Sascha David

Publications

• 2.77

  Impact points

  Circulatory and renal consequences of pregnancy in diabetic NOD mice.

  S D Burke, V F Barrette, S David, E V Khankin, M A Adams, B A Croy

  Placenta. 12/2011; 32(12):949-55.

  Women with diabetes have elevated gestational risks for severe hemodynamic complications, including preeclampsia in mid- to late pregnancy. This study employed continuous, chronic radiotelemetry to compare the hemodynamic patterns in non-obese diabetic (NOD) mice who were overtly diabetic or normogl... [more] Women with diabetes have elevated gestational risks for severe hemodynamic complications, including preeclampsia in mid- to late pregnancy. This study employed continuous, chronic radiotelemetry to compare the hemodynamic patterns in non-obese diabetic (NOD) mice who were overtly diabetic or normoglycemic throughout gestation. We hypothesized that overtly diabetic, pregnant NOD mice would develop gestational hypertension and provide understanding of mechanisms in progression of this pathology. Telemeter-implanted, age-matched NOD females with and without diabetes were assessed for six hemodynamic parameters (mean, systolic, diastolic, pulse pressures, heart rate and activity) prior to mating, over pregnancy and over a 72 h post-partum interval. Urinalysis, serum biochemistry and renal histopathology were also conducted. Pregnant, normoglycemic NOD mice had a hemodynamic profile similar to other inbred strains, despite insulitis. This pattern was characterized by an interval of pre-implantation stability, post implantation decline in arterial pressure to mid gestation, and then a rebound to pre-pregnancy baseline during later gestation. Overtly diabetic NOD mice had a blood pressure profile that was normal until mid-gestation then become mildly hypotensive (-7 mmHg, P < 0.05), severely bradycardic (-80 bpm, P < 0.01) and showed signs of acute kidney injury. Pups born to diabetic dams were viable but growth restricted, despite their mothers' failing health, which did not rebound post-partum (-10% pre-pregnancy pressure and HR, P < 0.05). Pregnancy accelerates circulatory and renal pathologies in overtly diabetic NOD mice and is characterized by depressed arterial pressure from mid-gestation and birth of growth-restricted offspring.
• 4.93

  Impact points

  The synthetic Tie2 agonist peptide vasculotide protects against vascular leakage and reduces mortality in murine abdominal sepsis.

  Philipp Kümpers, Faikah Gueler, Sascha David, Paul Van Slyke, Daniel J Dumont, Joon-Keun Park, Clemens L Bockmeyer, Samir M Parikh, Hermann Pavenstädt, Hermann Haller, Nelli Shushakova

  Critical care (London, England). 10/2011; 15(5):R261.

  ABSTRACT: INTRODUCTION: Angiopoietin-1 (Angpt1), the natural agonist ligand for the endothelial Tie2 receptor, is a non-redundant endothelial survival and vascular stabilization factor that reduces endothelial permeability and inhibits leukocyte-endothelium interactions. Here we evaluate the efficac... [more] ABSTRACT: INTRODUCTION: Angiopoietin-1 (Angpt1), the natural agonist ligand for the endothelial Tie2 receptor, is a non-redundant endothelial survival and vascular stabilization factor that reduces endothelial permeability and inhibits leukocyte-endothelium interactions. Here we evaluate the efficacy of a novel polyethylene glycol (PEG)-clustered Tie2 agonist peptide, vasculotide (VT), to protect against vascular leakage and mortality in a murine model of polymicrobial abdominal sepsis. METHODS: Polymicrobial abdominal sepsis in C57BL6 mice was induced by cecal-ligation-and-puncture (CLP). Mice were treated with different dosages of VT or equal volume of phosphate-buffered saline (PBS). Sham-operated animals served as time-matched controls. RESULTS: Systemic administration of VT induced long-lasting Tie2 activation in vivo. VT protected against sepsis-induced endothelial barrier dysfunction, as evidenced by attenuation of vascular leakage and leukocyte transmigration into the peritoneal cavity. Histological analysis revealed that VT treatment ameliorated leukocyte infiltration in kidneys of septic mice, probably due to reduced endothelial adhesion molecule expression. VT-driven effects were associated with significantly improved organ function and reduced circulating cytokine levels. The endothelial-specific action of VT was supported by additional in vitro studies showing no effect of VT on either cytokine release from isolated peritoneal macrophages, or migratory capacity of isolated neutrophils. Finally, administration of VT pre-CLP (hazard ratio 0.39 [95% confidence interval 0.19-0.81] P < 0.001) and post-CLP reduced mortality in septic mice (HR 0.22 [95% CI 0.06-0.83] P < 0.05). CONCLUSIONS: We provide proof of principle in support of the efficacious use of PEGylated VT, a drug-like Tie2 receptor agonist, to counteract microvascular endothelial barrier dysfunction and reduce mortality in a clinically relevant murine sepsis model. Further studies are needed to pave the road for clinical application of this therapeutic concept.
• 3.31

  Impact points

  Angiopoietin-2 levels predict mortality in CKD patients.

