Hermann Haller

Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document.

Abbreviations ACE: angiotensin-converting enzyme; BP: blood pressure; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; ESC: European Society of Cardiology; ESH: European Society of Hypertension; ET: endothelin; IMT: carotid intima-media thickness; JNC: Joint National Commit

Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document

Reappraisal of European guid elines on hypertension management: a European Society of Hypertension Task Force document Giuseppe Mancia, Stephane Laurent, Enrico Agabiti-Rosei, Ettore Ambrosioni, Michel Burnier, Mark J. Caulfield, Renata Cifkova, Denis Clement, Antonio Coca, Anna Dominiczak, Serap Erdine, Robert Fagard, Csaba Farsang, Guido Grassi, Hermann Haller, Anthony Heagerty, Sverre E. Kjeldsen, Wolfgang Kiowski, Jean Michel Mallion, Athanasios Manolis, Krzysztof Narkiewicz, Peter Nilsson, Michael H. Olsen, Karl Heinz Rahn, Josep Redon, Jose Rodicio, Luis Ruilope, Roland E. Schmieder, Harry A.J. Struijker-Boudier, Pieter A. van Zwieten, Margus Viigimaa and Alberto Zanchetti

The Hannover Dialysis Outcome study: comparison of standard versus intensified extended dialysis for treatment of patients with acute kidney injury in the intensive care unit

BACKGROUNDnIncreasing the dose of renal replacement therapy has been shown to improve survival in critically ill patients with acute kidney injury (AKI) in several smaller European trials. However, a very recent large multicentre trial in the USA could not detect an effect of dose of renal replacement therapy on mortality. Based on those studies, it is not known whether a further increase in dialysis dose above and beyond the currently employed doses would improve survival in patients with AKI. We therefore aimed to assess mortality and renal recovery of patients with AKI receiving either standard (SED) or intensified extended dialysis (IED) therapy in the intensive care unit.nnnMETHODSnA prospective randomized parallel group study was conducted in seven intensive care units of a tertiary university hospital. Pre-existing chronic kidney disease was an exclusion criterion. A total of 156 patients (570 screened) with AKI requiring renal replacement therapy were randomly assigned to receive standard dialysis [dosed to maintain plasma urea levels between 120 and 150 mg/dL (20-25 mmol/L)] or intensified dialysis [dosed to maintain plasma urea levels <90 mg/dL (<15 mmol/L)]. Outcome measures were survival at Day 14 (primary) and survival and renal recovery at Day 28 (secondary) after initiation of renal replacement therapy.nnnRESULTSnTreatment intensity differed significantly (P < 0.01 for plasma urea and administered dose). No differences between intensified and standard treatment were seen for survival by Day 14 (70.4% versus 70.7%) or Day 28 (55.6% versus 61.3%), or for renal recovery amongst the survivors by Day 28 (60.0% versus 63.0%).nnnCONCLUSIONSnAlthough this study cannot deliver a definitive answer, it suggests that increasing the dose of extended dialysis above the currently recommended dose might neither reduce mortality nor improve renal recovery in critically ill patients, mainly septic patients, with AKI.

Time course of angiopoietin-2 release during experimental human endotoxemia and sepsis

IntroductionEndothelial activation leading to vascular barrier breakdown denotes a devastating event in sepsis. Angiopoietin (Ang)-2, a circulating antagonistic ligand of the endothelial specific Tie2 receptor, is rapidly released from Weibel-Palade and has been identified as a non-redundant gatekeeper of endothelial activation. We aimed to study: the time course of Ang-2 release during human experimental endotoxemia; the association of Ang-2 with soluble adhesion molecules and inflammatory cytokines; and the early time course of Ang-2 release during sepsis in critically ill patients.MethodsIn 22 healthy volunteers during a 24-hour period after a single intravenous injection of lipopolysaccharide (LPS; 4 ng/kg) the following measurement were taken by immuno luminometric assay (ILMA), ELISA, and bead-based multiplex technology: circulating Ang-1, Ang-2, soluble Tie2 receptor, the inflammatory molecules TNF-alpha, IL-6, IL-8 and C-reactive protein, and the soluble endothelial adhesion molecules inter-cellular adhesion molecule-1 (ICAM-1), E-selectin, and P-selectin. A single oral dose of placebo or the p38 mitogen activated protein (MAP) kinase inhibitor drug, RWJ-67657, was administered 30 minutes before the endotoxin infusion. In addition, the course of circulating Ang-2 was analyzed in 21 septic patients at intensive care unit (ICU) admission and after 24 and 72 hours, respectively.ResultsDuring endotoxemia, circulating Ang-2 levels were significantly elevated, reaching peak levels 4.5 hours after LPS infusion. Ang-2 exhibited a kinetic profile similar to early pro-inflammatory cytokines TNF-alpha, IL-6, and IL-8. Ang-2 levels peaked prior to soluble endothelial-specific adhesion molecules. Finally, Ang-2 correlated with TNF-alpha levels (r = 0.61, P = 0.003), soluble E-selectin levels (r = 0.64, P < 0.002), and the heart rate/mean arterial pressure index (r = 0.75, P < 0.0001). In septic patients, Ang-2 increased in non-survivors only, and was significantly higher compared with survivors at baseline, 24 hours, and 72 hours.ConclusionsLPS is a triggering factor for Ang-2 release in men. Circulating Ang-2 appears in the systemic circulation during experimental human endotoxemia in a distinctive temporal sequence and correlates with TNF-alpha and E-selectin levels. In addition, not only higher baseline Ang-2 concentrations, but also a persistent increase in Ang-2 during the early course identifies septic patients with unfavorable outcome.

