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Urinary thrombin: a novel marker of glomerular inflammation for the diagnosis of crescentic glomerulonephritis
Yasunori Kitamoto1, Kenji Arizono2, Hiroyoshi Fukui2
1Department of Laboratory Medicine, JCHO Sendai Hospital, Sendai, Japan.
Insights
Urinary thrombin activity (thrombinuria) is a specific biomarker for crescentic glomerulonephritis (CresGN). This novel diagnostic tool shows high accuracy for CresGN, including ANCA-negative cases, offering a risk-free screening method.
Area of Science:
- Nephrology
- Biomarker Discovery
- Glomerular Diseases
Background:
- Crescentic glomerulonephritis (CresGN) is a severe, rapidly progressive kidney disease.
- Lack of specific biomarkers delays CresGN diagnosis and treatment.
- Fibrin deposition in CresGN suggests active thrombin generation.
Purpose of the Study:
- To investigate urinary thrombin activity as a specific biomarker for CresGN.
- To assess the diagnostic accuracy of thrombinuria for CresGN.
- To explore the relationship between thrombinuria and disease characteristics.
Main Methods:
- Measured urinary thrombin activity in 200 patients with glomerulonephritis and controls.
- Assessed diagnostic accuracy of thrombinuria for CresGN in patients with hematuria and proteinuria.
- Analyzed correlations with clinical and histological parameters, including fibrin deposition and ANCA status.
Main Results:
- Thrombinuria was detected in 70.6% of CresGN patients, with 90.1% specificity.
- Thrombinuria was absent in controls and rare in other glomerulonephritis types.
- Thrombinuria correlated with glomerular fibrin deposition and resolved after glucocorticoid treatment.
Conclusions:
- Urinary thrombin activity is a specific indicator of glomerular inflammation in CresGN.
- Thrombinuria demonstrates good diagnostic accuracy for CresGN, including ANCA-negative cases.
- Thrombinuria measurement offers a potential risk-free diagnostic and screening tool for CresGN.
Background:
Crescentic glomerulonephritis (CresGN), an uncommon rapidly progressive disease, is characterized by severe glomerular inflammation with fibrin deposition. The lack of specific CresGN biomarkers delays diagnosis and threatens life. Because fibrin deposits in CresGN glomeruli indicate thrombin generation, we hypothesized that thrombin is excreted in urine and is a specific CresGN biomarker.
Methods:
We measured urinary thrombin activity in 200 untreated patients (17 with CresGN, 183 with primary glomerulonephritis) and controls (8 patients with healed CresGN, 11 with nephrosclerosis, and 10 with tubulointerstitial nephritis, and 66 healthy volunteers). CresGN types included 15 pauci-immune and 2 immune complex. We assessed the diagnostic accuracy of thrombinuria in 169 patients with hematuria and proteinuria. Renal biopsy tissues were immunostained for tissue factor and fibrin. We analyzed the relationship of thrombinuria to plasma thrombin-antithrombin complex, hematuria, proteinuria, glomerular filtration rate, glomerular fibrin deposition, antineutrophil cytoplasmic antibodies (ANCAs), and C-reactive protein (CRP). We studied changes in thrombin activities after glucocorticoid treatment in 12 patients with thrombinuria.
Results:
The highest thrombinuria occurrence was in CresGN (70.6%), followed by membranoproliferative glomerulonephritis (41.7%), IgA nephropathy (9.2%), and acute glomerulonephritis (0%). More than 75% of patients with nonproliferative glomerulonephritis manifested no thrombinuria. No controls had thrombinuria. Thrombinuria showed high CresGN specificity (90.1%) and moderate sensitivity (70.6%) and was detected in 4 of 7 patients with ANCA-negative CresGN. In CresGN, thrombinuria was associated with fibrin deposition in glomerular extracapillary tissue, where monocytes/macrophages expressed tissue factor. Thrombinuria in CresGN was unrelated to plasma thrombin-antithrombin complex, hematuria, proteinuria, glomerular filtration rate, and CRP. After glucocorticoid treatment, thrombinuria in patients with CresGN rapidly disappeared but proteinuria and hematuria persisted.
Conclusions:
Thrombinuria was specific for glomerular inflammation, was unaffected by systemic inflammation or coagulation, and demonstrated good diagnostic accuracy for CresGN including ANCA-negative cases. Thrombinuria measurement may provide risk-free diagnosis and screening for CresGN.