  Sascha David, Stephen G John, Helen J Jefferies, Mhairi K Sigrist, Philipp Kümpers, Jan T Kielstein, Hermann Haller, Christopher W McIntyre

  Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 10/2011;

  BACKGROUND: The pathophysiology of aggravated atherosclerosis in chronic kidney disease (CKD) is still incompletely understood. However, there is an increasing focus on non-traditional risk factors, including endothelial dysfunction. Angiopoietin-2 (Ang-2) impairs endothelial function by inhibiting ... [more] BACKGROUND: The pathophysiology of aggravated atherosclerosis in chronic kidney disease (CKD) is still incompletely understood. However, there is an increasing focus on non-traditional risk factors, including endothelial dysfunction. Angiopoietin-2 (Ang-2) impairs endothelial function by inhibiting the binding of Angiopoietin-1 (Ang-1) to their shared receptor Tie2 and is increased in diabetes, hypertension, coronary heart disease and CKD. Furthermore, Ang-2 levels are associated with the prevalent vascular burden of CKD patients. Thus, we aimed to investigate its impact on outcome in CKD, the population most likely to die of cardiovascular events.METHODS: We prospectively studied 128 CKD patients [43 CKD Stage 4, 85 CKD Stage 5 (57 haemodialysis, 28 peritoneal dialysis)] over a follow-up period of 4 years. Biochemical and clinical parameters, including objective scoring of vascular calcification (VC) by computed tomography (CT) and arterial stiffness by applanation tonometry (including radial-dorsalis pedis pulse wave velocity (PWVrd)) were recorded. Baseline Ang-1 [enzyme-linked immunosorbent assay (ELISA)], Ang-2 [immunoluminometric assay (ILMA)] and soluble Tie2 (sTie2) (ELISA) levels were measured in this group as well as in 20 healthy controls.RESULTS: Ang-2 values were significantly higher in CKD patients than in controls (2.01 ± 0.94 versus 1.00 ± 0.47 ng/mL, P < 0.0001). Furthermore, Ang-2 was significantly higher in dialysis than in Stage 4 CKD patients and correlated with markers of vascular disease [cholesterol, hsCRP, osteoprotegerin (OPG)]. However, elevated Ang-2 was not associated with the degree of VC or with arterial stiffness. Cox-regression analysis detected Ang-2 as an independent predictor of mortality in both unadjusted [hazard ratio (HR) 1.15; P = 0.002] and models adjusted for age and VC (HR 1.14; P = 0.003).CONCLUSIONS: Ang-2 levels are associated with systemic markers/mediators of micro-inflammation in CKD patients. Furthermore, elevated Ang-2 levels are strong predictors of long-term mortality, independent of conduit arterial stiffness or VC.
• 7.24

  Impact points

  Angiopoietin-1 requires IQ domain GTPase-activating protein 1 to activate Rac1 and promote endothelial barrier defense.

  Sascha David, Chandra C Ghosh, Aditi Mukherjee, Samir M Parikh

  Arteriosclerosis, thrombosis, and vascular biology. 09/2011; 31(11):2643-52.

  IQ domain GTPase-activating protein 1 (IQGAP1) contributes to cytoskeletal network regulation in epithelial cells by its scaffolding properties and by binding the Rho GTPase Rac1 to maintain its activity. The functions of IQGAP1 in endothelial cells beyond angiogenesis remain unclear. We hypothesize... [more] IQ domain GTPase-activating protein 1 (IQGAP1) contributes to cytoskeletal network regulation in epithelial cells by its scaffolding properties and by binding the Rho GTPase Rac1 to maintain its activity. The functions of IQGAP1 in endothelial cells beyond angiogenesis remain unclear. We hypothesized that IQGAP1 participates in the regulation of endothelial barrier function. Silencing IQGAP1 in human microvascular endothelial cells resulted in a disruption of adherens junctions, formation of interendothelial gaps, and a reduction in barrier function. Furthermore, silencing of IQGAP1 abrogated the barrier enhancement effect of angiopoietin-1 (Angpt-1) and abolished the barrier-stabilizing effect of Angpt-1 on thrombin-stimulated cells. Coimmunoprecipitation detected binding of endogenous IQGAP1 with Rac1 at baseline that was stronger when Rac1 was activated and weaker when it was deactivated. Measurement of GTP-bound Rac1 revealed that Angpt-1 failed to activate Rac1 not only if IQGAP1 was silenced but also if cells were transfected with a mutant disabled in Rac1 binding (T1050AX2). Furthermore, a dominant-active Rac1 was sufficient to completely reverse the morphological and functional changes induced by reduction in IQGAP1. These experiments are the first demonstration of IQGAP1 regulating barrier function in any cell type. Further, our data show that Angpt-1 requires IQGAP1 as an indispensable activator of Rac1.
• 15.39

  Impact points

  PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice.