B-cell-attracting chemokine CXCL13 as a marker of disease activity and renal involvement in systemic lupus erythematosus (SLE)

OBJECTIVESnThe chemokine CXCL13, also known as BCA-1 (B-cell-attracting chemokine-1) or BLC (B-lymphocyte chemoattractant), is a major regulator of B-cell trafficking. We have recently shown that excessive expression of dendritic cell-derived CXCL13 is a distinctive early event for nephritis in a murine model of systemic lupus erythematosus (SLE). Furthermore, in kidney biopsies from SLE patients, CXCL13 protein and mRNA are strongly expressed in B-cell-containing inflammatory lesions. Here, we ask whether serum levels of CXCL13 correlate with disease activity and renal involvement in SLE patients.nnnMETHODSnCXCL13 was measured in sera obtained from 91 patients with SLE and 40 healthy controls by ELISA methodology. Disease activity was calculated according to the SLE Disease Activity Index (SLEDAI).nnnRESULTSnMedian (IQR) serum CXCL13 concentrations were increasingly higher across the following groups: healthy controls [31.6 (26.8-41.3) pg/ml], SLE patients with inactive disease (SLEDAI <6) [68.2 (27.8-133.0) pg/ml, P = 0.0006 versus controls] and active disease [196.0 (75.9-416.8) pg/ml, P = 0.0001 versus controls] (inactive versus active P < 0.0001). Concentrations of circulating CXCL13 correlated with SLEDAI (r = 0.56, P < 0.0001) and double-stranded DNA titres (r = 0.36, P < 0.0005). Moreover, median CXCL13 concentrations were higher in patients with renal involvement [175.5 (105.3-422.6) pg/ml] compared to those without renal involvement [82.1 (42.9-219.8) pg/ml].nnnCONCLUSIONSnOur data indicate that increased level of CXCL13 is a feature of SLE that correlates with disease activity. Furthermore, CXCL13 might be a readily available surrogate marker to monitor the extent of aberrant B-cell (dys-)function.

The balance of autocrine VEGF-A and VEGF-C determines podocyte survival

Podocytes are an important component of the glomerular filtration barrier and are the major source of vascular endothelial growth factor (VEGF) in the glomerulus. The role of VEGF for the phenotype of the glomerular endothelium has been intensely studied; however, the direct effects of autocrine VEGF on the podocyte are largely unknown. In this study we characterized the expression of VEGF isoforms and VEGF receptors in cultured human podocytes and examined direct effects on cell signaling and apoptosis after stimulation with exogenous VEGF or ablation of autocrine VEGF. We identified VEGF-A and VEGF-C as the dominant isoforms in human podocytes and showed that autocrine levels of both are important for the intracellular activation of antiapoptotic phosphoinositol 3-kinase/AKT and suppression of the proapoptotic p38MAPK via VEGFR-2. We demonstrated that ablation of VEGF-A or VEGF-C as well as treatment with bevacizumab or a VEGFR-2/-3 tyrosine kinase inhibitor led to reduced podocyte survival. In contrast, ablation of VEGF-B had no effect on podocyte survival. Treatment with exogenous VEGF-C reversed the effect of VEGF-A neutralization, and exogenous VEGF-A abrogated the effect of VEGF-C ablation in human podocytes. Our results underline the importance of autocrine VEGF for podocyte survival and indicate the delicate balance of VEGF-A and VEGF-C to influence progression of glomerular diseases.

