Urinary Fibrinogen Research Articles

Combination of urinary fibrinogen β-chain and tyrosine-phosphorylated proteins for the detection of bladder cancer.

Aim:To evaluate the performance of urinary fibrinogen β-chain (FBC) – either alone or associated with urinary tyrosine-phosphorylated proteins (UPY) – as bladder cancer (BCa) diagnostic biomarker.Materials & methods:164 subjects were tested.Results:Significantly different FBC and UPY levels were found between BCa patients and controls, as well as between low-grade and high-grade cancers. The diagnostic accuracy was 0.84 for FBC and 0.87 for UPY. The combination of FBC and UPY improved the accuracy to 0.91. The addition of clinical variables (age, gender, and smoking habit) to FBC and UPY into a model for BCa prediction significantly improved the accuracy to 0.99. The combination of FBC and UPY adjusted for clinical variables associates with the highest sensitivity and good specificity.Conclusion:Urinary FBC and UPY could be used as biomarkers for BCa diagnosis.

Association of age-adjusted D-dimer with deep vein thrombosis risk in patients with spinal cord injury: a cross-sectional study.

Article. To elucidate the association of age-adjusted D-dimer (AAD) with deep vein thrombosis (DVT) risk to lower limbs in patients with spinal cord injury (SCI). Rehabilitation Medicine Department of the First Affiliated Hospital of China University of Science and Technology. Retrospective analysis of 250 patients with SCI in the rehabilitation department from August 2018 to December 2021. Quartiles divided the D-dimer level into four groups to analyze the association between AAD level and DVT risk. Age was identified as a covariate of D-dimer and DVT risk. For non-adjusted model, when D-dimer increased by 1 mg/L, DVT risk increased 0.23-fold (P < 0.05); for minimally-adjusted model (adjusted for age), the risk increased 0.22-fold (P < 0.05); and for fully-adjusted model (adjusted for age, sex, pulmonary infection, degree, grades, and career), it increased 0.19-fold (P < 0.05). AAD had a curvilinear association with DVT risk, and the fold point was 1.9 mg/L (P < 0.05). When serum AAD level was <1.9 mg/L (K < 1.9), the estimated change in DVT risk was 3.34 (P < 0.05), and when serum AAD level was >1.9 mg/L (K > 1.9), the estimated change was 1.14 (P < 0.05). Urinary tract infection (UTI) and fibrinogen(tertile) had a interaction association with D-dimer level and DVT risk (P interaction < 0.05). Patients with SCI who receive rehabilitation treatment with AAD level >1.9 mg/L need to be paid close attention to, especially those with UTI and high levels of fibrinogen.

Urinary fibrinogen is elevated in hospitalized patients undergoing angiography.

Previously, we found that urinary fibrinogen (Fg) levels were positively related to contrast-induced acute renal injury degree in mice. Reduction of fibrinogen in heterozygous mice can improve renal function. Here, we prospectively observed the variation in urinary Fg levels in patients undergoing angiography to determine the relationship between serum creatinine (Scr) and serum cystatin C (Cys C) levels. Serum Cys C and urinary Fg levels were evaluated by ELISA before and 2, 12, and 24 h after angiography in 115 enrolled inpatients. Scr was assessed before and 24 and 48 h after angiography. Data were analyzed using ANOVA or Kruskal-Wallis ANOVA and Spearman correlation. Urinary Fg levels were elevated as early as 2 h after angiography and decreased thereafter before returning to baseline levels 24 h after angiography. Urinary Fg was correlated with the amount of contrast agent ( r = 0.24, p = 0.036) and the presence of diabetes and hypertension ( r = 0.31, r = 0.28, p < 0.05, respectively). Urinary Fg levels 2 h after angiography were positively related with Cys C at 12 and 24 h and Scr at 48 h after angiography ( r = 0.34, r = 0.51, r = 0.85, p < 0.05, respectively). Our results showed that variations in urinary Fg levels are consistent with serum Cys C and Scr in patients undergoing angiography and that urinary Fg levels were the earliest parameter to become elevated. Urinary Fg should be investigated as a useful predictor for abnormal renal function after angiography.

Urinary Fibrinogen as a Predictor of Progression of CKD.

