Grégoire Wuerzner

Blood pressure changes after renal denervation at 10 European expert centers

We did a subject-level meta-analysis of the changes (Δ) in blood pressure (BP) observed 3 and 6 months after renal denervation (RDN) at 10 European centers. Recruited patients (n=109; 46.8% women; mean age 58.2 years) had essential hypertension confirmed by ambulatory BP. From baseline to 6 months, treatment score declined slightly from 4.7 to 4.4 drugs per day. Systolic/diastolic BP fell by 17.6/7.1 mm Hg for office BP, and by 5.9/3.5, 6.2/3.4, and 4.4/2.5 mm Hg for 24-h, daytime and nighttime BP (P⩽0.03 for all). In 47 patients with 3- and 6-month ambulatory measurements, systolic BP did not change between these two time points (P⩾0.08). Normalization was a systolic BP of <140 mm Hg on office measurement or <130 mm Hg on 24-h monitoring and improvement was a fall of ⩾10 mm Hg, irrespective of measurement technique. For office BP, at 6 months, normalization, improvement or no decrease occurred in 22.9, 59.6 and 22.9% of patients, respectively; for 24-h BP, these proportions were 14.7, 31.2 and 34.9%, respectively. Higher baseline BP predicted greater BP fall at follow-up; higher baseline serum creatinine was associated with lower probability of improvement of 24-h BP (odds ratio for 20-μmol l−1 increase, 0.60; P=0.05) and higher probability of experiencing no BP decrease (OR, 1.66; P=0.01). In conclusion, BP responses to RDN include regression-to-the-mean and remain to be consolidated in randomized trials based on ambulatory BP monitoring. For now, RDN should remain the last resort in patients in whom all other ways to control BP failed, and it must be cautiously used in patients with renal impairment.

Safety and immunogenicity of a chimpanzee adenovirus-vectored Ebola vaccine in healthy adults: a randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a study

BACKGROUND The ongoing Ebola outbreak led to accelerated efforts to test vaccine candidates. On the basis of a request by WHO, we aimed to assess the safety and immunogenicity of the monovalent, recombinant, chimpanzee adenovirus type-3 vector-based Ebola Zaire vaccine (ChAd3-EBO-Z). METHODS We did this randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a trial at the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Participants (aged 18-65 years) were randomly assigned (2:2:1), via two computer-generated randomisation lists for individuals potentially deployed in endemic areas and those not deployed, to receive a single intramuscular dose of high-dose vaccine (5 × 10(10) viral particles), low-dose vaccine (2·5 × 10(10) viral particles), or placebo. Deployed participants were allocated to only the vaccine groups. Group allocation was concealed from non-deployed participants, investigators, and outcome assessors. The safety evaluation was not masked for potentially deployed participants, who were therefore not included in the safety analysis for comparison between the vaccine doses and placebo, but were pooled with the non-deployed group to compare immunogenicity. The main objectives were safety and immunogenicity of ChAd3-EBO-Z. We did analysis by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02289027. FINDINGS Between Oct 24, 2014, and June 22, 2015, we randomly assigned 120 participants, of whom 18 (15%) were potentially deployed and 102 (85%) were non-deployed, to receive high-dose vaccine (n=49), low-dose vaccine (n=51), or placebo (n=20). Participants were followed up for 6 months. No vaccine-related serious adverse events were reported. We recorded local adverse events in 30 (75%) of 40 participants in the high-dose group, 33 (79%) of 42 participants in the low-dose group, and five (25%) of 20 participants in the placebo group. Fatigue or malaise was the most common systemic adverse event, reported in 25 (62%) participants in the high-dose group, 25 (60%) participants in the low-dose group, and five (25%) participants in the placebo group, followed by headache, reported in 23 (57%), 25 (60%), and three (15%) participants, respectively. Fever occurred 24 h after injection in 12 (30%) participants in the high-dose group and 11 (26%) participants in the low-dose group versus one (5%) participant in the placebo group. Geometric mean concentrations of IgG antibodies against Ebola glycoprotein peaked on day 28 at 51 μg/mL (95% CI 41·1-63·3) in the high-dose group, 44·9 μg/mL (25·8-56·3) in the low-dose group, and 5·2 μg/mL (3·5-7·6) in the placebo group, with respective response rates of 96% (95% CI 85·7-99·5), 96% (86·5-99·5), and 5% (0·1-24·9). Geometric mean concentrations decreased by day 180 to 25·5 μg/mL (95% CI 20·6-31·5) in the high-dose group, 22·1 μg/mL (19·3-28·6) in the low-dose group, and 3·2 μg/mL (2·4-4·9) in the placebo group. 28 (57%) participants given high-dose vaccine and 31 (61%) participants given low-dose vaccine developed glycoprotein-specific CD4 cell responses, and 33 (67%) and 35 (69%), respectively, developed CD8 responses. INTERPRETATION ChAd3-EBO-Z was safe and well tolerated, although mild to moderate systemic adverse events were common. A single dose was immunogenic in almost all vaccine recipients. Antibody responses were still significantly present at 6 months. There was no significant difference between doses for safety and immunogenicity outcomes. This acceptable safety profile provides a reliable basis to proceed with phase 2 and phase 3 efficacy trials in Africa. FUNDING Swiss State Secretariat for Education, Research and Innovation (SERI), through the EU Horizon 2020 Research and Innovation Programme.

