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Circulating soluble urokinase plasminogen activator receptor levels and peripheral arterial disease outcomes.

ABSTRACT: BACKGROUND AND AIMS:Circulating soluble urokinase plasminogen activator receptor (suPAR) is a marker of immune activation associated with atherosclerosis. Whether suPAR levels are associated with prevalent peripheral arterial disease (PAD) and its adverse outcomes remains unknown and is the aim of the study. METHODS:SuPAR levels were measured in 5810 patients (mean age 63 years, 63% male, 77% with obstructive coronary artery disease [CAD]) undergoing cardiac catheterization. The presence of PAD (n = 967, 17%) was classified as carotid (36%), lower/upper extremities (30%), aortic (15%) and multisite disease (19%). Multivariable logistic and Cox regression models were used to determine independent predictors of prevalent PAD and outcomes including all-cause death, cardiovascular death and PAD-related events after adjustment for age, gender, race, body mass index, smoking, diabetes, hypertension, hyperlipidemia, renal function, heart failure history, and obstructive CAD. RESULTS:Plasma suPAR levels were 22.5% (p < 0.001) higher in patients with PAD compared to those without PAD. Plasma suPAR was higher in patients with more extensive PAD (?2 compared to single site) p < 0.001. After multivariable adjustment, suPAR was associated with prevalent PAD; odds ratio (OR) for highest compared to lowest tertile of 2.0, 95% CI (1.6-2.5) p < 0.001. In Cox survival analyses adjusted for clinical characteristics and medication regimen, suPAR (in the highest vs. lowest tertile) remained an independent predictor of all-cause death [HR 3.1, 95% CI (1.9-5.3)], cardiovascular death [HR 3.5, 95% CI (1.8-7.0)] and PAD-related events [HR = 1.8, 95% CI (1.3-2.6) p < 0.001 for all]. CONCLUSIONS:Plasma suPAR level is predictive of prevalent PAD and of incident cardiovascular and PAD-related events. Whether SuPAR measurement can help screen, risk stratify, or monitor therapeutic responses in PAD requires further investigation.

SUBMITTER: Samman Tahhan A

PROVIDER: S-EPMC5808930 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Circulating soluble urokinase plasminogen activator receptor levels and peripheral arterial disease outcomes.

Samman Tahhan Ayman A Hayek Salim S SS Sandesara Pratik P Hajjari Jamal J Hammadah Muhammad M O'Neal Wesley T WT Kelli Heval M HM Alkhoder Ayman A Ghasemzadeh Nima N Ko Yi-An YA Aida Hiroshi H Gafeer Mohamad Mazen MM Abdelhadi Naser N Mohammed Kareem Hosny KH Patel Keyur K Arya Shipra S Reiser Jochen J Vaccarino Viola V Sperling Laurence L Quyyumi Arshed A

Atherosclerosis 20170608

<h4>Background and aims</h4>Circulating soluble urokinase plasminogen activator receptor (suPAR) is a marker of immune activation associated with atherosclerosis. Whether suPAR levels are associated with prevalent peripheral arterial disease (PAD) and its adverse outcomes remains unknown and is the aim of the study.<h4>Methods</h4>SuPAR levels were measured in 5810 patients (mean age 63 years, 63% male, 77% with obstructive coronary artery disease [CAD]) undergoing cardiac catheterization. The p ...[more]

PMID: 28728756

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Project description:Background & Aims:Surgical resection is the only potentially curative therapy for patients with biliary tract cancer (BTC), but 5-year survival rates after tumor resection have remained below 30%, corroborating the need for better stratification tools to identify the ideal surgical candidates. The soluble urokinase plasminogen activator receptor (suPAR) represents a mediator of inflammation and has been associated with distinct types of cancer. In this study, we evaluated a potential role of suPAR as a novel biomarker in patients undergoing BTC resection. Methods:Tumor expression of uPAR was analyzed by immunohistochemistry in 108 BTC samples. Serum levels of suPAR were analyzed by ELISA in a training and validation cohort comprising a total of 117 patients with BTC and 76 healthy controls. Results:High tumoral uPAR expression was associated with an adverse outcome after BTC resection. Accordingly, circulating levels of suPAR were significantly elevated in patients with BTC compared to healthy controls, as well as in patients with primary sclerosing cholangitis. Using a small training set, we established an optimal prognostic suPAR cut-off value of 3.72 ng/ml for patients with BTC. Importantly, preoperative suPAR serum levels above this cut-off value were associated with significantly impaired overall survival in both the training and validation cohort. Multivariate Cox-regression analysis including various clinicopathological parameters such as tumor stage, markers of inflammation and organ dysfunction, as well as tumor markers, revealed circulating suPAR levels as an independent prognostic marker following BTC resection. Finally, high preoperative suPAR levels were indicative of acute kidney injury after tumor resection. Conclusion:Circulating suPAR represents a previously unrecognized biomarker in patients with resectable BTC, which might help to preoperatively identify the ideal candidates for liver surgery. Lay summary:Surgical resection represents the only curative treatment option for patients with biliary tract cancer, but not all patients benefit to the same extent in terms of overall survival. Here, we provide evidence that serum levels of an inflammatory mediator (suPAR) are indicative of a patient's postoperative outcome and might thus help to identify the ideal surgical candidates.