Fibrinogen has been reported to be involved in kidney tubulointerstitial fibrosis and podocyte injury in mouse models. However, the relationship between urinary fibrinogen and kidney outcomes has not been clarified in patients with CKD. We evaluated 402 patients with CKD and kidney biopsies, including 101 with diabetic nephropathy, 94 with idiopathic membranous nephropathy, 55 with idiopathic FSGS, and 152 with IgA nephropathy. We quantified urinary fibrinogen by ELISA and tested associations with kidney histology and progression to ESRD. Median (interquartile range) urinary fibrinogen-to-creatinine ratio was 536 (191-1461) ng/mg for patients with CKD, significantly higher than 2 (2-3) ng/mg for healthy controls (P<0.001). Urinary fibrinogen was positively correlated with urine protein (r=0.64; P<0.001) and interstitial fibrosis and tubular atrophy (r=0.10; P=0.04), and it was negatively correlated with eGFR (r=-0.20; P<0.001). Over a median follow-up period of 35 months (interquartile range, 24-78 months), 68 of 402 patients (17%) developed ESRD. Higher urinary fibrinogen level was associated with increased risk of ESRD (hazard ratio, 2.12; 95% confidence interval, 1.31 to 3.26) per log10 higher urinary fibrinogen-to-creatinine ratio (P=0.003) adjusting for age, sex, BP, urine protein, disease type, eGFR, and interstitial fibrosis and tubular atrophy. For prediction of ESRD, the addition of urinary fibrinogen to eGFR, urine protein, and BP increased the area under the receiver operating curve from 0.73 to 0.76, and the Akaike information criterion improved from 333.6 to 327.0. Urinary fibrinogen correlated with interstitial fibrosis and tubular atrophy and was an independent risk factor for progression of CKD to ESRD.

Urinary fibrinogen and renal tubulointerstitial fibrinogen deposition: Discriminating between primary FSGS and minimal change disease

Primary focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) are common types of primary glomerular disease; they share numerous clinical and pathological similarities but have different treatment regimens and prognoses. It is therefore necessary to distinguish between them and to explore the mechanism underlying their differences. Fibrinogen is reportedly involved in podocyte damage and in renal fibrosis in vitro and in animal models of kidney disease. We thus tested urinary fibrinogen, serum fibrinogen, and renal fibrinogen deposition levels in a cohort comprising 50 patients with FSGS and 40 patients with MCD. Our results suggested that urinary fibrinogen and renal interstitial fibrinogen deposition levels were significantly higher in the FSGS patients than in the MCD patients, while serum fibrinogen levels did not differ between the groups. Receiver operating characteristic (ROC) curve analysis showed an excellent diagnostic ability for urinary fibrinogen and a fair diagnostic ability for tubulointerstitial fibrinogen deposition in differentiating FSGS from MCD. Additionally, we found that urinary fibrinogen levels were positively correlated with the 24-h urine protein levels in patients with FSGS but not in patients with MCD. In conclusion, urinary fibrinogen and renal interstitial fibrinogen deposition is elevated in primary FSGS compared to MCD, which may be relevant to both diagnosis and pathogenesis.

Evaluation of urine fibrinogen level in a murine model of contrast-induced nephropathy.

The mechanisms of contrast-induced nephropathy are not fully understood and sensitive biomarkers of contrast-induced nephropathy are yet to be found. We investigated whether urinary fibrinogen could be a potential biomarker for contrast-induced nephropathy. To create a contrast-induced nephropathy model, mice received a prostaglandin synthesis inhibitor (indomethacin) and a nitric oxide synthase inhibitor (Nω-Nitro-L-arginine methyl ester) intraperitoneally followed by a different dose of iodixanol. In the control group, normal saline was administered. Urinary fibrinogen and serum creatinine were analyzed using enzyme-linked immunosorbent assay. Kidneys were used to quantify fibrinogen using qRT-PCR and Western blot and for histopathological examination. Histopathological examination demonstrated mild renal injury in the low-dose group, and moderate renal injury in the high-dose group. Urinary fibrinogen levels were significantly increased in an iodixanol dose-dependent manner (control vs. low-dose group, P < 0.05; control vs. high-dose group P < 0.01). Serum creatinine levels were only increased in the high-dose group (P < 0.01 compared to control), but not in the low-dose group. For fibrinogen-gene expression, in the low-dose group, Fgγ increased (qRT-PCR, Western blot, P < 0.05) in the high-dose group, Fgβ and Fgγ decreased (qRT-PCR, P < 0.01; Western blot, P < 0.05), and Fgα increased (qRT-PCR, P < 0.05; Western blot, P < 0.05). We propose that urinary fibrinogen could be used as a potential biomarker for early contrast-induced nephropathy diagnosis.