Eligibility for Renal Denervation: Experience at 11 European Expert Centers

Based on the SYMPLICITY studies and CE (Conformité Européenne) certification, renal denervation is currently applied as a novel treatment of resistant hypertension in Europe. However, information on the proportion of patients with resistant hypertension qualifying for renal denervation after a thorough work-up and treatment adjustment remains scarce. The aim of this study was to investigate the proportion of patients eligible for renal denervation and the reasons for noneligibility at 11 expert centers participating in the European Network COordinating Research on renal Denervation in treatment-resistant hypertension (ENCOReD). The analysis included 731 patients. Age averaged 61.6 years, office blood pressure at screening was 177/96 mm Hg, and the number of blood pressure–lowering drugs taken was 4.1. Specialists referred 75.6% of patients. The proportion of patients eligible for renal denervation according to the SYMPLICITY HTN-2 criteria and each center’s criteria was 42.5% (95% confidence interval, 38.0%–47.0%) and 39.7% (36.2%–43.2%), respectively. The main reasons of noneligibility were normalization of blood pressure after treatment adjustment (46.9%), unsuitable renal arterial anatomy (17.0%), and previously undetected secondary causes of hypertension (11.1%). In conclusion, after careful screening and treatment adjustment at hypertension expert centers, only ≈40% of patients referred for renal denervation, mostly by specialists, were eligible for the procedure. The most frequent cause of ineligibility (approximately half of cases) was blood pressure normalization after treatment adjustment by a hypertension specialist. Our findings highlight that hypertension centers with a record in clinical experience and research should remain the gatekeepers before renal denervation is considered.Based on the SYMPLICITY studies and CE (Conformite Europeenne) certification, renal denervation is currently applied as a novel treatment of resistant hypertension in Europe. However, information on the proportion of patients with resistant hypertension qualifying for renal denervation after a thorough work-up and treatment adjustment remains scarce. The aim of this study was to investigate the proportion of patients eligible for renal denervation and the reasons for noneligibility at 11 expert centers participating in the European Network COordinating Research on renal Denervation in treatment-resistant hypertension (ENCOReD). The analysis included 731 patients. Age averaged 61.6 years, office blood pressure at screening was 177/96 mm Hg, and the number of blood pressure–lowering drugs taken was 4.1. Specialists referred 75.6% of patients. The proportion of patients eligible for renal denervation according to the SYMPLICITY HTN-2 criteria and each center’s criteria was 42.5% (95% confidence interval, 38.0%–47.0%) and 39.7% (36.2%–43.2%), respectively. The main reasons of noneligibility were normalization of blood pressure after treatment adjustment (46.9%), unsuitable renal arterial anatomy (17.0%), and previously undetected secondary causes of hypertension (11.1%). In conclusion, after careful screening and treatment adjustment at hypertension expert centers, only ≈40% of patients referred for renal denervation, mostly by specialists, were eligible for the procedure. The most frequent cause of ineligibility (approximately half of cases) was blood pressure normalization after treatment adjustment by a hypertension specialist. Our findings highlight that hypertension centers with a record in clinical experience and research should remain the gatekeepers before renal denervation is considered. # Novelty and Significance {#article-title-32}