  Mei Tran, Denise Tam, Amit Bardia, Manoj Bhasin, Glenn C Rowe, Ajay Kher, Zsuzsanna K Zsengeller, M Reza Akhavan-Sharif, Eliyahu V Khankin, Magali Saintgeniez, Sascha David, Deborah Burstein, S Ananth Karumanchi, Isaac E Stillman, Zoltan Arany, Samir M Parikh

  The Journal of clinical investigation. 09/2011; 121(10):4003-14.

  Sepsis-associated acute kidney injury (AKI) is a common and morbid condition that is distinguishable from typical ischemic renal injury by its paucity of tubular cell death. The mechanisms underlying renal dysfunction in individuals with sepsis-associated AKI are therefore less clear. Here we have s... [more] Sepsis-associated acute kidney injury (AKI) is a common and morbid condition that is distinguishable from typical ischemic renal injury by its paucity of tubular cell death. The mechanisms underlying renal dysfunction in individuals with sepsis-associated AKI are therefore less clear. Here we have shown that endotoxemia reduces oxygen delivery to the kidney, without changing tissue oxygen levels, suggesting reduced oxygen consumption by the kidney cells. Tubular mitochondria were swollen, and their function was impaired. Expression profiling showed that oxidative phosphorylation genes were selectively suppressed during sepsis-associated AKI and reactivated when global function was normalized. PPARγ coactivator-1α (PGC-1α), a major regulator of mitochondrial biogenesis and metabolism, not only followed this pattern but was proportionally suppressed with the degree of renal impairment. Furthermore, tubular cells had reduced PGC-1α expression and oxygen consumption in response to TNF-α; however, excess PGC-1α reversed the latter effect. Both global and tubule-specific PGC-1α-knockout mice had normal basal renal function but suffered persistent injury following endotoxemia. Our results demonstrate what we believe to be a novel mechanism for sepsis-associated AKI and suggest that PGC-1α induction may be necessary for recovery from this disorder, identifying a potential new target for future therapeutic studies.
• 3.12

  Impact points

  Acute administration of recombinant Angiopoietin-1 ameliorates multiple-organ dysfunction syndrome and improves survival in murine sepsis.

  Sascha David, Joon-Keun Park, Matijs van Meurs, Jan G Zijlstra, Christian Koenecke, Claudia Schrimpf, Nelli Shushakova, Faikah Gueler, Hermann Haller, Philipp Kümpers

  Cytokine. 04/2011; 55(2):251-9.

  Endothelial activation leading to vascular barrier breakdown plays an essential role in the pathophysiology of multiple-organ dysfunction syndrome (MODS) in sepsis. Increasing evidence suggests that the function of the vessel-protective factor Angiopoietin-1 (Ang-1), a ligand of the endothelial-spec... [more] Endothelial activation leading to vascular barrier breakdown plays an essential role in the pathophysiology of multiple-organ dysfunction syndrome (MODS) in sepsis. Increasing evidence suggests that the function of the vessel-protective factor Angiopoietin-1 (Ang-1), a ligand of the endothelial-specific Tie2 receptor, is inhibited by its antagonist Angiopoietin-2 (Ang-2) during sepsis. In order to reverse the effects of the sepsis-induced suppression of Ang-1 and elevation of Ang-2 we aimed to investigate whether an intravenous injection of recombinant human (rh) Ang-1 protects against MODS in murine sepsis. Polymicrobiological abdominal sepsis was induced by cecal ligation and puncture (CLP). Mice were treated with either 1 μg of intravenous rhAng-1 or control buffer immediately after CLP induction and every 8h thereafter. Sham-operated animals served as time-matched controls. Compared to buffer-treated controls, rhAng-1 treated septic mice showed significant improvements in several hematologic and biochemical indicators of MODS. Moreover, rhAng-1 stabilized endothelial barrier function, as evidenced by inhibition of protein leakage from lung capillaries into the alveolar compartment. Histological analysis revealed that rhAng-1 treatment attenuated leukocyte infiltration in lungs and kidneys of septic mice, probably due to reduced endothelial adhesion molecule expression in rhAng-1 treated mice. Finally, the protective effects of rhAng-1 treatment were reflected by an improved survival time in a lethal CLP model. In a clinically relevant murine sepsis model, intravenous rhAng-1 treatment alone is sufficient to significantly improve a variety of sepsis-associated organ dysfunctions and survival time, most likely by preserving endothelial barrier function. Further studies are needed to pave the road for clinical application of this therapy concept.
• 6.19

  Impact points

  Circulating angiopoietin-1 could be confounded by ex vivo platelet activation.

  Sascha David, Philipp Kümpers

  Kidney international. 03/2011; 79(6):687; author reply 687-8.
• 4.04

  Impact points

  Effects of a synthetic PEG-ylated Tie-2 agonist peptide on endotoxemic lung injury and mortality.

  Sascha David, Chandra C Ghosh, Philipp Kümpers, Nelli Shushakova, Paul Van Slyke, Eliyahu V Khankin, S Ananth Karumanchi, Dan Dumont, Samir M Parikh

  American journal of physiology. Lung cellular and molecular physiology. 03/2011; 300(6):L851-62.