Determinants of urinary albumin excretion within the normal range in patients with type 2 diabetes: the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study

Aims/hypothesisIn contrast to microalbuminuric type 2 diabetic patients, the factors correlated with urinary albumin excretion are less well known in normoalbuminuric patients. This may be important because even within the normoalbuminuric range, higher rates of albuminuria are known to be associated with higher renal and cardiovascular risk.MethodsAt the time of screening for the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) Study, the urinary albumin/creatinine ratio (UACR) was 0.44xa0mg/mmol in 4,449 type 2 diabetic patients. The independent correlates of UACR were analysed.ResultsIndependent correlates of UACR during baseline were (in descending order): night-time systolic BP (rsu2009=u20090.19); HbA1c (rsu2009=u20090.18); mean 24xa0h systolic BP (rsu2009=u20090.16); fasting blood glucose (rsu2009=u20090.16); night-time diastolic BP (rsu2009=u20090.12); office systolic BP, sitting (rsu2009=u20090.11), standing (rsu2009=u20090.10); estimated GFR (rsu2009=u20090.10); heart rate, sitting (rsu2009=u20090.10); haemoglobin (rsu2009=u2009−0.10); triacylglycerol (rsu2009=u20090.09); and uric acid (rsu2009=u2009−0.08; all pu2009≤u20090.001). Significantly higher albumin excretion rates were found for the following categorical variables: higher waist circumference (more marked in men); presence of the metabolic syndrome; smoking (difference more marked in males); female sex; antihypertensive treatment; use of amlodipine; insulin treatment; family history of diabetes; and family history of cardiovascular disease (more marked in women).Conclusions/interpretationAlthough observational correlations do not prove causality, in normoalbuminuric type 2 diabetic patients the albumin excretion rate is correlated with many factors that are potentially susceptible to intervention.Trial registration:ClinicalTrials.gov ID no.: NCT00185159Funding:This study was sponsored by Daichii-Sankyo.

Angiopoietin 2 and Cardiovascular Disease in Dialysis and Kidney Transplantation

BACKGROUNDnAccelerated atherosclerosis in patients with chronic kidney disease (CKD) is still incompletely understood. Angiopoietin 1 (Ang-1) and Ang-2 are 55-kDa antagonistic nonredundant gatekeepers of endothelial activation and thus are potential important factors in accelerated atherosclerosis. We aimed to study: (1) angiopoietin levels in patients treated by means of dialysis and kidney transplantation, (2) the association of altered angiopoietin levels with atherosclerosis, and (3) changes in altered levels after renal transplantation.nnnSTUDY DESIGNnCross-sectional and longitudinal observational study.nnnSETTING & PARTICIPANTSn117 patients with CKD (61 hemodialysis [HD] patients, 24 peritoneal dialysis [PD] patients, and 32 renal transplant recipients) and 22 healthy controls.nnnPREDICTORnTreatment by means of HD or PD or renal transplantation versus healthy controls.nnnOUTCOMEnSerum Ang-1 and Ang-2 levels and ratio and changes in levels before and 3 months after transplantation. Correlations of angiopoietin levels with the presence and severity of coronary heart disease and peripheral arterial disease.nnnMEASUREMENTSnAng-1 and Ang-2 were measured in sera by using an immunoradiometric sandwich assay and enzyme-linked immunosorbent assay, respectively. Coronary heart disease was scored by using coronary angiography, and peripheral arterial disease, by using ultrasonography.nnnRESULTSnAng-1 level was decreased in HD patients compared with controls (29.1 +/- 12 versus 45.3 +/- 11.5 ng/mL; P < 0.001). In contrast, Ang-2 level was increased (HD, 8.7 +/- 0.64; PD, 6.48 +/- 8.1 ng/mL versus controls, 0.88 +/- 0.43 ng/mL; P < 0.001). Ang levels in renal transplant recipients were not different from healthy controls. Longitudinally, individual Ang-2 levels decreased after kidney transplantation (P = 0.01). In addition, in patients with CKD, Ang-2 level correlated significantly with scores of coronary heart disease (r = 0.486; P < 0.001) and peripheral arterial disease (r = 0.648; P < 0.001).nnnLIMITATIONSnCross-sectional study design.nnnCONCLUSIONSnCirculating Ang-2 level was increased in patients treated with dialysis, although the mechanism is unknown. Kidney transplantation normalized circulating Ang-2 levels after 3 months. In addition, Ang-2 might be a mediator (and thus a marker) that accounts for accelerated atherosclerosis in dialysis patients.

