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Abstract Renal denervation (RDN) is one of the most frequently used invasive methods for the treatment of arterial hypertension. However, recent randomized sham-controlled studies raised concern about the efficacy and predictability of response. We retrospectively analyzed outcomes of patients, who underwent RDN in our hypertension center between November 2010 and April 2014 and report here outcomes twelve months after procedure based on 24-hours ambulatory blood pressure monitoring. We defined ten-mm Hg decrease in office systolic blood pressure (SBP) as a cut-off for response and looked for possible predictors of this response using binary multiple regression analysis. 42 patients were included. Their mean age was 59.6 ± 9.2 years and 24% were female. Baseline office SBP and diastolic blood pressure (DBP) were 164.1 ± 20.3 and 91.8 ± 12.4 mm Hg respectively. Mean 24 h-SBP significantly decreased from 149.8 ± 13.3 mm Hg to 141.2 ± 14.6 mm Hg. Mean 24 h-DBP significantly decreased from 83.3 ± 11.7 mm Hg to 78.8 ± 11.2 mm Hg. A higher level of mean 24 h-DBP and office DBP was shown to be predictive for response in office BP and a higher level of mean 24 h-DBP for response in 24 h-SBP and 24 h-DBP. Further properly designed randomized trials are warranted to confirm this finding as well as further investigate the role of diabetes mellitus and arterial stiffness in RDN.

Background/Aims: To date, there is no imaging technique to assess tubular function in vivo. Blood oxygen level-dependent magnetic resonance imaging (BOLD MRI) measures tissue oxygenation based on the transverse relaxation rate (R2*). The present study investigates whether BOLD MRI can assess tubular function using a tubule-specific pharmacological maneuver. Methods: Cross sectional study with 28 participants including 9 subjects with ATN-induced acute kidney injury (AKI), 9 healthy controls, and 10 subjects with nephron sparing tumor resection (NSS) with clamping of the renal artery serving as a model of ischemia/reperfusion (I/R)-induced subclinical ATN (median clamping time 15 min, no significant decrease of eGFR, p=0.14). BOLD MRI was performed before and 5, 7, and 10 min after intravenous administration of 40 mg furosemide. Results: Urinary neutrophil gelatinase-associated lipocalin was significantly higher in ATN-induced AKI and NSS subjects than in healthy controls (p=0.03 and p=0.01, respectively). Before administration of furosemide, absolute medullary R2*, cortical R2*, and medullary/cortical R2* ratio did not significantly differ between ATN-induced AKI vs. healthy controls and between NSS-I/R vs. contralateral healthy kidneys (p>0.05 each). Furosemide led to a significant decrease in the medullary and cortical R2* of healthy subjects and NSS contralateral kidneys (p0.05 each). Conclusion: BOLD-MRI is able to detect even mild tubular injury but necessitates a tubule-specific pharmacological maneuver, e.g. blocking the Na+-K+-2Cl- transporter by furosemide.

ObjectiveCurrent methods do not predict the acute renal allograft injury immediately after kidney transplantation. We evaluated the diagnostic performance of urinary calprotectin for predicting immediate posttransplant allograft injury.MethodsIn a multicenter, prospective-cohort study of 144 incipient renal transplant recipients, we postoperatively measured urinary calprotectin using an enzyme-linked immunosorbent assay and estimated glomerular filtration rate (eGFR) after 4 weeks, 6 months, and 12 months.ResultsWe observed a significant inverse association of urinary calprotectin concentrations and eGFR 4 weeks after transplantation (Spearman r = -0.33; PConclusionsUrinary calprotectin is an early, noninvasive predictor of immediate renal allograft injury after kidney transplantation.

Vascular mineralization contributes to the high cardiovascular morbidity and mortality in patients who suffer from chronic kidney disease and in individuals who have undergone solid organ transplantation. The immunosuppressive regimen used to treat these patients appears to have an impact on vascular alterations. The effect of 6-mercaptopurine (6-MP) on vascular calcification has not yet been determined. This study investigates the effect of 6-MP on vascular mineralization by the induction of trans-differentiation of rat vascular smooth muscle cells in vitro. 6-MP not only induces the expression of osteo-chondrocyte-like transcription factors and proteins but also activates alkaline phosphatase enzyme activity and produces calcium deposition in in vitro and ex vivo models. These processes are dependent on 6-MP-induced production of reactive oxygen species, intracellular activation of mitogen-activated kinases and phosphorylation of the transcription factor Cbfa1. Furthermore, the metabolic products of 6-MP, 6-thioguanine nucleotides and 6-methyl-thio-inosine monophosphate have major impacts on cellular calcification. These data provide evidence for a possible harmful effect of the immunosuppressive drug 6-MP in vascular diseases, such as arteriosclerosis.