Effect of an increased clopidogrel maintenance dose or lansoprazole co-administration on the antiplatelet response to clopidogrel in CYP2C19-genotyped healthy subjects.

human endothelial cells. Circ J 2009; 73: 1746–52. 16 Kasthuri RS, Taubman MB, Mackman N. Role of tissue factor in cancer. J Clin Oncol 2009; 27: 4834–8. 17 van den Berg YW, van den Hengel LG, Myers HR, Ayachi O, Jordanova E, Ruf W, Spek CA, Reitsma PH, Bogdanov VY, Versteeg HH. Alternatively spliced tissue factor induces angiogenesis through integrin ligation. Proc Natl Acad Sci USA 2009; 106: 19497–502.

Effect of Sodium Loading/Depletion on Renal Oxygenation in Young Normotensive and Hypertensive Men

The goal of this study was to investigate the effect of sodium intake on renal tissue oxygenation in humans. To this purpose, we measured renal hemodynamics, renal sodium handling, and renal oxygenation in normotensive (NT) and hypertensive (HT) subjects after 1 week of a high-sodium and 1 week of a low-sodium diet. Renal oxygenation was measured using blood oxygen level–dependent magnetic resonance. Tissue oxygenation was determined by the measurement of R2* maps on 4 coronal slices covering both kidneys. The mean R2* values in the medulla and cortex were calculated, with a low R2* indicating a high tissue oxygenation. Ten male NT (mean age: 26.5±7.4 years) and 8 matched HT subjects (mean age: 28.8±5.7 years) were studied. Cortical R2* was not different under the 2 conditions of salt intake. Medullary R2* was significantly lower under low sodium than high sodium in both NT and HT subjects (28.1±0.8 versus 31.3±0.6 s−1; P<0.05 in NT; and 27.9±1.5 versus 30.3±0.8 s−1; P<0.05, in HT), indicating higher medullary oxygenation under low-sodium conditions. In NT subjects, medullary oxygenation was positively correlated with proximal reabsorption of sodium and negatively with absolute distal sodium reabsorption, but not with renal plasma flow. In HT subjects, medullary oxygenation correlated with the 24-hour sodium excretion but not with proximal or with the distal handling of sodium. These data demonstrate that dietary sodium intake influences renal tissue oxygenation, low sodium intake leading to an increased renal medullary oxygenation both in normotensive and young hypertensive subjects.

Glomerular hyperfiltration and increased proximal sodium reabsorption in subjects with type 2 diabetes or impaired fasting glucose in a population of the African region

BACKGROUND. Glomerular hyperfiltration (GHF) is a well-recognized early renal alteration in diabetic patients. As the prevalence of GHF is largely unknown in populations in the African region with respect to normal fasting glucose (NFG), impaired fasting glucose (IFG) and type 2 diabetes [diabetes mellitus (DM)], we conducted a cross-sectional study in the Seychelles islands among families including at least one member with hypertension. METHODS. The glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and proximal tubular sodium reabsorption were measured using inulin, p-aminohippurate (PAH) and endogenous lithium clearance, respectively. Twenty-four-hour urine was collected on the preceding day. RESULTS. Of the 363 participants (mean age 44.7 years), 6.6% had IFG, 9.9% had DM and 63.3% had hypertension. The prevalence of GHF, defined as a GFR >140 ml/min, was 17.2%, 29.2% and 52.8% in NFG, IFG and DM, respectively (P trend <0.001). Compared to NFG, the adjusted odds ratio for GHF was 1.99 [95% confidence interval (CI) 0.73-5.44] for IFG and 5.88 (2.39-14.45) for DM. Lithium clearance and fractional excretion of lithium were lower in DM and IFG than NFG (P < 0.001). CONCLUSION. In this population of African descent, subjects with impaired fasting glucose or type 2 diabetes had a high prevalence of GHF and enhanced proximal sodium reabsorption. These findings provide further insight on the elevated incidence of nephropathy reported among African diabetic individuals.

