Genetic and gene expression studies have identified structural abnormalities in the podocyte cytoskeleton and slit diaphragms, as well as signaling and inflammatory pathways that contribute to the cause of FSGS.