X-linked hereditary nephropathy

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Ultrastructural appearance of glomerular basement membrane from a normal (left) and abnormal (right) X-linked herediary nephropathy-affected Dalmatian.[1]

X-linked hereditary nephropathy is an autosomal-dominant genetic kidney disease of dogs characterized by juvenile-onset renal failure due to glomerulonephritis.

This disease primarily affects male Cocker Spaniels, Samoyed, Navasotas, Bull Terriers and Dalmatians, but heterozygous females can also be affected.

The disease is caused by mutations affect the COL4A5 gene and results in the loss of collagen chains (α3(IV), α4(IV), and α5(IV))[2] from the glomerular and other basement membranes due to excess production of metalloproteases, leading to widening of the glomerular basement membrane and resultant protein-losing glomerulonephropathy[3].

This disease, which mirrors Alport syndrome in many respects[4], is not associated with sensorineural deafness or ocular lesions that are observed with the human condition[5].

Clinically affected dogs are young (often under 18 months of age) and present with uremia, anorexia, vomiting, polydipsia, polyuria and dehydration. Urinalysis usually reveals a protein creatinine ≥ 0.3[6].

Mild glomerulopathy is commonly observed in females, whereas males often present with acute, non-responsive renal failure[7].

Histological examination of renal biopsies usually reveals hypercellular glomeruli, glomerular sclerosis, periglomerular fibrosis, interstitial fibrosis and cystic dilatation of Bowman's capsular space and tubules[8].

A definitive diagnosis requires transmission electron microscopy, renal immunohistochemistry and PCR-based molecular assays for detection of urinary biomarkers[9].

A differential diagnosis would include bilateral hereditary nephropathy, urolithiasis and bacterial nephritis.

Cyclosporine A has been beneficial in slowing, but not stopping, the clinical and pathologic progression for this condition in male dogs[10], who invariably succumb to renal failure without renal dialysis or renal transplantation[11].

Additionally, female carriers respond in the short-term to dietary modifications (protein restriction)[12].


  1. Hood JC et al (2002) A novel model of autosomal dominant Alport syndrome in Dalmatian dogs. Nephrol Dial Transplant 17(12):2094-2098
  2. Thorner P et al (1996) Coordinate gene expression of the α3, α4 and α5 chains of collagen type IV: evidence from a canine model of X-linked nephritis with a COL4A5 gene mutation. J Biol Chem 271:13821-13828
  3. Rao VH et al (2003) Increased expression of MMP-2, MMP-9 (type IV collagenases/gelatinases), and MT1-MMP in canine X-linked Alport syndrome (XLAS). Kidney Int 63(5):1736-1748
  4. Bell RJ et al (2008) X chromosome inactivation patterns in normal and X-linked hereditary nephropathy carrier dogs. Cytogenet Genome Res 122(1):37-40
  5. Jais J et al (2000) X-linked Alport syndrome: natural history in 195 families and genotype-phenotype correlations in males. J Am Soc Nephrol 11:649-657
  6. Hood JC et al (2002) A novel model of autosomal dominant Alport syndrome in Dalmatian dogs. Nephrol Dial Transplant 17(12):2094-2098
  7. Nabity MB et al (2007) Day-to-Day variation of the urine protein: creatinine ratio in female dogs with stable glomerular proteinuria caused by X-linked hereditary nephropathy. J Vet Intern Med 21(3):425-430
  8. Hood JC et al (2002) Correlation of histopathological features and renal impairment in autosomal dominant Alport syndrome in Bull terriers. Nephrol Dial Transplant 17(11):1897-1908
  9. Nabity MB et al (2012) Urinary biomarkers of renal disease in dogs with X-linked hereditary nephropathy. J Vet Intern Med 26(2):282-293
  10. Chen D et al (2003) Cyclosporine a slows the progressive renal disease of alport syndrome (X-linked hereditary nephritis): results from a canine model. J Am Soc Nephrol 14(3):690-698
  11. Cox ML et al (2003) Genetic cause of X-linked Alport syndrome in a family of domestic dogs. Mamm Genome 14(6):396-403
  12. Burkholder WJ et al (2004) Diet modulates proteinuria in heterozygous female dogs with X-linked hereditary nephropathy. J Vet Intern Med 18(2):165-175