Soluble Urokinase Plasminogen Activator Receptor is Associated With Progressive Liver Fibrosis in Hepatitis C Infection

ArticleinJournal of clinical gastroenterology 46(4):334-8 · September 2011with16 Reads
DOI: 10.1097/MCG.0b013e31822da19d · Source: PubMed
Abstract
Progressive liver fibrosis is the main predictor of disease outcome in chronic hepatitis C viral (HCV) infection. Although the importance of the coagulation cascade has been suggested in liver fibrogenesis, the role of the fibrinolytic pathway is yet unclear. We evaluated the association of serum levels of the fibrinolysis-associated soluble urokinase plasminogen activator receptor (suPAR) with the severity of liver fibrosis in HCV infection. suPAR serum levels were assessed in 146 chronically HCV-infected patients of 2 independent cohorts (64 subjects in the screening cohort, 82 in the validation cohort) by enzyme-linked immunosorbent assay and correlated with biopsy-proven histologic stage of liver fibrosis and noninvasive liver fibrosis markers (aspartate transaminase to platelets ratio index score, transient elastography). suPAR serum levels were strongly associated with the histologic stage of liver fibrosis in both cohorts (P<0.0001). Although mean suPAR levels in patients with F1 and F2 fibrosis were not different from healthy control subjects, they were significantly increased at higher stages of liver fibrosis (F3 and F4, P<0.0001). suPAR values had a high diagnostic specificity and sensitivity to differentiate mild/moderate fibrosis (F1/F2) from severe fibrosis (F3/F4) with an area under curve of 0.774 (P=0.0001) and for the differentiation of noncirrhosis from cirrhosis (F1/F2/F3 vs. F4, area under curve 0.791, P=0.0001). SuPAR serum levels were also strongly correlated to the noninvasive fibrosis markers aspartate transaminase to platelets ratio index score (r=0.52) and transient elastography (r=0.44, both P<0.0001). Serum suPAR levels were robust markers of liver fibrosis in 2 cohorts with a comparable diagnostic accuracy for prediction of severe liver fibrosis as established noninvasive marker.
    • "uPAR can be released from the plasma membrane as a soluble molecule (suPAR) by cleavage of the GPI anchor. Elevated serum levels of suPAR have been reported under various disease conditions, such as sepsis [37] , liver cirrho- sis [38], rheumatic arthritis [39] and malignancies [40]. Wei et al. described that the serum levels of suPAR were elevated in 70% of FSGS patients and that the suPAR levels in FSGS patients were significantly higher than those in patients with MCD (either in relapse or in remission), membranous nephropathy (MN), preeclampsia or in healthy control subjects. "
    [Show abstract] [Hide abstract] ABSTRACT: Primary focal segmental glomerulosclerosis (FSGS) is one of the major causes of steroid-resistant nephrotic syndrome, and renal prognosis in patients with steroid-resistant FSGS is poor. It has been long speculated that a circulating permeability factor should be implicated in the pathogenesis of the disease because a substantial portion of the patients with primary FSGS experience recurrence shortly after transplantation. Although molecules such as cardiotrophin-like cytokine 1 (CLC-1) and anti-CD40 antibody have been proposed to be potential circulating permeability factors, a definitive factor remains to be discovered. Soluble urokinase-type plasminogen activator receptor (suPAR) has attracted substantial attention and garnered scrutiny by renal researchers since Reiser's group suggested that it was linked to the pathogenesis of primary FSGS and that it might be useful as a diagnostic biomarker. A number of different cohort studies have shown that serum suPAR levels are negatively associated with renal function and can scarcely differentiate FSGS from the other glomerular/renal diseases. In contrast to initial studies, several in vivo studies investigating the effects of forced suPAR upregulation could not show the induction of proteinuria or podocyte injury. Currently it is suggested that a different form of suPAR, which cannot be measured by presently available enzyme-linked immunosorbent assay, might be the culprit; however, it remains to be determined whether this is the case. Because a circulating permeability factor might be a useful biomarker for diagnosing FSGS as well as a potent therapeutic target for primary and recurrent FSGS, further dedicated work will be needed.
