Urinary Thrombin: A Novel Marker of Glomerular Inflammation for the Diagnosis of Crescentic Glomerulonephritis (Prospective Observational Study)

Abstract

BackgroundCrescentic 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.MethodsWe 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.ResultsThe 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.ConclusionsThrombinuria 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.

A Nanoparticle‐Decorated Biomolecule‐Responsive Polymer Enables Robust Signaling Cascade for Biosensing

“…Given its high sensitivity and selectivity, this UPSS could potentially be used to detect early biomarkers in complex body fluid in chronic diseases such as cancer. For example, thrombin‐specific UPSS could be used for accurate detection of urinary thrombin, which was found to be present in patients with glomerulonephritis or lupus nephritis . Also, the UPSS possesses potential in monitoring the quality and safety of drinking water portably and rapidly.…”

Urinary Prothrombin Fragment 1 + 2 as an Endogenous Marker of Venous Thromboembolism

“…Contrary to the previous studies, a study on THR surgery patients published in 2017 showed increased post-operative levels of F1 + 2 in plasma and urine, however, the correlation was poor and urinary F1 + 2 levels did not reflect coagulation activation post-operatively [32]. Thrombin measurements in urine have been reported for the diagnosis of crescenting glomerulonephritis [33]. Increased thrombin levels as measured by using amidolytic methods were associated with fibrin deposits in the kidney and other associated pathologic manifestations.…”

<p>Hirudin Protects Against Kidney Damage in Streptozotocin-Induced Diabetic Nephropathy Rats by Inhibiting Inflammation via P38 MAPK/NF-κB Pathway</p>

“…Here, the coagulation cascade is initiated after vascular injury, which promotes inflammation, and inflammation in turn accelerates the production of thrombin, which eventually leads to the occurrence of disease. 23 – 25 Simultaneously, DN is considered as a chronic inflammatory disease and is one of the most common microvascular complications of diabetes. 3 In the present study, our results showed that HIR could markedly reduce macrophage infiltration and pro-inflammatory cytokine expression in renal tissues of DN rats.…”