Fibrinogen Excretion in the Urine and Immunoreactivity in the Kidney Serves as a Translational Biomarker for Acute Kidney Injury

Abstract

Fibrinogen (Fg) is significantly up-regulated in the kidney after acute kidney injury (AKI). We evaluated the performance of Fg as a biomarker for early detection of AKI. In rats and mice with kidney tubular damage induced by ischemia/reperfusion (I/R) or cisplatin administration, respectively; kidney tissue and urinary Fg increased significantly and correlated with histopathological injury, urinary kidney injury molecule-1 (KIM-1) and N-acetyl glucosaminidase (NAG) corresponding to the progression and regression of injury temporally. In a longitudinal follow-up of 31 patients who underwent surgical repair of abdominal aortic aneurysm, urinary Fg increased earlier than SCr in patients who developed postoperative AKI (AUC-ROC = 0.72). Furthermore, in a cohort of patients with biopsy-proven AKI (n = 53), Fg immunoreactivity in the tubules and interstitium increased remarkably and was able to distinguish patients with AKI from those without AKI (n = 59). These results suggest that immunoreactivity of Fg in the kidney, as well as urinary excretion of Fg, serves as a sensitive and early diagnostic translational biomarker for detection of AKI.

Pharmacological and genetic depletion of fibrinogen protects from kidney fibrosis

“…In UUO kidneys, the interstitial areas that showed more intense ␣-SMA staining, indicative of the presence of myofibroblasts, also stained for Fg, indicating a close spatial relation of the two and a possible mechanistic connection between Fg and fibroblasts that we investigated further in vitro. The interstitial presence of Fg in the kidney confirms previous results from our group (34,38) and other groups (55).…”

“…While our previous studies (34,38) showed this after rodent ischemia-reperfusion injury and cisplatin-induced nephrotoxicity, the data presented here show that after murine FA nephropathy, kidney Fg expression and urinary excretion are high early, when AKI is present, but not at 14 days, when tubulointerstitial fibrosis develops. Urinary levels reflecting the injured kidney cannot be measured after UUO, but kidney expression of Fg was increased throughout time points in fibrosis development.…”

“…Contrary to suggestions that Fg increases after injury merely reflect extravasation of hepatic sourced protein (17), we show here that kidney mRNA expression of all Fg chains is upregulated after UUO and FA nephropathy. Our previous studies (34,38) showed this to be true for other AKI models induced by ischemia-reperfusion and cisplatin. We wanted to find a mechanism for this increased kidney expression.…”

“…We have previously reported that urinary Fg excretion is increased in AKI animal models (34,38). Since urine produced by the fibrotic kidney cannot be collected after UUO, urinary Fg excretion could not be tested.…”

The gene expression of adenosine receptors in the processes of contrast induced nephropathy in mouse kidney

“…Histopathology evaluation was performed as described by Hoffmann et al [14]. Briefly, the embedded tissues were cut into 5-µm sections and stained with Hematoxylin and eosin stain (H&E stain).…”