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:

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  Viral infection: HIV, parvovirus

  
  
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  Drugs: heroin, pamidronate

  
  
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  Postinflammatory conditions: autoimmune diseases

  
  
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  Vascular issues: atheroembolic disease, hypertension, sickle cell disease

  
  
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  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.

5. What genetic defects lead to sporadic and familial FSGS?

Over the past decade, much of the biology of the glomerular filtration barrier has been explained and defects in multiple structural and functional components of this barrier have been implicated in FSGS. There are more than 50 genetic mutations associated with FSGS. Mutations may occur in podocyte structural components from genes such as NPHS2 (podocin), NPHS1 (nephrin), ACTN4 (alpha-actinin 4), TRPC6, alpha-5, beta-4 integrins, CD2AP may present as kidney-limited structural anomalies. Mutations in WT1, LAMB2, COQ2, and LMX1B have been identified as causative of syndromic conditions in which FSGS in only one of the multiple anomaly manifestations within an individual. Autosomal dominant inheritance patterns are documented in familial FSGS with ACTN4, TRPC6, and INF2, which were first implicated in adult-onset disease. Familial FSGS of childhood with NPHS1, NPHS2, and PLCE1 mutations are transmitted in an autosomal recessive pattern. Autosomal recessive and dominant inheritance patterns have been documented with child- and adult-onset FSGS ( Table 27.1 ).

The prevalence of specific gene mutations in patients with FSGS depends on the ancestry of the cohort being studied. For example, NPHS2 mutations are found in 26% of children from families of Eastern European and Middle Eastern descent with familial FSGS and 19% of sporadic cases in that population. These mutations are rare causes of FSGS in Asian, African-American, and European-American populations of the United States. Apolipoprotein L1 (APOL1) has alleles that increase the risk of FSGS. These risk alleles are found in African Americans of west African descent. APOL1 polymorphisms convey protection against Trypanosoma brucei .

Genotype/phenotype correlations are still being investigated and have not yet reached the point of guiding clinical care with a few notable exceptions:

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  Genetic testing of patients with FSGS may be considered during the assessment of infantile FSGS

  
  
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  FSGS that is part of a multiple congenital anomaly syndrome

  
  
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  Familial FSGS, in regions with a high prevalence of consanguinity

  
  
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  In some cases, prior to kidney transplantation to assess the risk of FSGS recurrence