Analysis of the urinary peptidome associated withHelicobacter pyloriinfection

To investigate the relationship between urinary peptide changes and Helicobacter pylori (H. pylori) infection using urinary peptidome profiling. The study was performed in volunteers (n=137) who gave informed consent. Urinary peptides were enriched by magnetic beads based weak cation exchange chromatography and spectrums acquired by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS). ClinProTools bioinformatics software was used for statistical analysis and the recognition of peptide patterns. The marker peptides were identified by LTQ Obitrap XL tandem MS. Approximately 50 proteins or peptides which loaded onto the magnetic beads were detected by MALDI-TOF MS. By optimizing the parameters of the model, the Genetic Algorithm model had good recognition capability (97%) and positive predictive value (94%). Based on the model, 2 markers with molecular masses of 6788 and 1912 Da were found that differentiated between H. pylori positive and negative volunteers. The m/z 1912 sequence was parsed as SKQFTSSTSYNRGDSTF. The peptide was identified as isoform 1 of the fibrinogen α chain precursor, whose concentration in urine was markedly higher in H. pylori infected volunteers than in H. pylori non-infected ones. The appearance of urinary fibrinogen degradation products is caused by an active H. pylori-induced process.

Proteomic analysis of urinary fibrinogen degradation products in patients with urothelial carcinomas

Despite many years of research efforts and continued progress in the identification of urine markers for detection of bladder cancer, none of the markers described to date has been able to replace cystoscopy and urine cytology, the current gold standards for diagnosis. Here, we present a comprehensive gel-based proteomic study in which we have analyzed the presence and origin of fibrinogen (FG) and its degradation products (FDPs) in the urine of patients with and without urothelial carcinoma (UCs), with the aim of evaluating the potential of two-dimensional (2D) gel FDP profiling for detecting bladder cancer. A total of 151 urine samples collected from patients with Ucs of varying degrees of atypia and stages of invasion were compared with a control group consisting of 34 healthy volunteers with no clinical history of bladder cancer. The level and degree of degradation of FG in the urine were determined by 2D gel Western blotting in combination with enhanced chemilumenscence detection. Elevated levels of urine FG/FDPs were found in 99% of patients bearing superficial tumors, in 97% of the cases with early invasive disease, and in 96% of patients with highly invasive tumors. 2D gel profiling of urine FG/FDPs showed that the FG chains exhibited differential susceptibility to in situ proteolysis, with the α-chain being the most susceptible and the γ-chain the most resistant. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry identified peptide sequence regions in several of the most representative and common FDPs, which can be of value for producing novel specific antibodies to detect FG/FDPs in the urine. In addition, we present evidence indicating that FG is not produced by normal or malignant urothelium, although it is present both in the stroma of malignant tissue and tumor lesions. Taken together, the data indicate that increased levels of FG/FDPs amounts in the urine are a characteristic feature of bladder cancer, and emphasize the value of 2D gel profiling of urine FG/FDPs for detecting low-grade, noninvasive UCs.

Significance of Glomerular Deposition of C3c and C3d in IgA Nephropathy

Background: Complement activation plays an important role in the pathogenesis of IgA nephropathy. The clinico-pathological significance of the glomerular deposition of complement breakdown products, C3c and C3d in IgA nephropathy remains to be clarified. Methods: We examined the relationship between glomerular staining patterns of C3c and C3d and clinico-pathological findings with 163 patients with IgA nephropathy. Renal biopsy specimens were stained with C3c and C3d by immunofluorescence, and patients were divided into the following two groups: the intensity of C3c deposition stronger than C3d deposition, or equal to it (group A); the intensity of C3d deposition stronger than C3c deposition (group B). Results: In group A, the incidence of severe hematuria (over 20 urinary red blood cells in high-power field microscope (×400)) or of higher urinary fibrinogen degenerated products (over 0.1 μg/ml) was significantly higher than that in group B. In addition, group A showed a significant decrease in the glomerular filtration rate. Group A also showed a significantly higher incidence of glomerular endocapillary proliferation than in group B. Conclusion: These findings suggest that the glomerular deposition of C3c is associated with the inflammatory active phase of glomeruli in IgA nephropathy.

Urinary fibrin and fibrinogen degradation products and the origin of hematuria.

We examined urinary fibrin and fibrinogen degradation product (U-FDP) concentrations in pediatric patients with hematuria using the rapid and highly-sensitive latex particle agglutination test (LPAT), and assessed the value of this test for the localization of the site of hematuria. Patients with hematuria were divided into two groups: 60 with glomerular hematuria and 46 with non-glomerular hematuria. If U-FDP concentrations less than 0.25 microgram/ml are accepted as an indicator of glomerular bleeding, the sensitivity and specificity of localization of glomerular hematuria in the present study were 78% (47/60) and 89% (41/46), respectively. The high U-FDP concentrations observed in patients with non-glomerular hematuria may reflect direct bleeding into the urinary tract. Since all 13 patients with glomerular hematuria and U-FDP concentrations of 0.25 microgram/ml or more had coexistent erythrocyte cylindruria, the U-FDP test seems to be compensated with combined urinalysis for the relatively lower sensitivity. We conclude that a knowledge of U-FDP concentrations by LPAT can be of help in localizing the site of bleeding in hematuria.

