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Kidney non-tumor

Hereditary renal disease

Alport’s syndrome


Reviewers: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 10 December 2014, last major update June 2012
Copyright: (c) 2003-2014, PathologyOutlines.com, Inc.

General
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● 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)

Clinical features
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● 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

Variants
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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
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● 28 year old man with development of anti-glomerular and anti-tubular basement membrane antibodies after renal transplant (Arch Pathol Lab Med 1994;118:728)

Treatment
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● Kidney transplant has acceptable graft and patient survival rates (Transplant Proc 2012;44:261)

Clinical images
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Perifoveal dot and fleck retinopathy

Micro description
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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

Micro images
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Foamy renal tubular cells plus EM images


Variant with late onset renal failure, no hearing loss, no eye abnormalities


Immunofluorescence for alpha 3, 4 and 5 shows segmental staining

Immunofluorescence
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● 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
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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
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Splitting and lamellation of basement membrane

           
Irregular contours of glomerular basement membrane


Long term effects of cyclosporine A

Differential diagnosis
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Secondary changes following a variety of glomerular diseases such as:
Membranous glomerulonephritis-resolving stage
Familial thin glomerular basement membrane disease: positive staining with anti-GBM antibodies, which is negative in Alport’s syndrome

End of Kidney non-tumor > Hereditary renal disease > Alport’s syndrome

Ref Updated: 6/5/12


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