Prospective evaluation of an in-centre conversion from conventional haemodialysis to an intensified nocturnal strategy

INTRODUCTIONnUnder physiological conditions kidneys work continuously, 168 h/week. In contrast, patients with end-stage renal disease are usually dialyzed only 12-15 h/ week. This unphysiological dialysis dose, even if considered adequate by current Kt/V-based dose estimates, is just capable to maintain the alterations of multiple metabolic parameters at a level that permits an unacceptable annual mortality rate of 10-20%, mainly due to cardiovascular events, protein energy wasting and infections.nnnPATIENTS AND METHODSnThirteen haemodialysis patients were converted from conventional (3 x 4 h/week) to an intensified nocturnal (3 x 8 h/week) dialysis and were longitudinally followed up for 12 months. Different parameters were evaluated before treatment conversion and quarterly during the follow-up period [i.e. dialysis efficacy (eKt/V), mean arterial pressure (MAP), antihypertensive drug score, extra-cellular volume (ECV), haemoglobin, transferrin saturation, ferritin, dose of erythropoiesis-stimulating agents (ESA), iron requirement, parameters of nutrition (body weight (BW), albumin, protein, normalized protein catabolic rate (nPCR), bioelectrical impedance analysis (BIA)), C-reactive protein, calcium-phosphate product, alkaline phosphatase (AP), intact parathyroid hormone (iPTH) and amount of phosphate-binding pharmacotherapy].nnnRESULTSnThe calculated dialysis efficacy rose after switching the treatment mode (eKt/V 1.87 versus 2.7, P < 0.0001). Further, a significantly decreased MAP in the pre- (100 versus 89 mmHg) and postdialytic period (97 versus 83 mmHg), and a decreased ECV (13.8 versus 13.2 L; P = 0.03) even though antihypertensive pharmacotherapy could be substantially reduced (P < 0.0001), was found. Concomitant with a reduction of ESA (66.5 versus 45.2 IU/ kg/week; P = 0.006), the haemoglobin level rose significantly (11.4 versus 12.5 g/dL, P = 0.01). Nutritional status assessed by BW (70.9 +/- 20.2 versus 72.1 +/- 19.8 kg, P = 0.02), nPCR (1.39 versus 2.25 g/kg/day, P = 0.02) and BIA (phase angle: 6.2 versus 6.9 degrees, P < 0.001) improved. The calcium-phosphate product slightly declined, without changes in the dose of any phosphate binders. Surprisingly, iPTH of those patients with intact parathyroid glands (n = 7) increased approximately 3-fold (27.9 versus 59.35 pmol/L, P = 0.009), while the AP was found stable.nnnCONCLUSIONnThis study demonstrates improvements in numerous dialysis-associated metabolic variables after intensification of HD time. Of note, an increase of iPTH was detected in those patients with intact parathyroid glands.

Circulating angiopoietin-2 in essential hypertension: relation to atherosclerosis, vascular inflammation, and treatment with olmesartan/pravastatin.

Background Endothelial activation has emerged as an early event in the pathogenesis of cardiovascular disease. Angiopoietin-2 (Ang-2) has been identified as a nonredundant endothelial-specific facilitator of vascular responsiveness to inflammatory stimuli. We have earlier shown that angiotensin II receptor blocker (ARB) reduces mediators of vascular inflammation in hypertension and cardiovascular disease. We aimed at studying the effect of ARB and/or 3-hydroxy-3-methyl-glutaryl-CoA blockade on Ang-2 and the association between vascular inflammation markers and Ang-2 levels in hypertensive patients. Methods We assessed a panel of vascular inflammation markers and Ang-2 during 12 weeks of therapy with the ARB olmesartan (n = 94) or placebo (n = 96) in a prospective, double-blind, multicenter study in patients with essential hypertension (re-evaluation of the European Trial on Olmesartan and Pravastatin in Inflammation blood samples). Pravastatin was added to the double-blind therapy at week 6 in both arms. The association of demographic variables and inflammation markers with Ang-2 has been investigated. Results Initial Ang-2 concentrations in the study population were elevated compared with healthy controls (4.23 ± 3.1 versus 0.88 ± 0.43 ng/ml; P < 0.0001). Ang-2 was higher in the elderly (P = 0.01), women (P < 0.001), and in the presence of atherosclerosis (P = 0.02). Ang-2 correlated significantly with soluble TEK tyrosine kinase-2, interleukin-6, vascular cell adhesion molecule-1, and inter-cellular adhesion molecule-1. Surprisingly, neither monotherapy with olmesartan or pravastatin nor the combination therapy affected Ang-2 concentrations. Conclusion Ang-2 concentrations are elevated in hypertensive patients, particularly those with atherosclerosis, possibly reflecting pronounced endothelial activation. ARBs effectively decreased several inflammatory mediators, but did not affect vascular responsiveness in an Ang-2-dependent manner. Elevated Ang-2 levels in hypertensive patients correlate with adhesion molecules.