Alport Syndrome

Alport syndrome, also called hereditary nephritis, is a genetic disorder caused by a mutation in the genes encoding for the alpha chains of type IV collagen, resulting in the production of abnormal type IV collagen strands. Patients present with glomerulonephritis, hypertension, edema, hematuria, and proteinuria, as well as with ocular (cataract, retinopathy) and auditory (sensorineural hearing loss) findings. Diagnosis is established with urinalysis, urine microscopy, and a renal function panel. A renal biopsy showing characteristic glomerular basement membrane splitting may be used to confirm the diagnosis. Treatment for Alport syndrome is focused on limiting disease progression with angiotensin receptor blockers and angiotensin-converting enzyme inhibitors. Hearing aids are used for hearing loss associated with Alport syndrome.

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Epidemiology and Etiology

Epidemiology

  • Most common type of hereditary nephritis
  • Affects 1 in 50,000 newborns
  • Men more commonly symptomatic than women (X-linked inheritance)
  • 80% of males affected with X-linked Alport syndrome will develop some degree of hearing loss by adolescence.

Etiology

  • Caused by mutation in:  
    • COL4A3 
    • COL4A4 
    • COL4A5
  • X-linked in 80% of cases
  • May be autosomal recessive or autosomal dominant:
    • Autosomal recessive: a mutation in both COL4A3 and COL4A4
    • Autosomal dominant: 
      • Heterozygous mutation
      • Compared to X-linked inheritance, slower progression to end-stage renal disease (ESRD) 
      • Compared to X-linked inheritance, less likely to have extrarenal manifestations

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Pathophysiology

Alport syndrome is a genetic disorder arising from a mutation in genes encoding for the alpha chains of type IV collagen, which is primarily located in the lens, cochlea, and kidneys (glomerulus).

  • Alport syndrome = production of impaired strands + deposition of type IV collagen in basement membrane 
  • Glomerular basement membrane (GBM) in Alport syndrome is prone to proteolytic injury → adhesion kinase activation in podocytes and endothelin receptors
    • Leads to:
      • Glomerular inflammation
      • Tubulointerstitial fibrosis
      • ESRD
  • Pathologic results of kidney biopsy:
    • Light microscopy:
      • Normal on early light microscopy
      • With progression, nonspecific findings: focal and segmental glomerulosclerosis, interstitial fibrosis, tubular atrophy, and presence of lymphocytes and plasma cells
    • Immunofluorescence: negative
    • Electron microscopy: 
      • Longitudinal splitting of GBM lamina densa (allows for hematuria)
      • Basket-weave appearance
Alport syndrome kidney biopsy

Glomerular basement membrane (GBM) in a patient with Alport syndrome:
Electron microscopy of a kidney shows the characteristic basket-weave appearance of the GBM in a patient with Alport syndrome.

Image: “Electron micrograph from kidney biopsy” by University of North Carolina School of Medicine, Chapel Hill, NC. License: CC BY 2.5

Clinical Presentation

Alport syndrome most often presents with renal, ocular, and auditory findings.

Renal presentation (glomerulonephritis)

  • Symptoms:
    • Gross hematuria following infection (commonly upper respiratory infections)
    • Edema
    • Hypertension
  • Lab findings:
    • Proteinuria
    • Progressive decline in renal function → eventual ESRD (usually presents at 16–35 years of age)

Ocular findings

  • Cone-shaped lens (anterior lenticonus) leads to:
    • Decreased visual acuity 
    • Abnormal refraction
  • Subcapsular cataract
  • Retinopathy: pigmentary retinal changes, with yellow or white flecks (e.g., dot-and-fleck retinopathy)
  • Corneal erosion

Auditory findings

Sensorineural hearing loss:

  • Begins with loss of high-frequency sounds
  • Apparent late in childhood or early puberty, prior to onset of ESRD
  • Secondary to type IV collagen abnormalities in inner ear

Diagnosis

A complete history, including family history, and physical exam are required to make a diagnosis. 

  • Urinalysis:
    • Persistent microscopic hematuria noted in patients < 10 years of age
    • Gross hematuria
    • Proteinuria
    • Oliguria 
  • Urine microscopy:
    • Presence of acanthocytes
    • RBC casts
  • Renal function panel: to assess presence and degree of renal failure 
  • Renal biopsy:
    • Indicated in patients with:
      • Abnormal urinalysis
      • Acanthocytes on urine microscopy
      • Abnormal renal function panel
    • Light microscopy:
      • GBM splitting
      • Hypercellular and inflamed glomeruli 
      • If light microscopy is normal, perform immunostaining for type IV collagen of alpha-3, -4, and -5 chains.
  • Skin biopsy:
    • Less invasive than renal biopsy
    • Can also be used to establish diagnosis 
    • Usually used in children with suspected X-linked Alport syndrome
    • Monoclonal antibody against alpha-5 chain of type IV collagen, usually expressed in epidermis
  • Genetic testing: 
    • Used to confirm diagnosis
    • Used to identify inheritance pattern

Management and Prognosis

Management

Treatment is focused on limiting the progression of kidney disease and proteinuria. No definitive treatment is currently available.