  A synthetic 7-mer, HHHRHSF, was recently identified by screening a phage display library for binding to the Tie-2 receptor. A polyethylene-oxide clustered version of this peptide, termed vasculotide (VT), was reported to activate Tie-2 and promote angiogenesis in a mouse model of diabetic ulcer. We ... [more] A synthetic 7-mer, HHHRHSF, was recently identified by screening a phage display library for binding to the Tie-2 receptor. A polyethylene-oxide clustered version of this peptide, termed vasculotide (VT), was reported to activate Tie-2 and promote angiogenesis in a mouse model of diabetic ulcer. We hypothesized that VT administration would defend endothelial barrier function against sepsis-associated mediators of permeability, prevent lung vascular leakage arising in endotoxemia, and improve mortality in endotoxemic mice. In confluent human microvascular endothelial cells, VT prevented endotoxin-induced (lipopolysaccharides, LPS O111:B4) gap formation, loss of monolayer resistance, and translocation of labeled albumin. In 8-wk-old male C57Bl6/J mice given a ∼70% lethal dose of endotoxin (15 mg/kg ip), VT prevented lung vascular leakage and reversed the attenuation of lung vascular endothelial cadherin induced by endotoxemia. These protective effects of VT were associated with activation of Tie-2 and its downstream mediator, Akt. Echocardiographic studies showed only a nonsignificant trend toward improved myocardial performance associated with VT. Finally, we evaluated survival in this mouse model. Pretreatment with VT improved survival by 41.4% (n = 15/group, P = 0.02) and post-LPS administration of VT improved survival by 33.3% (n = 15/group, P = 0.051). VT-mediated protection from LPS lethality was lost in Tie-2 heterozygous mice, in agreement with VT's proposed receptor specificity. We conclude that this synthetic Tie-2 agonist, completely unrelated to endogenous Tie-2 ligands, is sufficient to activate the receptor and its downstream pathways in vivo and that the Tie-2 receptor may be an important target for therapeutic evaluation in conditions of pathological vascular leakage.
• 3.31

  Impact points

  TLR-4+ peripheral blood monocytes and cardiovascular events in patients with chronic kidney disease--a prospective follow-up study.

  Johan M Lorenzen, Sascha David, Alena Richter, Kirsten de Groot, Jan T Kielstein, Hermann Haller, Thomas Thum, Danilo Fliser

  Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 01/2011; 26(4):1421-4.

  Atherosclerosis is an inflammatory process mediated by circulating immune cells, including monocytes. There is accumulating evidence for the involvement of Toll-like receptor 4 (TLR-4) as a mediator of atherogenesis. We evaluated the association between CD14+/TLR-4+ monocytes in peripheral blood (fl... [more] Atherosclerosis is an inflammatory process mediated by circulating immune cells, including monocytes. There is accumulating evidence for the involvement of Toll-like receptor 4 (TLR-4) as a mediator of atherogenesis. We evaluated the association between CD14+/TLR-4+ monocytes in peripheral blood (flow cytometry) and future cardiovascular events (CVE), e.g. myocardial infarction, percutaneous transluminal coronary angioplasty (including stenting), aortocoronary bypass, stroke and angiographically verified stenosis of peripheral arteries and cardiovascular (CV) death, in 191 patients with chronic kidney disease Stage V receiving hemodialysis therapy. At baseline, CD14+/TLR-4+ monocytes correlated significantly with age (r = 0.2; P = 0.007), high-sensitivity C-reactive protein (r = 0.2; P = 0.008) and mean arterial pressure (r = -0.2; P = 0.02), but not with gender (P = 0.5), smoking (P = 0.6) and the presence of diabetes (P = 0.5). During a median follow-up period of 36 [1-54] months, 79 (41%) patients experienced a CVE. A total of 55 patients died during the follow-up period, 25 of those due to a confirmed CV cause. Log-rank test did not reveal statistical significance for TLR-4+ monocytes concerning incident CVE (P = 0.3), CV death (P = 0.85) and overall death (P = 0.8). In a multiple Cox-regression analysis, we identified age (P = 0.003) and smoking (P = 0.001) as the only independent variables associated with incident CVE. Unexpectedly, we could not detect an association between CD14+/TLR-4+ monocytes and incident CVE as well as CV death in stable hemodialysis patients. Further studies have to clarify the potential role of this cell population for CV outcome in this population.

• The angiopoietin/Tie-2 axis: a novel player in chronic kidney disease.

  S David, H Haller, P Kümpers

  Minerva urologica e nefrologica = The Italian journal of urology and nephrology. 09/2010; 62(3):319-26.

