Renal Digest
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    Thin glomerular basement membrane disease (TBMD)
     Key features:
 
Clinical: Asymptomatic microscopic hematuria due to genetically heterogeneous abnormality in GBM structure
Clinical: Asymptomatic microscopic hematuria due to genetically heterogeneous abnormality in GBM structure
Clinical: Asymptomatic microscopic hematuria due to genetically heterogeneous abnormality in GBM structure
Light microscopy: Minimal light microscopic alterations
Light microscopy: Minimal light microscopic alterations
Light microscopy: Minimal light microscopic alterations
Immunofluorescence: No immune deposits
Immunofluorescence: No immune deposits
Immunofluorescence: No immune deposits
Electron microscopy: The hallmark of TBMD is the diffuse attenuation of the GBMs detected by electron microscopy, with average mean thickness below 264 nm
Electron microscopy: The hallmark of TBMD is the diffuse attenuation of the GBMs detected by electron microscopy, with average mean thickness below 264 nm
Electron microscopy: The hallmark of TBMD is the diffuse attenuation of the GBMs detected by electron microscopy, with average mean thickness below 264 nm


Definition:  
Thin glomerular basement membrane disease results from various genetic defects in the synthesis or assembly of basement membrane collagens, ultrastructurally characterized by diffuse attenuation of the glomerular basement membranes and clinically by hematuria.
Thin glomerular basement membrane disease results from various genetic defects in the synthesis or assembly of basement membrane collagens, ultrastructurally characterized by diffuse attenuation of the glomerular basement membranes and clinically by hematuria.
Thin glomerular basement membrane disease results from various genetic defects in the synthesis or assembly of basement membrane collagens, ultrastructurally characterized by diffuse attenuation of the glomerular basement membranes and clinically by hematuria.

Synonym:
Syndrome of benign familial hematuria
Syndrome of benign familial hematuria
Syndrome of benign familial hematuria

Differential diagnosis:
Hereditary nephritis and Alport's syndrome
Minimal change disease
Lupus nephritis, class I
Immunoglobulin A (IgA) nephropathy, with no lesion by light microscopy

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

Clinical:  
Asymptomatic microscopic hematuria
Asymptomatic microscopic hematuria
Asymptomatic microscopic hematuria
Protein excretion is usually absent, however, may be present in rare cases to a mild extent (< 1.5 g/day) {4}
Protein excretion is usually absent, however, may be present in rare cases to a mild extent (< 1.5 g/day) {4}
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
The capillary loops are of normal contour and may appear delicate
The capillary loops are of normal contour and may appear delicate
Normocellular mesangium
Normocellular mesangium
Normocellular mesangium
The tubules and interstitium are usually unremarkable; foamy macrophages may be seen on rare occasions in the interstitium
The tubules and interstitium are usually unremarkable; foamy macrophages may be seen on rare occasions in the interstitium
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
More pronounced interstitial fibrosis and tubular atrophy may be seen in elderly patients with comorbid states
More pronounced interstitial fibrosis and tubular atrophy may be seen in elderly patients with comorbid states

Immunofluorescence:   

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Electron microscopy:  
Visceral epithelial cells:
The visceral epithelial cells and their foot processes are well preserved.
Visceral epithelial cells:
The visceral epithelial cells and their foot processes are well preserved.
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 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 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
Glomerular endothelial cells: Unremarkable and do not contain tubuloreticular structures
Glomerular endothelial cells: Unremarkable and do not contain tubuloreticular structures
Mesangium: Normal cell elements and an extracellular matrix without electron-dense deposits
Mesangium: Normal cell elements and an extracellular matrix without electron-dense deposits
Mesangium: Normal cell elements and an extracellular matrix without electron-dense deposits
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Glomerulus showing delicate capillary loops and no significant hypercellularity; PAS, 400x
Glomerulus with no distinct histologic abnormalities; PAS, 400x
Example of GBM measurements by the method of orthogonal intercepts: the membrane is measured at the points of intersecting with superimposed grid, from the epithelial towards the endothelial side of the membrane; EM, 11,000x
Thin glomerular basement membrane disease; EM, 7,100x
Very thin glomerular basement membranes; average thickness about 180 nm; EM, 5,600x
Thin basement membrane disease, with average GBM thickness less than 264 nm; EM, 3,500x
The GBMs show segmental irregularities in thickness, but are overall very thin; EM, 5,600x
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References :
1. Kashtan CE. Familial hematuria due to type IV collagen mutations: Alport syndrome and thinbasement membrane nephropathy.Curr Opin Pediatr. 2004 Apr;16(2):177-81. Review.  PUBMED  
2. Wang YY, Rana K, Tonna S, Lin T, Sin L, Savige J. COL4A3 mutations and their clinical consequences in thin basement membranenephropathy (TBMN).Kidney Int. 2004 Mar;65(3):786-90.  PUBMED  
3. Buzza M, Dagher H, Wang YY, Wilson D, Babon JJ, Cotton RG, Savige J. Mutations in the COL4A4 gene in thin basement membrane disease.Kidney Int. 2003 Feb;63(2):447-53.  PUBMED  
4. Hall CL, Bradley R, Kerr A, Attoti R, Peat D. Clinical value of renal biopsy in patients with asymptomatic microscopichematuria with and without low-grade proteinuria.Clin Nephrol. 2004 Oct;62(4):267-72.  PUBMED  
5. Tiebosch AT, Frederik PM, van Breda Vriesman PJ, Mooy JM, van Rie H, van deWiel TW, Wolters J, Zeppenfeldt E. Thin-basement-membrane nephropathy in adults with persistent hematuria.N Engl J Med. 1989 Jan 5;320(1):14-8.  PUBMED