Hereditary nephritis refers to a group heterogeneous hereditary-familia renal disease associated primarily with glomerular injury. Two deserve discussion: Alport syndrome because the lesions and genetic defects have been most well studied and thin membrane disease, the most common cause of benign familial hematuria.



Alport syndrome

Alport syndrome is the name uaually given to the disease in which nephritis is accompanied by nerve deafness and various eye disorders including lens dislocation, posterior cataracts, and coroneal dystrophy. Males tend to be affected more frequently and more severly than females and are more likely to progress to renal failure. Females, however are not completely spared. The mode of inheritance is heterogeneous. Most patients have an X-linked dominano pattern, but autosomal recessive and autosomal dominant pedigrees also exist.

On histologic examination the glomeruli are always involved . The most common early lesion is segmental proliferation or sclerosis, or both. There is an increase in mesangial matrix and in some patients the persistence of fetal like glomeruli in some kidneys, glomerular or tubular epithelial cells acquire a foamy appearance owing to accumulation of neutral fats and mucopolysaccharides. As the disease progresses, there is increasing glomerulosclerosis, vascular narrowing , tubular atrophy and interstitial fibrosis.

The characteristic findings are seen with the electron microscope and are found in some patients with hereditary nephritis. The GBM shows irregular foci of thickening or attenuation with pronounced splitting and lamination of the lamina densa. Similar alterations are found in the tubular basement membranes. Although such basement membrane changes may be seen focally in disease other than hereditary nephritis, they are most wide spread and pronounced in patients with this disorder.

Immunohistochemistry is helpful in cases with absent or borderline basement membrane lesions, because antibodies to ?3,?4 and ?5 collagen fail to stain both glomerular and tubular basement membranes. There is also absence of ?5 staining in skin biopsy specimens.

Defective GBM synthesis underlies the renal lesions. In patients with X-linked disease, the defect is caused by mutations in the gene encoding the ?5 chain. This is thought to interfere with the structure and function of collagen type IV as a result of this defect patients synthesized lesser amounts of other collagen of other collagen components including the ?3 chain which as you recall includes the Goodpasture antigen and also the ?3 chain. Indeed, glomeruli lacking the ?3 chain fail to react with anti-GBM antibodies from patients with Goodpasture syndrome. Certain patients with the X-linked from associated with diffuse leiomyomatosis have additional mutations in the ?6 chain of collagen. In the autosomal recessive pedigrees, mutations in the ?3and ?4 chains have been reported.

Clinical picture

The most common presenting sign is gross or microscopic hematuria frequently accompanied by erythrocyte casts. Proteinuria may occur and rarely the nephrotic syndrome develops. Syndromes appear at ages 5 to 20 and the onset of overt renal failure is between ages 20 and 50 years in men. The audiotory defects may be subtle requring sensitive testing.