The secretion of angiogenic factors by vascular endothelial cells is one of the key mechanisms of angiogenesis. Here we report on the isolation of a new potent angiogenic factor, diuridine tetraphosphate (Up4U) from the secretome of human endothelial cells. The angiogenic effect of the endothelial secretome was partially reduced after incubation with alkaline phosphatase and abolished in the presence of suramin. In one fraction, purified to homogeneity by reversed phase and affinity chromatography, Up4U was identified by MALDI-LIFT-fragment-mass-spectrometry, enzymatic cleavage analysis and retention-time comparison. Beside a strong angiogenic effect on the yolk sac membrane and the developing rat embryo itself, Up4U increased the proliferation rate of endothelial cells and, in the presence of PDGF, of vascular smooth muscle cells. Up4U stimulated the migration rate of endothelial cells via P2Y2-receptors, increased the ability of endothelial cells to form capillary-like tubes and acts as a potent inducer of sprouting angiogenesis originating from gel-embedded EC spheroids. Endothelial cells released Up4U after stimulation with shear stress. Mean total plasma Up4U concentrations of healthy subjects (N=6) were sufficient to induce angiogenic and proliferative effects (1.34 ± 0.26 nmol L(-1)). In conclusion, Up4U is a novel strong human endothelium-derived angiogenic factor.

Metabolic stimuli, pressure, and fluid shear stress (FSS) are major mediators of vascular plasticity. The exposure of the vessel wall to increased laminar FSS is the main trigger of arteriogenesis, the remodelling of pre-existent arterio-arteriolar anastomoses to functional conductance arteries. In this study, we have used an in vitro bioreactor to investigate cell-specific interactions, molecular mechanisms as well as time-dependent effects under laminar FSS conditions. This bioreactor termed "artificial artery" can be used for screening potential arterio-protective substances, pro-arteriogenic factors, and for investigating biomarkers of cardiovascular diseases such as cardiac diseases. The bioreactor is built up out of 14 hollow fiber membranes colonized with endothelial cells (HUVECs) on the inside and smooth muscle cells (HUASMCs) on the outside. By means of Hoechst 33342 staining as well as immunocytochemistry of ß-catenin and α-smooth-muscle-actin, a microporous polypropylene membrane was characterized as being the appropriate polymer for co-colonization. Defined arterial flow conditions (0.1 N/m2 and 3 N/m2), metabolic exchange, and cross-talk of HUVECs and HUASMCs through hollow fibers mimic physiological in vivo conditions of the vasculature. Analysing mono- and co-culture secretomes by MALDI-TOF-TOF mass spectrometry, we could show that HUVECs secreted Up4A upon 3 N/m2. A constant cellular secretion of randomly chosen peptides verified viability of the "artificial artery" for a cultivation period up to five days. qRT-PCR analyses revealed an up-regulation of KLF2 and TIMP1 as mechano-regulated genes and demonstrated arterio-protective, homeostatic FSS conditions by a down-regulation of EDN1. Expression analyses of VWF and EDN1 furthermore confirmed that RNA of both cell types could separately be isolated without cross-contamination. CCND1 mRNA expression in HUVECs did not change upon FSS indicating a quiescent endothelial phenotype. Taken together, the "artificial artery" provides a solid in vitro model to test pharmacological active compounds for their impact on arterio-damaging or arterio-protective properties on vascular response.

BackgroundAlthough "uremic fetor" has long been felt to be diagnostic of renal failure, the compounds exhaled in uremia remain largely unknown so far. The present work investigates whether breath analysis by ion mobility spectrometry can be used for the identification of volatile organic compounds retained in uremia.MethodsBreath analysis was performed in 28 adults with an eGFR ≥ 60 ml/min per 1.73 m(2), 26 adults with chronic renal failure corresponding to an eGFR of 10-59 ml/min per 1.73 m(2), and 28 adults with end-stage renal disease (ESRD) before and after a hemodialysis session. Breath analysis was performed by ion mobility spectrometryafter gas-chromatographic preseparation. Identification of the compounds of interest was performed by thermal desorption gas chromatography/mass spectrometry.ResultsBreath analyses revealed significant differences in the spectra of patients with and without renal failure. Thirteen compounds were chosen for further evaluation. Some compounds including hydroxyacetone, 3-hydroxy-2-butanone and ammonia accumulated with decreasing renal function and were eliminated by dialysis. The concentrations of these compounds allowed a significant differentiation between healthy, chronic renal failure with an eGFR of 10-59 ml/min, and ESRD (pConclusionImpairment of renal function induces a characteristic fingerprint of volatile compounds in the breath. The technique of ion mobility spectrometry can be used for the identification of lipophilic uremic retention molecules.