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Tissue factor pathway inhibitor expression in human crescentic glomerulonephritis
M A Cunningham1, T Ono, T D Hewitson
1Department of Medicine, Monash University, Monash Medical Center, Clayton, Australia. malcolmc@its-mmcc1.cc.monash.edu.au
Insights
Tissue factor pathway inhibitor (TFPI) is expressed late in crescent formation in human kidney disease. This late TFPI expression correlates with reduced fibrin deposition, suggesting a role in chronic crescentic glomerulonephritis.
Area of Science:
- Nephrology
- Pathology
- Immunology
Background:
- Tissue factor (TF) pathway inhibitor (TFPI) is a key regulator of coagulation.
- TFPI protects renal function in experimental crescentic glomerulonephritis (GN).
- Glomerular TFPI expression in human crescentic GN remains uncharacterized.
Purpose of the Study:
- To investigate glomerular TFPI, TF, and fibrin-related antigen (FRA) expression in human crescentic GN.
- To correlate TFPI expression with disease chronicity and markers of coagulation.
Main Methods:
- Analysis of renal biopsies from 11 patients with crescentic GN.
- Comparison with control biopsies from 11 patients with thin basement membrane disease and 2 normal kidneys.
- Immunohistochemical assessment of TFPI, TF, and FRA expression.
Main Results:
- TFPI was undetectable in control glomeruli but present in interstitial microvessels.
- TFPI expression increased with crescent chronicity, being prominent in fibrous/fibrocellular crescents.
- TF and FRA were highly expressed in early lesions, while TFPI was maximal in late lesions with less FRA.
Conclusions:
- TFPI is upregulated in later stages of human crescent formation.
- TFPI expression is inversely correlated with fibrin deposition in chronic crescentic GN.
- Late TFPI induction may limit TF activity and fibrin deposition in chronic disease.
Background:
Tissue factor (TF) pathway inhibitor (TFPI), the major endogenous inhibitor of extrinsic coagulation pathway activation, protects renal function in experimental crescentic glomerulonephritis (GN). Its glomerular expression and relationship to TF expression and fibrin deposition in human crescentic GN have not been reported.
Methods:
Glomerular TFPI, TF, and fibrin-related antigen (FRA) expression were correlated in renal biopsies from 11 patients with crescentic GN. Biopsies from 11 patients with thin basement membrane disease and two normal kidneys were used as controls.
Results:
TFPI was undetectable in control glomeruli but was detectable in interstitial microvessels. In crescentic biopsies, TFPI was detected in cellular crescents and was more prominent in fibrous/fibrocellular crescents, indicating a correlation with the chronicity of crescentic lesions. TFPI appeared to be associated with macrophages but not endothelial or epithelial cells. TFPI was generally undetectable in regions of the glomerular tuft with minimal damage. In contrast, TF and FRA were strongly expressed in regions of minimal injury, as well as in more advanced proliferative and necrotizing lesions. Despite prominent TF expression, FRA was less prominent in fibrous/fibrocellular crescents in which TFPI expression was maximal.
Conclusions:
These data suggest that TFPI is strongly expressed in the later stages of crescent formation and is inversely correlated with the presence of FRA in human crescentic GN. This late induction of TFPI may inhibit TF activity and favor reduced fibrin deposition in the chronic stages of crescent formation.