Alport Syndrome

Diagnosis

Indications for Testing

• X-linked Alport syndrome
  • Unexplained, persistent hematuria, proteinuria, or progressive decline in kidney function, with accompanying hearing loss and eye abnormalities (males)
  • Unexplained, persistent hematuria or chronic kidney disease and a family history of adult chronic kidney disease (females)
  • A family history of X-linked Alport syndrome (diagnostic, presymptomatic, or carrier testing)
• Autosomal Alport syndrome
  • Unexplained, persistent hematuria, proteinuria, or progressive decline in kidney function, with accompanying hearing loss and eye abnormalities (males and females)

Criteria for Diagnosis

• Clinical signs and symptoms
  • Changes in renal function (eg, hematuria, proteinuria)
  • Sensorineural hearing loss
  • Eye abnormalities
  • Thinning of basement membrane, as determined by renal biopsy with electron microscopy
  • Abnormalities in type IV collagen protein, as determined by immunohistochemical analysis of renal or skin biopsy and/or electron microscopy of renal biopsy
• Family history of X-linked Alport syndrome
• Confirmation by genetic testing

Laboratory Testing

• Initial tests
  • Urinalysis         
    • Gross hemoglobinuria (often first clinical sign)
    • Proteinuria
  • Urine albumin
    • Often manifests after hematuria, prior to gross proteinuria
    • Testing for albuminuria should be used, rather than standard urinalysis
  • Urine protein quantification
    • Urine protein:creatinine ratio >0.2 mg/mg, or
    • Urinary protein excretion >4 mg/m² per hour in timed collection (4 g over 24 hours)
  • Glomerular filtration rate
    • Standard calculations (Modification of Diet in Renal Disease [MDRD] or Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) based on serum creatinine concentrations provide rough estimate of degree of kidney injury (chronic kidney disease [CKD] level 1 to 5)

Genetic Testing

• Use to confirm diagnosis
  • COL4A5 gene sequencing and deletion/duplication analysis detects ~92% of COL4A5 variants, if present
    • COL4A5 variants are responsible for 80-85% of all Alport cases
    • The remaining 15-20% of Alport cases are due to variants in COL4A3 or COL4A4 genes
  • Sequencing alone – reasonable first-line test
• Use to exclude diagnosis of Alport syndrome in patients with thin basement membrane nephropathy

Histology

• Immunohistochemical analysis of collagen IV expression using renal or skin biopsy specimen
  • Skin biopsy specimens have a higher incidence of false negatives than renal biopsy specimens
• Electron microscopy of renal biopsy specimen

Differential Diagnosis

• Thin basement membrane nephropathy
• Other glomerular diseases (eg, IgA nephropathy)
• Inherited hearing loss syndromes
• Fechtner-Epstein syndrome

Screening

Presymptomatic and carrier testing is recommended for at-risk individuals with previously diagnosed family members.

Monitoring

Proteinuria and albuminuria testing should be initiated by age 1 in children at risk and repeated annually (Kashtan, 2013).

Background

Epidemiology

• Incidence – 1/5,000-50,000 births
• Age – variable
  • Autosomal recessive – earliest onset
  • X linked – later onset, but earlier than autosomal dominant form
  • Autosomal dominant – middle-age onset
• Sex
  • M>F for X-linked Alport syndrome – 100% penetrance in males, variable in females
  • M:F, equal for autosomal dominant and autosomal recessive forms

Inheritance

• Autosomal recessive and autosomal dominant forms
  • 15-20% of Alport syndrome cases
  • Pathogenic variant(s) in the COL4A3 or COL4A4 genes
• X-linked form (end-stage renal disease [ESRD])
  • 80% of Alport syndrome cases
  • Pathogenic variant(s) in the COL4A5 gene
    • Sequencing of COL4A5 gene identifies >80% of pathogenic variants, regardless of age
• X-linked heterozygotes (Kashtan, 2015)
  • Females with heterozygous COL4A5 variants
  • 95% appear to have hematuria, and there may be an increased lifetime risk of ESRD (probability of developing ESRD by age 60 is 30%)
  • Carriers are better described as “affected” (Savige, 2013) because they exhibit signs/symptoms
• 10-15% of affected males have de novo variants

Pathophysiology

• Type IV collagen α3, α4, α5 chains in kidney, cochlea, cornea, lens, and retina (Kashtan, 2015) exhibit defects
• Defects lead to loss of type IV collagen in the basement membranes in these structures
• In the kidney, weakened basal lamina results in focal rupture of glomerular capillary walls, resulting in scarring and progressive loss of function

Clinical Presentation

• Renal
  • Hematuria and proteinuria, progressive renal insufficiency
    • 95% of females and 100% of males have microscopic hematuria in early childhood
  • ESRD
    • X linked
      • 60% of males have ESRD by 30 years and 90% have ESRD by 40 years (Kashtan, 2015)
      • 30% of females have ESRD by 60 years and 40% by 80 years (Kashtan, 2015)
    • Autosomal recessive – most individuals have ESRD before 30 years
    • Autosomal dominant – ESRD onset usually in middle age
• Cochlear
  • Sensorineural hearing loss
    • X linked
      • Usually presents in late childhood
      • 85% of males have sensorineural deafness by 40 years
    • Autosomal recessive – juvenile onset
    • Autosomal dominant – associated with later adult onset
• Ocular
  • Lenticonus, maculopathy, corneal endothelial vesicles, recurrent corneal abrasions
  • Ocular lesions uncommon in adult-onset disease
• Gastrointestinal and bronchopulmonary
  • Leiomyomatosis occasionally associated with Alport syndrome
  • Thoracic and abdominal aortic aneurysms