Relationship between urinary fibrinogen degradation products and various types of chronic nephritis

The concentration of urinary fibrin(ogen) degradation products (FDP) was determined by using enzyme immunoassay and radio immunoassay, and their urinary levels were compared with histologically classified types of glomerulonephritis. Urinary FDP levels were higher in the severe type of proliferative glomerulonephritis and at the active phase of systemic lupus erythematosus (SLE). They were also high in the membranous glomerulonephritis. Molecular weight of urinary FDP of a patient with severe proliferative glomerulonephritis was determined to be 150,000 and 68,000, respectively after gel filtration. Urinary FDP levels were higher in patients with glomerular fibrin deposit than in patients without fibrin deposit or normal volunteers. The amounts of excreted protein in urine was not related to the amounts of FDP. Decrease in the reciprocal of serum creatinine levels resulted in high urinary FDP levels, indicating that high urinary FDP levels may represent deterioration of renal function.

Urinary fibrinogen and fibrin fragments in children with renal disease.

Fibrinogen fragments (X, Y, D and E) and fibrin fragments (D-dimer and E) were examined in the urine of 52 patients with various types of renal diseases. One or more of the fibrinogen fragments were detectable in all the urine specimens. D-Dimer together with fibrinogen fragments was found in 38 of the 52 patients. The clearance ratio of D-dimer to IgG, which indicates D-dimer generated in the kidney, was lower than 1 in all the patients with the minimal changes nephrotic syndrome, and was greater than 1 in the majority of patients with acute glomerulonephritis, rapidly progressive glomerulonephritis, mesangial proliferative glomerulonephritis and membranoproliferative glomerulonephritis. Our results suggest that urinary fibrin/fibrinogen degradation products (FDP) in renal diseases are derived primarily from increased filtration of FDP from the plasma through a damaged glomerular basement membrane, and that the mechanism of lysis of cross-linked fibrin deposited in the glomeruli occurs simultaneously in some types of glomerulonephritis. It seems that the determination of the clearance ratio of D-dimer to IgG may be useful in assessing the activation of the coagulation and fibrinolysis systems in the kidney in patients with renal diseases.

Prognostic value of urinary fibrinogen degradation products in bladder carcinoma.

In this study, the value of urinary fibrinogen degradation products as a biological marker of bladder carcinoma has been studied. An increase in fibrinogen degradation products was found in 86% of bladder cancer patients independent of the fact that they had active tumors or that they were disease free. A highly significant correlation between the amount of the increase, the grade, local invasiveness, and the risk of recurrence of the tumor has been established. One can conclude that urinary fibrinogen degradation products are of great prognostic value in patients with bladder carcinoma.

Unusual Immunologic Findings in Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is an inherited disease of unknown etiology. We report a case in which, during an acute febrile attack, rheumatoid factor and immunoglobulin levels rose, and the levels of complement components fell. The level of urinary fibrinogen degradation products also increased, and all results of tests returned to normal at the end of the acute attack. This suggests that an immunologic phenomenon may play a substantial role in the etiology of FMF.

Urinary fibrinogen degradation products (FDP) in bladder cancer.

The value of urinary fibrinogen degradation products (EPD) as a biological marker of bladder cancer has been studied. An increase in FDP was found in 75% of bladder cancer patients, independent of the fact that they had active tumours or that they were disease free. A high correlation between the amount of the increase and the grade, local invasiveness, and risk of recurrence of the tumour has been established. The assessment of urinary FDP is considered as a valuable screening and follow-up test in patients with bladder neoplasms.

Evaluation of Biological Markers in Bladder Cancer

The value of biological markers of bladder cancer was studied in 66 patients. The markers included serum and urine carcinoembryonic antigens, serum and urine fibrinogen degradation products, total lymphocyte counts, urine lymphocytes and urine cytology. A high degree of accuracy (90 per cent) was found in correlating cytology and urinary fibrinogen degradation products with the activity of the disease. Serum and urine carcinoembryonic antigens, serum fibrinogen degradation products, total lymphocyte counts and urine lymphocytes were found to have no value in screening bladder cancer patients. Urinary fibrinogen degradation products and cytology in combination are recommended for screening and followup of patients at high risk.

The Significance of Plasma Proteins in Urinary Casts

Immunofiuorescent staining of casts in urinary sediments was compared with that of renal tissue in 12 patients with various renal diseases. With the possible exception of IgG, no relationship was found between the plasma proteins in urinary casts and the same proteins inrenal biopsies or concentrated urine specimens. The presence of urinary fibrinogen or its degradation products in three patients did not correlate with the demonstration of fibrinogen in either urinary or renal casts but, rather, with amount and/or selectivity of proteinuria. Thus, the presence of specific plasma proteins in urinary casts does not appear to reflect their presence or absence in renal lesions.