Drug adherence in chronic kidney diseases and dialysis

Poor long-term adherence and persistence to drug therapy is universally recognized as one of the major clinical issues in the management of chronic diseases, and patients with renal diseases are also concerned by this important phenomenon. Chronic kidney disease (CKD) patients belong to the group of subjects with one of the highest burdens of daily pill intake with up to >20 pills per day depending on the severity of their disease. The purpose of the present review is to discuss the difficulties encountered by nephrologists in diagnosing and managing poor adherence and persistence in CKD patients including in patients receiving maintenance dialysis. Our review will also attempt to provide some clues and new perspectives on how drug adherence could actually be addressed and possibly improved. Working on drug adherence may look like a long and tedious path, but physicians and healthcare providers should always be aware that drug adherence is in general much lower than what they may think and that there are many ways to improve and support drug adherence and persistence so that renal patients obtain the full benefits of their treatments.

Renal perfusion evaluation with contrast-enhanced ultrasonography

BACKGROUND Contrast-enhanced ultrasonography (CEUS) is a novel imaging technique that is safe and applicable on the bedside. Recent developments seem to enable CEUS to quantify organ perfusion. We performed an exploratory study to determine the ability of CEUS to detect changes in renal perfusion and to correlate them with effective renal plasma flow. METHODS CEUS with destruction-refilling sequences was studied in 10 healthy subjects, at baseline and during infusion of angiotensin II (AngII) at low (1 ng/kg/min) and high dose (3 ng/kg/min) and 1 h after oral captopril (50 mg). Perfusion index (PI) was obtained and compared with the effective renal plasma flow (ERPF) obtained by parallel para-aminohippurate (PAH) clearance. RESULTS Median PI decreased from 188.6 (baseline) to 100.4 with low-dose AngII (-47%; P < 0.02) and to 66.1 with high-dose AngII (-65%; P < 0.01) but increased to 254.7 with captopril (+35%; P > 0.2). These changes parallelled those observed with ERPF, which changed from a median of 672.1 mL/min (baseline) to 572.3 (low-dose AngII, -15%, P < 0.05) and to 427.2 (high-dose AngII, -36%, P < 0.001) and finally 697.1 (captopril, +4%, P < 0.02). CONCLUSIONS This study demonstrates that CEUS is able to detect changes in human renal cortical microcirculation as induced by AngII infusion and/or captopril administration. The changes in perfusion indices parallel those in ERPF as obtained by PAH clearance.

Direct analysis of valsartan or candesartan in human plasma and urines by on-line solid phase extraction coupled to electrospray tandem mass spectrometry.

AT1 receptor blockers are agents for the treatment of hypertension. Rapid and precise assay methods are needed to evaluate possible sub- or overdosage. A direct on-line solid phase extraction coupled to tandem mass spectrometry was developed and validated to determine valsartan (5-2000ng/mL) or candesartan (1-200ng/mL) in human plasma and urines. Both intra- and inter-assay accuracy and precision were in the range 89.2-111% and 0.9-16.9% RSD. Total run time was 4.5min. This on-line clean-up-MS method was found to be robust for the analysis of a high number of samples with unvarying performance.

Epidemiology of Masked and White-Coat Hypertension: The Family-Based SKIPOGH Study

Objective We investigated factors associated with masked and white-coat hypertension in a Swiss population-based sample. Methods The Swiss Kidney Project on Genes in Hypertension is a family-based cross-sectional study. Office and 24-hour ambulatory blood pressure were measured using validated devices. Masked hypertension was defined as office blood pressure<140/90 mmHg and daytime ambulatory blood pressure≥135/85 mmHg. White-coat hypertension was defined as office blood pressure≥140/90 mmHg and daytime ambulatory blood pressure<135/85 mmHg. Mixed-effect logistic regression was used to examine the relationship of masked and white-coat hypertension with associated factors, while taking familial correlations into account. High-normal office blood pressure was defined as systolic/diastolic blood pressure within the 130–139/85–89 mmHg range. Results Among the 652 participants included in this analysis, 51% were female. Mean age (±SD) was 48 (±18) years. The proportion of participants with masked and white coat hypertension was respectively 15.8% and 2.6%. Masked hypertension was associated with age (odds ratio (OR) = 1.02, p = 0.012), high-normal office blood pressure (OR = 6.68, p<0.001), and obesity (OR = 3.63, p = 0.001). White-coat hypertension was significantly associated with age (OR = 1.07, p<0.001) but not with education, family history of hypertension, or physical activity. Conclusions Our findings suggest that physicians should consider ambulatory blood pressure monitoring for older individuals with high-normal office blood pressure and/or who are obese.