Glomerular Basement Membrane abnormalities

• Glomerular basement membrane (GBM) abnormalities are inherited disorders of basement membrane collagens, X-linked in about 80% of cases. The phenotype of thin GBMs is seen in up to 9% of general population and it is an expression of various genetic defects.

• It is most commonly seen in patients with so-called benign hematuria or thin GBM disease.

• This pattern of injury can also been seen in women carriers of the Alport's syndrome or in males in early stage of this syndrome.

Thin GBM• Etiology: • The phenotype of thin GBMs is an expression of various genetic

defects; in 80% of cases, they are affecting the genes encoding subunits 5 and 6 of collagen 4 (X-linked, genes COL4A5 or COL4A6 {1}), and in the remaining 20% of cases, the defects are inherited in autosomal dominant or recessive fashion and are affecting subunits 3 and 4 of collagen 4 (COL4A3 {2} and COL4A4 {3}). Compound mutations result in more aggressive clinical course, with progressive proteinuria and renal insufficiency

• Young men in early stages of Alport’s syndrome and female carriers of this disease also present with thin GBMs

• Clinical: • Asymptomatic microscopic hematuria• Protein excretion is usually absent, however, may be present in rare

cases to a mild extent (< 1.5 g/day) {4}

• Histopathology: • The capillary loops are of normal contour and

may appear delicate• Normocellular mesangium• The tubules and interstitium are usually

unremarkable; foamy macrophages may be seen on rare occasions in the interstitium

• More pronounced interstitial fibrosis and tubular atrophy may be seen in elderly patients with comorbid states

• IF- usu –ve . Maybe weak positive IgM/C3• Electron microscopy: • Visceral epithelial cells:• The visceral epithelial cells and their foot processes are well

preserved.• Glomerular basement membranes: Morphometric

measurements disclose diffuse thinning, with the mean thickness below the lower normal limit of 264 nm {5}. Electron-dense deposits are not seen along the capillary loops

• Glomerular endothelial cells: Unremarkable and do not contain tubuloreticular structures

• Mesangium: Normal cell elements and an extracellular matrix without electron-dense deposits

Hereditary Nephritis/ Alport’s Syndrome

• Definition: • Hereditary nephritis is a genetically

heterogeneous disease of collagen IV, ultrastructurally characterized by splitting, lamellation, and thickening of the GBMs and clinically presenting by hematuria, with renal failure in more advanced cases. If the hereditary nephritis is associated with sensorineural hearing loss, the syndrome is referred to as Alport’s syndrome.

• Etiology: • Genetic defects in alpha 3, 4, or 5 chains of collagen

IV; most commonly X-linked, but cases of autosomal recessive and dominant inheritance, as well as de novo mutations, have been described in the literature

• Clinical: • Hematuria• Renal failure in more advanced cases• Associated with sensorineural hearing loss (Alport’s

syndrome)

• Histopathology: • Early stage: Normal appearance• Advanced disease: Mesangial expansion, segmental

irregularities in GBM thickness with lamellation and splitting

• Focal segmental and global glomerulosclerosis• The tubules and interstitium show different degrees of

atrophy and fibrosis; foamy macrophages may be seen in the interstitium

• Immunofluorescence: • Negative

• Electron microscopy: • Visceral epithelial cells: Focal, sometimes marked

effacement of foot processes• Glomerular basement membranes: Early in the disease,

diffusely attenuated GBMs. In advanced disease, thin GBM segments alternate with segments with GBM splitting, lamellation, and thickening Electron-dense deposits are not seen along the capillary loops

• Glomerular endothelial cells: Usually unremarkable and do not contain tubuloreticular structures

• Mesangium: May be mildly expanded, but without electron-dense deposits