    Full-text · Article · Sep 2015
    • "In patients with Crimean-Congo hemorrhagic fever, suPAR is elevated and also predictive for mortality [42]. Systemic suPAR levels also predict the progression of liver fibrosis to cirrhosis in patients with chronic hepatitis C [45,46]. Furthermore, elevated suPAR levels have been found in the cerebrospinal fluid of patients with viral meningitis [44]. "
    [Show abstract] [Hide abstract] ABSTRACT: Urokinase-type plasminogen activator receptor is a multifunctional glycoprotein, the expression of which is increased during inflammation. It is known to bind to β3-integrins, which are elementary for the cellular entry of hantaviruses. Plasma soluble form of the receptor (suPAR) levels were evaluated as a predictor of severe Puumala hantavirus (PUUV) infection and as a possible factor involved in the pathogenesis of the disease. A single-centre prospective cohort study. Plasma suPAR levels were measured twice during the acute phase and once during the convalescence in 97 patients with serologically confirmed acute PUUV infection using a commercial enzyme-linked immunosorbent assay (ELISA). The plasma suPAR levels were significantly higher during the acute phase compared to the control values after the hospitalization (median 8.7 ng/ml, range 4.0-18.2 ng/ml vs. median 4.7 ng/ml, range 2.4-12.2 ng/ml, P<0.001). The maximum suPAR levels correlated with several variables reflecting the severity of the disease. There was a positive correlation with maximum leukocyte count (r = 0.475, p<0.001), maximum plasma creatinine concentration (r = 0.378, p<0.001), change in weight during the hospitalization (r = 0.406, p<0.001) and the length of hospitalization (r = 0.325, p = 0.001), and an inverse correlation with minimum platelet count (r = -0.325, p = 0.001) and minimum hematocrit (r = -0.369, p<0.001). Plasma suPAR values are markedly increased during acute PUUV infection and associate with the severity of the disease. The overexpression of suPAR possibly activates β3-integrin in PUUV infection, and thus might be involved in the pathogenesis of the disease.
    Full-text · Article · Aug 2013
    • "However, none of the patients in this study were suffering from glomerular disease and it is currently unknown if suPAR has an active role in disease outside FSGS. Two earlier studies found a strong connection between high suPAR and decreased liver biosynthesis and cirrhosis [6,18], and the association between ALAT and suPAR may support these findings: also, patients in the Charlson group 'Liver disease' had a mean suPAR of 11.8 ng/ml, the highest mean value among the groups. If suPAR does not play an active role in disease outside FSGS, it is likely that the suPAR level reflects a conglomerate of negative biological processes such as increased inflammation and fibrosis, organ dysfunction and decreased organ biosynthesis. "
    [Show abstract] [Hide abstract] ABSTRACT: Soluble urokinase plasminogen activator receptor (suPAR) is the soluble form of the membrane-bound receptor (uPAR) expressed predominantly on various immune cells. Elevated plasma suPAR concentration is associated with increased mortality in various patient groups, and it is speculated that suPAR is a low-grade inflammation marker reflecting on disease severity. The aim of this prospective observational study was to determine if the plasma concentration of suPAR is associated with admission time, re-admission, disease severity/Charlson Comorbidity Index Score, and mortality. We included 543 patients with various diseases from a Danish Acute Medical Unit during a two month period. A triage unit ensured that only medical patients were admitted to the Acute Medical Unit. SuPAR was measured on plasma samples drawn upon admission. Patients were followed-up for three months after inclusion by their unique civil registry number and using Danish registries to determine admission times, readmissions, International Classification of Diseases, 10th Edition (ICD-10) diagnoses, and mortality. Statistical analysis was used to determine suPAR's association with these endpoints. Increased suPAR was significantly associated with 90-day mortality (4.87 ng/ml in survivors versus 7.29 ng/ml in non-survivors, P < 0.0001), higher Charlson Score (P < 0.0001), and longer admission time (P < 0.0001), but not with readmissions. The association with mortality remained when adjusting for age, sex, C-reactive protein (CRP), and Charlson Score. Furthermore, among the various Charlson Score disease groups, suPAR was significantly higher in those with diabetes, cancer, cardiovascular disease, and liver disease compared to those without comorbidities. SuPAR is a marker of disease severity, admission time, and risk of mortality in a heterogeneous cohort of patients with a variety of diseases. The independent value of suPAR suggests it could be of value in prognostic algorithms.
    Full-text · Article · Jul 2012
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