  The development of atherosclerosis in patients with chronic kidney disease (CKD) is severely accelerated leading to life-threatening cardiovascular (CV) events and its pathogenesis is different from that in the general population. Mainly the so-called uremic toxins are thought to count responsible f... [more] The development of atherosclerosis in patients with chronic kidney disease (CKD) is severely accelerated leading to life-threatening cardiovascular (CV) events and its pathogenesis is different from that in the general population. Mainly the so-called uremic toxins are thought to count responsible for this phenomenon. Recently, the angiopoietin/Tie2 system has been identified as a potential new player in the uremia-associated pathogenesis of atherosclerosis. This review provides an overview of molecular mechanisms of angiopoietin-1/-2 and Tie2 signaling in regard to the endothelial activation status in health and disease. The first part reviews the role of angiopoietins in experimental models of inflammation. Then, we summarize the most important clinical trials showing a severely altered angiopoietin balance in favor of Ang-2. Those trials contain data on patients with CKD stage 1-4, on dialysis (CKD stage 5), arterial hypertension, and diabetes mellitus. Future experiments to prove a direct mechanism by which angiopoietins accelerate and/or aggravate atherosclerotic burden in CKD patients are highly desirable. Very recently, a clinical trial (in oncology) proved safety of a selective angiopoietin inhibitor. Those latest drugs might represent a future treatment option against CKD-associated micro-inflammation.
• 9.80

  Impact points

  Circulating angiopoietins in idiopathic pulmonary arterial hypertension.

  Philipp Kümpers, Nils Nickel, Alexander Lukasz, Heiko Golpon, Volker Westerkamp, Karen M Olsson, Danny Jonigk, Lavinia Maegel, Clemens L Bockmeyer, Sascha David, Marius M Hoeper

  European heart journal. 09/2010; 31(18):2291-300.

  To determine the diagnostic utility of circulating angiopoietin-1 (Ang-1) and its antagonist angiopoietin-2 (Ang-2) as potential biomarkers of disease severity or response to treatment in idiopathic pulmonary arterial hypertension (IPAH). Imbalances in angiogenic factors including vascular endotheli... [more] To determine the diagnostic utility of circulating angiopoietin-1 (Ang-1) and its antagonist angiopoietin-2 (Ang-2) as potential biomarkers of disease severity or response to treatment in idiopathic pulmonary arterial hypertension (IPAH). Imbalances in angiogenic factors including vascular endothelial cell growth factor (VEGF) and the angiopoetin-Tie2 receptor system have been implicated in the pathogenesis of IPAH. Plasma Ang-1, Ang-2, soluble Tie2 (sTie2), and VEGF were determined by in-house immunoassays in two cohorts of IPAH patients: a retrospective cohort (n = 81) and a prospective cohort (n = 25). Ten patients with normal pulmonary artery pressures and 14 apparently healthy subjects served as controls. Plasma levels of all angiogenic factors were elevated in IPAH patients compared with controls (all P < 0.005). Angiopoietin-2, but not Ang-1, sTie2, and VEGF correlated with cardiac index (r = -0.53, P < 0.001), pulmonary vascular resistance (PVR) (r= 0.60, P < 0.001), and mixed venous oxygen saturation (SvO(2)) (r= -0.63, P < 0.001). In multivariate analysis, elevated Ang-2 was an independent risk factor of mortality (P = 0.004). The patients in the prospective cohort were studied longitudinally at baseline and 3 months after initiation of therapy. Changes in Ang-2 after initiation of therapy correlated with changes in mean right atrial pressure (r = 0.6, P = 0.008), PVR (r = 0.51, P = 0.04), and inversely related to changes in SvO(2) (r = -0.75, P < 0.001). Histological studies showed that the expression of Ang-2 mRNA and protein was up-regulated in plexiform lesions from IPAH lung tissue samples. Ang-2 may be involved in the pathogenesis of IPAH, and plasma Ang-2 might serve as a promising new biomarker of disease severity and response to treatment in patients with IPAH.
• 3.31

  Impact points

  Circulating angiopoietin-2 levels increase with progress of chronic kidney disease.

  Sascha David, Philipp Kümpers, Alexander Lukasz, Danilo Fliser, Jens Martens-Lobenhoffer, Stefanie M Bode-Böger, Volker Kliem, Hermann Haller, Jan T Kielstein

  Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 02/2010; 25(8):2571-6.