Project description:Background and objectivesSoluble urokinase plasminogen activator receptor is a novel biomarker strongly predictive of cardiovascular outcomes implicated in the pathogenesis of kidney disease. Soluble urokinase plasminogen activator receptor levels, however, correlate with declining kidney function. It is unclear whether soluble urokinase plasminogen activator receptor levels remain associated with outcomes in patients with ESRD.Design, setting, participants, & measurementsWe measured plasma soluble urokinase plasminogen activator receptor levels in 1175 patients (mean age =66±8 years old, 54% men) with type 2 diabetes mellitus on hemodialysis participating in the German Diabetes and Dialysis Study followed for a median of 4 years for outcomes including all-cause death, cardiovascular events, and infection-related mortality. Survival analysis was performed using stepwise Cox proportional hazards models adjusted for potential confounders. Also, adjustments were made for inflammatory markers (C-reactive protein and leukocyte count) and the oxidative stress marker asymmetric dimethyl arginine to investigate potential mediators of the relationship between soluble urokinase plasminogen activator receptor and outcomes.ResultsMedian soluble urokinase plasminogen activator receptor levels were 10,521 pg/ml (interquartile range, 9105-12,543 pg/ml). When stratified by tertiles, patients with soluble urokinase plasminogen activator receptor >11,633 pg/ml (third tertile) had adjusted 1.6-fold higher mortality (hazard ratio, 1.60; 95% confidence interval, 1.27 to 2.03) compared with those with low soluble urokinase plasminogen activator receptor <9599 pg/ml (first tertile). Risks of sudden death and stroke were higher (adjusted hazard ratio, 1.98; 95% confidence interval, 1.27 to 3.09 and adjusted hazard ratio, 1.74; 95% confidence interval, 1.05 to 2.90, respectively), together accounting for higher incidence of cardiovascular events (adjusted hazard ratio, 1.48; 95% confidence interval, 1.15 to 1.89). Associations with outcomes persisted after adjusting for C-reactive protein, leukocyte count, and asymmetric dimethyl arginine. Addition of soluble urokinase plasminogen activator receptor to a risk factor model modestly improved risk discrimination for all-cause death (?C statistic, 0.02; 95% confidence interval, 0.00 to 0.03) and cardiovascular events (?C statistic, 0.02; 95% confidence interval, 0.00 to 0.05).ConclusionsThe association of soluble urokinase plasminogen activator receptor levels with outcomes persists in patients on hemodialysis. Additional study is warranted to characterize the underlying pathways of that association, which may yield opportunities to develop new therapeutic strategies.

Project description:BackgroundThe soluble urokinase plasminogen activator receptor (suPAR) is related to hepatic inflammation and fibrosis and has been suggested to participate in the development of liver cirrhosis. Therefore, the aim of the current study was to measure the concentration of suPAR in the hepatic vein of cirrhotic patients during a liver vein catheterization to identify a possible hepatic suPAR generation. Furthermore, we explored if suPAR levels were associated with the degree of cirrhosis and liver dysfunction.Methods and patientsWe included 105 cirrhotic patients and 19 liver-healthy controls. Blood was sampled from the hepatic vein and the femoral artery and suPAR was measured by enzyme-linked immunosorbent assay.ResultsWe identified significantly higher median suPAR concentrations among the cirrhotic patients (7.2 ng/ml in the hepatic vein; 6.8 ng/ml in the femoral artery) compared to the controls (2.6 ng/ml, respectively, p-values <0.001). However, the median hepatic suPAR formation was 0.0 ng/ml in both groups. We observed significantly increasing suPAR levels according to higher Child classes (4.5 ng/ml, 6.9 ng/ml and 9.0 ng/ml, Child A, B, C respectively; p-value<0.001), and significantly higher median suPAR concentrations in patients with ascites versus patients without ascites (8.1 ng/ml versus 5.3 ng/ml, respectively, p-value<0.001). suPAR levels were significantly related to bilirubin (r = 0.48, p<0.001), the hepatic venous pressure gradient (r = 0.39, p<0.001), the cardiac index (r = 0.24, p = 0.02) and the plasma volume (r = 0.33, p = 0.001), whereas suPAR levels were significantly inversely related to albumin (r = -0.59, p<0.001), plasma coagulation factors (r-0.39, p<0.001), the mean arterial pressure (r = -0.28, p = 0.004), the systemic vascular resistance (r = 0.26, p = 0.007), the indocyanine green clearance (r = -0.51, p<0,001) and the galactose elimination capacity (r = -0.39, p<0.001).ConclusionWe identified elevated suPAR concentration in cirrhotic patients, which correlated significantly with the degree of cirrhosis and liver failure, but we were not able to demonstrate hepatic suPAR generation per se. This suggests that further investigations of the source of suPAR in cirrhotic patients need to be undertaken.

Dataset Information

Circulating soluble urokinase plasminogen activator receptor levels and peripheral arterial disease outcomes.

Publications

Circulating soluble urokinase plasminogen activator receptor levels and peripheral arterial disease outcomes.

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