Urinary thrombin: a novel marker of glomerular inflammation for the diagnosis of crescentic glomerulonephritis (prospective observational study).
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.
Department of Laboratory Medicine, JCHO Sendai Hospital, Sendai, Japan.
Yasunori
Y
Kitamoto
Department of Nephrology, Kumamoto Chuo Hospital, Kumamoto, Japan.
Kenji
K
Arizono
Department of Nephrology, Kumamoto Chuo Hospital, Kumamoto, Japan.
Hiroyoshi
H
Fukui
Department of Nephrology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Kimio
K
Tomita
Department of Nephrology, JCHO Sendai Hospital, Sendai, Japan.
Hiroshi
H
Kitamura
Department of Nephrology, JCHO Sendai Hospital, Sendai, Japan.
Yoshio
Y
Taguma
Department of Molecular Pathology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Takahisa
T
Imamura
D000368:Aged; D015415:Biomarkers / Q000652:urine*; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D005919:Glomerular Filtration Rate; D005921:Glomerulonephritis / Q000175:diagnosis* / Q000188:drug therapy / Q000503:physiopathology / Q000652:urine; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012680:Sensitivity and Specificity; D013917:Thrombin / Q000652:urine*; D013925:Thromboplastin / Q000378:metabolism
D015415:Biomarkers; D005938:Glucocorticoids; D002097:C-Reactive Protein; D013925:Thromboplastin; D013917:Thrombin