  Angiopoietin-2 (Ang-2) is an antagonistic ligand of the endothelial-specific Tie2 receptor. Patients on dialysis have markedly elevated Ang-2 levels, and those correlate with their atherosclerotic burden. The aim of the current study was to investigate the relationship between the circulating levels... [more] Angiopoietin-2 (Ang-2) is an antagonistic ligand of the endothelial-specific Tie2 receptor. Patients on dialysis have markedly elevated Ang-2 levels, and those correlate with their atherosclerotic burden. The aim of the current study was to investigate the relationship between the circulating levels of Ang-2 and renal function throughout all stages of chronic kidney disease (CKD). In addition, we aimed to detect a potential link between the nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) and the Ang-2 levels. Glomerular filtration rate (GFR) was assessed by the inulin clearance technique ((i)GFR) and compared to serum Ang-2 (immunoluminometric assay) and ADMA levels (liquid chromatography-electrospray tandem mass spectrometry) in 44 untreated non-smokers at the different stages of CKD 1-4. Ang-2 was also measured in 19 patients on dialysis (CKD stage 5). In addition, the Ang-2 and (c)GFR (cystatin C) measurements were taken in 15 healthy individuals before and 72 h after kidney donation. The median Ang-2 levels steadily increased across the following groups: healthy controls: 0.77 (0.32-1.08) ng/mL; CKD 1: 0.83 (0.67-1.09) ng/mL; CKD 2: 0.93 (0.74-1.15) ng/mL; CKD 3: 1.13 (0.87-1.49) ng/mL; CKD 4: 1.75 (1.23-2.61) ng/mL; and CKD 5: 4.87 (3.22-7.59) ng/mL, respectively (non-parametric ANOVA P < 0.0001). Ang-2 was associated with the degree of CKD as evidenced by an inverse correlation with the (i)GFR (r = -0.509, P < 0.0001) and positive correlations with homocysteine (r = 0.365, P = 0.015) and phosphate (r = 0.53, P < 0.0001). Additionally, Ang-2 correlated with the ADMA levels (r = 0.35, P = 0.01). We detected a close inverse correlation between the mean changes in GFR and circulating Ang-2 at 72 h after kidney donation (r = -0.54, P = 0.03). Circulating Ang-2, a putative marker and potential mediator of accelerated atherosclerosis, is inversely related to GFR and increases with advanced CKD. The correlation between Ang-2 and ADMA points towards the hypothesis that the ADMA-driven NO deficiency might trigger Ang-2 release and account for the Ang-2 increase in CKD patients.
• 4.93

  Impact points

  Does low angiopoietin-1 predict adverse outcome in sepsis?

  Sascha David, Matijs van Meurs, Philipp Kümpers

  Critical care (London, England). 01/2010; 14(4):180.

  Endothelial injury has emerged as a crucial early event in the pathogenesis of microcirculatory dysfunction, capillary leakage and multiorgan dysfunction syndrome. The endothelial-specific angiopoietin (Ang)/Tie2 ligand-receptor system has been identified recently as a nonredundant regulator of endo... [more] Endothelial injury has emerged as a crucial early event in the pathogenesis of microcirculatory dysfunction, capillary leakage and multiorgan dysfunction syndrome. The endothelial-specific angiopoietin (Ang)/Tie2 ligand-receptor system has been identified recently as a nonredundant regulator of endothelial responsiveness. Ang-1 is a Tie2 agonist and promotes endothelial stabilization and quiescence, whereas Ang-2 is a Tie2 antagonist and promotes endothelial activation, destabilization, and inflammation. While the mediator function of both Ang-1 and Ang-2 has been well established in preclinical research, only Ang-2 has been identified as a clinically useful biomarker in the critical care arena. In the previous issue of Critical Care, Mankhambo and colleagues report on angiogenic factors in Malawian children with severe bacterial infection. Among those children, diminished levels of the vessel-protective factor Ang-1 remained a significant predictor of outcome after multivariate adjustment. Whether low Ang-1 represents an important risk factor of adverse outcome in critically ill adults remains to be seen.

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• 4.41

  Impact points

  Endothelial progenitor cells and cardiovascular events in patients with chronic kidney disease--a prospective follow-up study.

  Johan Lorenzen, Sascha David, Ferdinand H Bahlmann, Kirsten de Groot, Elisabeth Bahlmann, Jan T Kielstein, Hermann Haller, Danilo Fliser

  PloS one. 01/2010; 5(7):e11477.

  Endothelial progenitor cells (EPCs) mediate vascular repair and regeneration. Their number in peripheral blood is related to cardiovascular events in individuals with normal renal function. We evaluated the association between functionally active EPCs (cell culture) and traditional cardiovascular ri... [more] Endothelial progenitor cells (EPCs) mediate vascular repair and regeneration. Their number in peripheral blood is related to cardiovascular events in individuals with normal renal function. We evaluated the association between functionally active EPCs (cell culture) and traditional cardiovascular risk factors in 265 patients with chronic kidney disease stage V receiving hemodialysis therapy. Thereafter, we prospectively assessed cardiovascular events, e.g. myocardial infarction, percutaneous transluminal coronary angioplasty (including stenting), aorto-coronary bypass, stroke and angiographically verified stenosis of peripheral arteries, and cardiovascular death in this cohort. In our patients EPCs were related only to age (r=0.154; p=0.01). During a median follow-up period of 36 months 109 (41%) patients experienced a cardiovascular event. In a multiple Cox regression analysis, we identified EPCs (p=0.03) and patient age (p=0.01) as the only independent variables associated with incident cardiovascular events. Moreover, a total of 70 patients died during follow-up, 45 of those due to cardiovascular causes. Log rank test confirmed statistical significance for EPCs concerning incident cardiovascular events (p=0.02). We found a significant association between the number of functionally active EPCs and cardiovascular events in patients with chronic kidney disease. Thus, defective vascular repair and regeneration may be responsible, at least in part, for the enormous cardiovascular morbidity in this population.

• Angiopoietin-2 in der Intensivmedizin

  P. Kümpers, S. David

  Intensivmedizin und Notfallmedizin. 12/2009;

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• 5.17

  Impact points

  Angiopoietin-2 in patients requiring renal replacement therapy in the ICU: relation to acute kidney injury, multiple organ dysfunction syndrome and outcome.