  • Glomerulonephritis management:
    • Angiotensin-converting enzyme inhibitors (ACEis)
    • Angiotensin receptor blockers (ARBs): 
      • Reduce intraglomerular pressure
      • Reduce proteinuria
      • Proven to slow development of ESRD
    • Diuretics may be used, depending on degree of proteinuria.
  • Dialysis and kidney transplantation (once ESRD has developed):
    • Transplantation is curative for renal symptoms.
    • 3% risk of Alport post-transplantation nephritis or anti-GBM antibody disease developing de novo in 1st year after transplantation; high rate of retransplantation
  • Ocular management:  
    • Anterior lenticonus: Clear lens phacoemulsification with intraocular lens implantation may be considered.
  • Auditory management: 
    • Hearing aids beneficial 
    • Hearing loss not impacted by kidney transplantation

Prognosis

  • X-linked male form:
    • 50% require dialysis or kidney transplantation by age 30.
    • 90% develop ESRD by age 40.
  • X-linked female form: 
    • 12% develop ESRD by age 40.
    • 30%–40% develop ESRD by age 6.
  • Autosomal recessive form: kidney failure by age 20
  • Autosomal dominant form: delay of ESRD until middle age

Differential Diagnosis

  • IgA nephropathy (Berger’s disease): occurs when IgA builds up in kidneys: In most developed countries, IgA nephropathy is the most common cause of primary glomerulonephritis. Autoimmune disease is often triggered by an upper respiratory infection, but it can also be triggered by a gastrointestinal infection or exercise. The disease presents most commonly in the 2nd–3rd decades of life. 
  • Thin GBM disease: characterized by thinning of GBM; cause of isolated microscopic hematuria: In patients with thin GBM disease, blood pressure and protein excretion are normal. The characteristic manifestation is persistent or intermittent asymptomatic microscopic hematuria. 
  • Acute poststreptococcal glomerulonephritis: immune response seen 2–4 weeks after group A streptococcal infection of pharynx or skin: Acute poststreptococcal glomerulonephritis is characterized by the sudden appearance of edema, hematuria, hypertension, and proteinuria. 
  • Medullary cystic disease: also known as autosomal dominant tubulointerstitial kidney disease: Medullary cystic disease is an inherited disorder in which multiple, small, fluid-filled sacs (cysts) fill the medulla of the kidney. Scarring or tubulointerstitial fibrosis also occurs in tubules of the kidney. 
  • Multicystic renal dysplasia: congenital cystic renal disease: Multicystic renal dysplasia often presents as an abdominal mass in infants. Patients present with 1 or 2 large, nonfunctional kidneys that are distended with fluid-filled sacs or cysts.
  • Polycystic kidney disease: multisystem, progressive disorder that can be inherited in autosomal dominant or recessive form: Autosomal dominant polycystic kidney disease is more common and presents with large, multicystic kidneys with involvement of pancreas, spleen, and liver.

References

  1. Crockett, D. K., Pont-Kingdon, G., Gedge, F., Sumner, K., Seamons, R., Lyon, E. (2010). The Alport syndrome COL4A5 variant database. Human Mutation 31:E1652-7.
  2. Delimont, D., Dufek, B. M., Meehan, D. T., Zallocchi ,M., Gratton, M. A., Phillips, G., Cosgrove, D. (2014). Laminin α2-mediated focal adhesion kinase activation triggers Alport glomerular pathogenesis. PLoS One 9(6):e99083.
  3. Dufek, B., Meehan, D. T., Delimont, D., Cheung, L., Gratton, M. A., Phillips, G., Song, W., Liu, S., Cosgrove, D. (2016). Endothelin A receptor activation on mesangial cells initiates Alport glomerular disease. Kidney International 90:300-10.
  4. Giani, M., Castorina, P., Bresin, E., Giachino, D., De Marchi, M., Mari, F., Bruttini, M., Renieri, A., Ariani, F. (2014). Unbiased next-generation sequencing analysis confirms the existence of autosomal dominant Alport syndrome in a relevant fraction of cases. Clinical Genetics 86:252-7.

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