Project description:BackgroundKidney transplant recipients have high cardiovascular risk, and vascular inflammation may play an important role. We explored whether the inflammatory state in the vessel wall was related to carotid intima-media thickness (c-IMT) and patient survival following kidney transplantation.MethodsIn this prospective observational cohort study we measured c-IMT and expression of proinflammatory cytokines and adhesion molecules in the inferior epigastric artery in 115 kidney transplant candidates. Another c-IMT measurement was done 1-year post-transplantation in 107. By stepwise multiple regression analysis we explored factors associated with baseline c-IMT and their changes over time. Multivariate Cox regression analysis was constructed to identify risk factors for mortality.ResultsA worse cardiovascular profile (older age, smoker, diabetic, carotid plaque, systolic blood pressure and vascular calcification) and higher VCAM-1 levels were found in patients in the highest baseline c-IMT tertile, who also had a worse survival. Factors independently related to baseline c-IMT were age (?=0.369, P<0.0001), fasting glucose (?=0.168, P=0.045), smoking (?=0.228, P=0.003) and VCAM-1 levels (?=0.244, P=0.002). Independent factors associated with c-IMT measurement 1-year post-transplantation were baseline c-IMT (?=-0.677, P<0.0001), post-transplant diabetes (?=0.225, P=0.003) and triglycerides (?=0.302, P=0.023). Vascular VCAM-1 levels were associated with increased risk of mortality in bivariate and multivariate Cox regression. Notably, nearly 50% of patients showed an increase or maintenance of high c-IMT 1 year post-transplantation and these patients experienced a higher mortality (13 versus 3.5%; P=0.021).ConclusionA worse cardiovascular profile and a higher vascular VCAM-1 protein levels at time of KT are related to subclinical atheromatosis. This could lead to a higher post-transplant mortality. Pre-transplant c IMT, post-transplant diabetes and triglycerides at 1-year post-transplantation may condition a high c-IMT measurement post-transplantation, which may decrease patient survival.

Project description:BackgroundThe plasminogen (PLG) activation system is composed by a series of serine proteases, inhibitors and several binding proteins, which together control the temporal and spatial generation of the active serine protease plasmin. As this proteolytic system plays a central role in human physiology and pathophysiology it has been extensively studied in mammals. The serine proteases of this system are believed to originate from an ancestral gene by gene duplications followed by domain gains and deletions. However, the identification of ancestral forms in primitive chordates supporting these theories remains elusive. In addition, evolutionary studies of the non-proteolytic members of this system are scarce.ResultsOur phylogenetic analyses place lamprey PLG at the root of the vertebrate PLG-group, while lamprey PLG-related growth factors represent the ancestral forms of the jawed-vertebrate orthologues. Furthermore, we find that the earliest putative orthologue of the PLG activator group is the hyaluronan binding protein 2 (HABP2) gene found in lampreys. The prime plasminogen activators (tissue- and urokinase-type plasminogen activator, tPA and uPA) first occur in cartilaginous fish and phylogenetic analyses confirm that all orthologues identified compose monophyletic groups to their mammalian counterparts. Cartilaginous fishes exhibit the most ancient vitronectin of all vertebrates, while plasminogen activator inhibitor 1 (PAI-1) appears for the first time in cartilaginous fishes and is conserved in the rest of jawed vertebrate clades. PAI-2 appears for the first time in the common ancestor of reptiles and mammals, and represents the latest appearing plasminogen activator inhibitor. Finally, we noted that the urokinase-type plasminogen activator receptor (uPAR)-and three-LU domain containing genes in general-occurred later in evolution and was first detectable after coelacanths.ConclusionsThis study identifies several primitive orthologues of the mammalian plasminogen activation system. These ancestral forms provide clues to the origin and diversification of this enzyme system. Further, the discovery of several members-hitherto unknown in mammals-provide new perspectives on the evolution of this important enzyme system.

Project description:Background and objectives: This report describes an unusual presentation of severe hypertension (HTN) in a subset of pediatric kidney recipients treated with a steroid avoidance pediatric renal transplantation protocol. The HTN was secondary to atypical, reno-vascular abnormalities (RVA) of the transplanted vasculature, temporally associated with erythropoietin (EPO) use. Design, setting, participants, and measurements: To investigate the clinical significance underlying this event, a retrospective clinical study of 100 pediatric renal transplants was undertaken (50 steroid-free and 50 matched steroid-based controls), with peripheral blood transcriptional analysis of four RVA patients and controls. Results: Regardless of a higher observed incidence of anemia (p < 0.001) and greater overall EPO usage in the first post-transplant year in steroid-free patients, the incidence of new-onset HTN at one yr was significantly less in the steroid-free cohort (p = 0.03). Nevertheless, early EPO (first week post-transplant) was significantly associated with the combinatory findings of new-onset HTN (p = 0.03) and RVA (p = 0.007). Molecular mechanisms of RVA injury were investigated further by peripheral blood cDNA microarray gene expression profiling. A panel of 42 transcripts differentiated patients with RVA and HTN from three sets of matched controls, with and without HTN and EPO use, with 100% concordance (p < 0.001). The biological processes governed by these significant genes suggest a role for EPO regulation of growth factor receptor ubiquitination as a putative mechanism for renal vascular injury. Conclusion: This study cautions against the use early post-transplant use of EPO in immunosuppression regimens with steroid minimization/avoidance, which may have an increased incidence of post-transplant anemia. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Disease State: patient with high blood pressure Keywords: Logical Set Using regression correlation

Project description:Background and objectives: This report describes an unusual presentation of severe hypertension (HTN) in a subset of pediatric kidney recipients treated with a steroid avoidance pediatric renal transplantation protocol. The HTN was secondary to atypical, reno-vascular abnormalities (RVA) of the transplanted vasculature, temporally associated with erythropoietin (EPO) use. Design, setting, participants, and measurements: To investigate the clinical significance underlying this event, a retrospective clinical study of 100 pediatric renal transplants was undertaken (50 steroid-free and 50 matched steroid-based controls), with peripheral blood transcriptional analysis of four RVA patients and controls. Results: Regardless of a higher observed incidence of anemia (p < 0.001) and greater overall EPO usage in the first post-transplant year in steroid-free patients, the incidence of new-onset HTN at one yr was significantly less in the steroid-free cohort (p = 0.03). Nevertheless, early EPO (first week post-transplant) was significantly associated with the combinatory findings of new-onset HTN (p = 0.03) and RVA (p = 0.007). Molecular mechanisms of RVA injury were investigated further by peripheral blood cDNA microarray gene expression profiling. A panel of 42 transcripts differentiated patients with RVA and HTN from three sets of matched controls, with and without HTN and EPO use, with 100% concordance (p < 0.001). The biological processes governed by these significant genes suggest a role for EPO regulation of growth factor receptor ubiquitination as a putative mechanism for renal vascular injury. Conclusion: This study cautions against the use early post-transplant use of EPO in immunosuppression regimens with steroid minimization/avoidance, which may have an increased incidence of post-transplant anemia. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Disease State: patient with high blood pressure Keywords: Logical Set

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.

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Can components of the plasminogen activation system predict the outcome of kidney transplants?

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Can components of the plasminogen activation system predict the outcome of kidney transplants?

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