  Philipp Kümpers, Carsten Hafer, Sascha David, Hartmut Hecker, Alexander Lukasz, Danilo Fliser, Hermann Haller, Jan Kielstein, Robert Faulhaber-Walter

  Intensive care medicine. 12/2009;

  PURPOSE: Endothelial activation has emerged as an early event in the pathogenesis of microcirculatory dysfunction, capillary leakage and multi-organ dysfunction syndrome (MODS). Angiopoietin-2 (Ang-2), a circulating antagonistic ligand of the endothelial-specific Tie2 receptor, has been identified a... [more] PURPOSE: Endothelial activation has emerged as an early event in the pathogenesis of microcirculatory dysfunction, capillary leakage and multi-organ dysfunction syndrome (MODS). Angiopoietin-2 (Ang-2), a circulating antagonistic ligand of the endothelial-specific Tie2 receptor, has been identified as a non-redundant gatekeeper of endothelial activation. On the basis of our previous report demonstrating release of Ang-2 in endotoxemia and sepsis, we aimed to study the utility of Ang-2 to serve as an outcome-specific biomarker in patients requiring renal replacement therapy (RRT) in the intensive care unit (ICU). METHODS: We measured circulating Ang-2 by ELISA in 117 critically ill patients with AKI at inception of RRT in the ICU. Mortality, length of stay and renal recovery were prospectively assessed during a study period of 28 days after the inception of RRT. RESULTS: Circulating Ang-2 levels were significantly higher in AKI patients with RIFLE category-Injury or -Failure, compared to patients with RIFLE category-Risk. Elevated levels of circulating Ang-2 correlated with impaired oxygenation, low mean arterial pressure, vasopressor dose and the sequential organ failure assessment (SOFA) score. Ang-2 concentrations were significantly higher in non-survivors than in survivors at day 0 and day 14 after initiation of RRT. Multivariate Cox regression and decision tree analyses confirmed a strong independent prognostic impact of elevated Ang-2 as a predictor of 28-day survival. CONCLUSIONS: The results from this study indicate that circulating Ang-2 is as a strong and independent predictor of mortality in ICU patients with dialysis-dependent AKI.
• 4.42

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  Epac-1 activator 8-O-cAMP augments renoprotective effects of allogeneic murine EPCs in acute ischemic kidney injury.

  Daniel Patschan, Susann Andrea Patschan, Johannes T Wessels, Jan Ulrich Becker, Sascha David, Elvira Henze, Michael S Goligorsky, Gerhard A Müller

  American journal of physiology. Renal physiology. 11/2009;

  Endothelial progenitor cells (EPCs) protect kidneys from acute ischemic damage. Aim of this study was to identify treatment parameters which optimize an EPC-based therapy of acute ischemic renal failure. Male C57BL/6N mice underwent uni-lateral nephrectomy with simultaneous contralateral renal arter... [more] Endothelial progenitor cells (EPCs) protect kidneys from acute ischemic damage. Aim of this study was to identify treatment parameters which optimize an EPC-based therapy of acute ischemic renal failure. Male C57BL/6N mice underwent uni-lateral nephrectomy with simultaneous contralateral renal artery clamping for 30, 35, and 40 minutes. Tagged murine EPCs were systemically injected at the time of reperfusion. In some experiments, EPCs were pretreated with the integrin activator 8-pCPT-2'-O-Me-cAMP (Epac-1 Ac) and the integrin binding antagonist cyclic Arg-Gly-Asp peptide (cRGD). Injections of 10(6) EPCs after 30 and 35 minutes of renal ischemia protected animals from acute renal failure. The same effect occured with 0.5x10(6) EPCs after a 35 minutes period of ischemia. If ischemia lasted for 40 minu-tes, 0.5x10(6) cells mice did not prevent acute renal failure. To analyze whether EPC integrin receptor activation would modify the cells renoprotective activity, EPCs were pretreated with Epac-1 Ac. Such animals did not develop acute renal failure, even if ischemia lasted for 40 minutes. This effect was negated if the cells were pre-treated with both Epac-1 Ac and cRGD. In kidneys from those animals medullo-papillary EPCs were significantly accumulated. In vitro Epac-1 Ac preactivation of EPCs did not increase the overall expression intensity but induced a redistribution of beta1 integrins towards the cell membranes. We conclude that EPC pretreatment with the integrin receptor activator 8-pCPT-2'-O-Me-cAMP augments the antiischemic potential of the cells. Key words: acute renal failure, stem cells, endothelial progenitor cells.
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  A bitter pill to swallow.

  S David, S Merscher, H Schmidt-Guertler, J T Kielstein, T Kirchhoff, M Meier

  Clinical nephrology. 10/2009; 72(4):319-21.

