Kidney nontumor
Glomerular disease
Inherited glomerular disease
Alport syndrome


Topic Completed: 14 November 2018

Minor changes: 7 February 2020

Copyright: 2002-2020, PathologyOutlines.com, Inc.

PubMed Search: Alport’s syndrome kidney [title]

Nikhil Sangle, M.D.
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Cite this page: Sangle N. Alport syndrome. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/kidneyalport.html. Accessed September 29th, 2020.
Definition / general
  • Due to defects in collagen IV synthesis affecting basement membranes, caused by mutations in COL4A3, COL4A4 and COL4A5 genes, important structural component of basement membranes in kidney, inner ear, eye
  • Nephritis, subtle nerve deafness (55%, seen in adults), eye disorders (15 - 30%, anterior lens dislocation, posterior cataracts, corneal dystrophy)
  • Called hereditary nephritis if no hearing or vision defects
  • May share genetic defects and clinical features with thin glomerular basement membrane syndrome (Hum Pathol 2002;33:836)
  • First described in 1927 by Alport (eMedicine: Alport Syndrome)
Clinical features
  • Incidence of 1 per 5 - 10,000 in US
  • Ages 5 - 20 years, usually males (or mosaic females)
  • Causes 2.5% of end stage renal failure cases in US children, 0.3% in adults
  • Presents with gross or microscopic hematuria, red blood cell casts, often mild proteinuria, progressive loss of renal function and hypertension
  • 3 - 4% of males develop anti - glomerular basement membrane nephritis, usually due to antibodies to NC1 domain of alpha 5 chain of type IV collagen
  • Rate of progression to end stage renal disease and deafness (bilateral, sensorineural and high tone, Acta Otolaryngol 2009;129:982) are mutation dependent, and each kindred reported has different mutations
  • More likely to progress to renal failure in males


Ocular abnormalities
  • Anterior lenticonus (forward central protrusion of anterior surface of lens due to weakness in type IV collagen, relatively specific for Alport)
  • Also keratoconus, spherophakia (small, spherical lens), myopia, retinal flecks, cataracts, retinitis pigmentosa, amaurosis (blindness without an apparent ocular cause)
Variants
  • Juvenile variant: end stage renal disease develops in males before age 31 years; clinical course similar among all patients
  • Adult variant: end stage renal disease develops in males after 31 years; variable clinical course
  • X linked form (80%): due to mutations in alpha 5 gene at Xq22 coding collagen type IV (component of glomerular basement membrane); mutation interferes with its suprastructure, reducing production of alpha 3 (Goodpasture's antigen) and alpha 4; some X linked patients also have diffuse leiomyomatosis (Hum Pathol 1998;29:404)
  • Autosomal recessive: mutations in collagen type IV alpha 3 or alpha 4 genes, males and females have similar prognosis
  • Autosomal dominant form may exist, but is controversial
  • Screening: segmental glomerular basement membrane staining is suggestive
  • Diagnosis: skin or kidney biopsy; if necessary, can use skin biopsy for analysis of COL4A5 gene for X linked cases (Nephrol Dial Transplant 2011;26:4003) and peripheral WBC analysis of COL4A3 and COL4A4 for autosomal recessive (Zhonghua Yi Xue Za Zhi 2008;88:573)
Case reports
Treatment
Microscopic (histologic) description
    Early:
  • Segmental proliferation or sclerosis of glomeruli, increased mesangial matrix or cells causing mesangial widening (detected by JMS or PAS stain)
  • Thinned basement membranes (BM) fail to stain, while thickened BM may show reduplication mimicking membranoproliferative glomerulonephritis
  • May see fetal type glomeruli, foam cells in glomeruli or tubules

    Late:
  • Glomerulosclerosis, tubular atrophy
Microscopic (histologic) images

Images hosted on other servers:
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Foamy renal tubular cells plus EM images

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Immunofluorescence
for alpha 3, 4 and
5 shows segmental
staining

Immunofluorescence description
  • Negative or segmental staining for alpha 3, 4 and 5 collagen in glomerular basement membrane (normals have strong continuous staining); negative for alpha 5 collagen in skin biopsies (positive in normals)
  • Negative for immunoglobulin and complement
Electron microscopy description
    Early:
  • Thinning (< 150 nm) of glomerular basement membrane

    Later:
  • Splitting and lamination of lamina densa and granular inclusions
  • Children and women may have only thin glomerular basement membranes without other alterations
  • Abnormal distribution of laminin alpha1 and laminin alpha5 in glomerular basement membrane correlates with GBM thickening and splitting (Beijing Da Xue Xue Bao 2009;41:630)
Electron microscopy images

Images hosted on other servers:
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Splitting and lamellation of basement membrane

Differential diagnosis
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