  Foreign body aspiration can be a life-threatening emergency requiring immediate intervention. However, unlike in children, clinical presentation of foreign bodies in adults often varies with regard to symptoms and signs and occurs without asphyxia. We here describe the case of a 65-year-old man on m... [more] Foreign body aspiration can be a life-threatening emergency requiring immediate intervention. However, unlike in children, clinical presentation of foreign bodies in adults often varies with regard to symptoms and signs and occurs without asphyxia. We here describe the case of a 65-year-old man on maintenance hemodialysis who developed dyspnea and left chest aspiration pneumonia after swallowing one tablet of the phosphate binder sevelamer. This case illustrates that elderly patients with swallowing complaints should be taken serious when they complain about their subsequent frustration of ingestion of their pills.
• 4.29

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  Angiotensin II receptor blocker and statins lower elevated levels of osteopontin in essential hypertension-Results from the EUTOPIA trial.

  Johan M Lorenzen, Henrike Neunhöffer, Sascha David, Jan T Kielstein, Hermann Haller, Danilo Fliser

  Atherosclerosis. 09/2009;

  BACKGROUND: Osteopontin is a pleiotropic cytokine that has been implicated as a key factor in the development of atherosclerosis, a major complication of hypertension. We have earlier shown that olmesartan reduces mediators of vascular inflammation in patients with hypertension and cardiovascular di... [more] BACKGROUND: Osteopontin is a pleiotropic cytokine that has been implicated as a key factor in the development of atherosclerosis, a major complication of hypertension. We have earlier shown that olmesartan reduces mediators of vascular inflammation in patients with hypertension and cardiovascular disease. We aimed at studying the effect of olmesartan and/or pravastatin on osteopontin plasma levels, and the association between vascular inflammation markers and osteopontin in hypertensive patients. METHODS: We assessed a panel of vascular inflammation markers and osteopontin during 12 weeks of therapy with 20mg olmesartan (n=94) or placebo (n=96) in a prospective, double-blind, multi-center study in patients with essential hypertension (re-evaluation of the EUTOPIA trial blood samples). Pravastatin (20mg) was added to the double-blind therapy at week 6 in both arms. The association of demographic variables and inflammation markers with osteopontin has been analyzed as well. RESULTS: Baseline osteopontin plasma concentrations in the study population were elevated compared to healthy controls (32.85+/-19.04ng/mL vs. 23.82+/-3.69ng/mL, p=0.027). Mono-therapy with olmesartan and co-therapy with pravastatin reduced levels of circulating osteopontin (p<0.001). The addition of pravastatin to the placebo treatment-arm resulted in a reduction of osteopontin levels as well (p<0.01). osteopontin plasma levels correlated with VCAM-1 (r=0.27; p=0.0002), ICAM-1 (r=0.18; p=0.015), IL-6 (r=0.35; p<0.0001) and hsCRP (r=0.22; p=0.0022). CONCLUSION: We show, for the first time, that olmesartan significantly decreases osteopontin concentrations. Co-therapy with pravastatin also reduces osteopontin levels. Elevated osteopontin levels in hypertensive patients correlate with adhesion molecules and inflammation markers.
• 4.21

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  Mesenteric Lymph Nodes Confine DC-Mediated Dissemination of Salmonella and Limit Systemic Disease in Mice.

  Sabrina Voedisch, Christian Koenecke, Sascha David, Heike Herbrand, Reinhold Förster, Mikael Rhen, Oliver Pabst

  Infection and immunity. 07/2009;

  In human typhoid fever or in mouse strains susceptible to Salmonella Typhimurium infection, bacteria gain access to extraintestinal tissues causing severe systemic disease. Here we show that in the gut draining mesenteric lymph nodes (MLN) the majority of Salmonella carrying cells show DC morphology... [more] In human typhoid fever or in mouse strains susceptible to Salmonella Typhimurium infection, bacteria gain access to extraintestinal tissues causing severe systemic disease. Here we show that in the gut draining mesenteric lymph nodes (MLN) the majority of Salmonella carrying cells show DC morphology and express the DC marker CD11c, indicating that Salmonella are transported to the MLN by migratory dendritic cells (DC). In vivo FLT-3L induced expansion of DC as well as stimulation of DC migration by Toll-like receptor agonists result in increased numbers of Salmonella reaching the MLN. Conversely, genetically impaired DC migration in chemokine receptor CCR7-deficient mice reduces the number of Salmonella reaching the MLN. This indicates that transport of Salmonella from the intestine into the MLN is limited by the number of migratory DC carrying Salmonella. In contrast, modulation of DC migration does not affect the number of Salmonella reaching systemic tissues, indicating that DC-bound transport of Salmonella does not substantially contribute to systemic Salmonella infection. Surgical removal of the MLN results in increased numbers of Salmonella reaching systemic sites early after infection, thereby rendering otherwise resistant mice susceptible to fatal systemic disease development. This suggests that the MLN provide a vital barrier, shielding systemic compartments from DC-mediated dissemination of Salmonella. Thus confinement of Salmonella in gut associated lymphoid tissue and MLN delays massive extra-intestinal dissemination and at the same time allows for the establishment of protective adaptive immune responses.