Risk-based individualisation of target haemoglobin in haemodialysis patients with renal anaemia in the post-TREAT era: theoretical attitudes versus actual practice patterns (MONITOR-CKD5 study)

Purpose: Data from an ongoing European pharmacoepidemiological study (MONITOR-CKD5) were used to examine congruence between physician-reported risk-based individualisation of target haemoglobin (Hb) and the actual Hb targets set by these physicians for their patients, as well as actual Hb levels in their patients. Methods: Physician investigators participating in the study completed a questionnaire about their anaemia practice patterns and attitudes post-TREAT at the start of the study (T1) and in summer 2013 (T2). These data were compared with the Hb targets identified at baseline for actual patients (n = 1197) enrolled in the study. Risk groups included presence/absence of hypertension, diabetes, cardiovascular complications, history of stroke, history of cancer, and age/activity level (elderly/inactive or young/active). Results: At each time point, more than three quarters of physicians responded that results from the TREAT study, in patients not on dialysis, have influenced their use of erythropoiesis-stimulating agents in patients on haemodialysis. At T1, there was a clear difference in physician-reported (theoretical) target Hb levels for patients across the different risk groups, but there was no difference in patients’ actual Hb levels across the risk groups. A similar disparity was noted at T2. Conclusions: Physicians’ theoretical attitudes to anaemia management in patients on haemodialysis appear to have been influenced by the results of the TREAT study, which involved patients not on dialysis. Physicians claim to use risk-based target Hb levels to guide renal anaemia care. However, there is discrepancy between these declared risk-based target Hb levels and actual target Hb levels for patients with variable risk factors

Micromechanical Properties of Injection-Molded Starch–Wood Particle Composites

The micromechanical properties of injection molded starch–wood particle composites were investigated as a function of particle content and humidity conditions. The composite materials were characterized by scanning electron microscopy and X-ray diffraction methods. The microhardness of the composites was shown to increase notably with the concentration of the wood particles. In addition,creep behavior under the indenter and temperature dependence were evaluated in terms of the independent contribution of the starch matrix and the wood microparticles to the hardness value. The influence of drying time on the density and weight uptake of the injection-molded composites was highlighted. The results revealed the role of the mechanism of water evaporation, showing that the dependence of water uptake and temperature was greater for the starch–wood composites than for the pure starch sample. Experiments performed during the drying process at 70°C indicated that the wood in the starch composites did not prevent water loss from the samples.Peer reviewe

HX575: established biosimilarity in the treatment of renal anemia and 10 years of clinical experience

Frank Dellanna,1 David Goldsmith,2 Andriy Krendyukov,3 Andreas Seidl,4 Nadja Höbel,5 Christian Combe6,7 1MVZ Davita Rhein-Ruhr, Düsseldorf, Germany; 2Division of Nephrology, Guy’s and St Thomas’ Hospitals, London, UK; 3Hematology/Nephrology, Hexal AG, Holzkirchen, 4Technical Development Biosimilars, Hexal AG, Oberhaching, 5Biostatistics Medical Affairs/Late Phase, Hexal AG, Holzkirchen, Germany; 6Service de Néphrologie Transplantation Dialyse Aphérèse, Centre Hospitalier Universitaire de Bordeaux, 7Université Bordeaux, INSERM 1026, Bordeaux, France Abstract: Erythropoiesis-stimulating agents, such as recombinant human erythropoietin, are commonly used for the treatment of anemia in patients with chronic kidney disease (CKD). In 2007, HX575 (Binocrit®) became the first biosimilar epoetin alfa to be approved by the European Medicines Agency (EMA). The decision to approve a biosimilar is based on the totality of evidence obtained in a comprehensive comparability exercise that involves extensive analytical characterization, nonclinical studies and clinical studies. The development process for HX575 included extensive analytical characterization and comparison with the reference epoetin alfa. This was followed by a clinical development program, comprising Phase I pharmacokinetic/pharmacodynamic studies to show bioequivalence to the reference medicine and a confirmatory Phase III study to demonstrate therapeutic effectiveness in anemia related to CKD. In addition to the comparability exercises, extensive clinical experience over the last decade also confirms that HX575 provides an effective treatment for CKD-related anemia, with a favorable safety profile. Growing clinical experience with EMA-approved biosimilars, including HX575, should offer additional reassurance to health care professionals and patients that these agents are as effective and well tolerated as others in the therapeutic class. Keywords: Binocrit, HX575, anemia, chronic kidney disease, biosimilar

Determination of Vasopressin and Desmopressin in urine by means of liquid chromatography coupled to quadrupole time-of-flight mass spectrometry for doping control purposes.

The anti-diuretic neurohypophysial hormone Vasopressin (Vp) and its synthetic analogue Desmopressin (Dp, 1-desamino-vasopressin) have received considerable attention from doping control authorities due to their impact on physiological blood parameters. Accordingly, the illicit use of Desmopressin in elite sport is sanctioned by the World Anti-Doping Agency (WADA) and the drug is classified as masking agent. Vp and Dp are small (8-9 amino acids) peptides administered orally as well as intranasally. Within the present study a method to determine Dp and Vp in urinary doping control samples by means of liquid chromatography coupled to quadrupole high resolution time-of-flight mass spectrometry was developed. After addition of Lys-Vasopressin as internal standard and efficient sample clean up with a mixed mode solid phase extraction (weak cation exchange), the samples were directly injected into the LC-MS system. The method was validated considering the parameters specificity, linearity, recovery (80-100%), accuracy, robustness, limit of detection/quantification (20/50 pg mL(-1)), precision (inter/intra-day<10%), ion suppression and stability. The analysis of administration study urine samples collected after a single intranasal or oral application of Dp yielded in detection windows for the unchanged target analyte for up to 20 h at concentrations between 50 and 600 pg mL(-1). Endogenous Vp was detected in concentrations of approximately 20-200 pg mL(-1) in spontaneous urine samples obtained from healthy volunteers. The general requirements of the developed method provide the characteristics for an easy transfer to other anti-doping laboratories and support closing another potential gap for cheating athletes

Safety of Roxadustat Versus Erythropoiesis-Stimulating Agents in Patients with Anemia of Non-dialysis-Dependent or Incident-to-Dialysis Chronic Kidney Disease: Pooled Analysis of Four Phase 3 Studies

Introduction: This study was conducted to elucidate the safety of roxadustat, an oral medication, in patients with non-dialysis-dependent (NDD) or incident dialysis dialysis-dependent (ID-DD) chronic kidney disease (CKD). Methods: Safety results from four phase 3, randomized, open-label studies comparing roxadustat to an erythropoiesis-stimulating agent (ESA) in men and women with NDD or ID-DD CKD with anemia were pooled and evaluated. Endpoints were time to major adverse cardiovascular event (MACE; myocardial infarction, stroke, and all-cause mortality) and MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization), all-cause mortality, and treatment-emergent adverse events (TEAEs). MACE and MACE+ were evaluated for non-inferiority at 1.8- and 1.3-margins using hazard ratios (HRs) and 95% confidence intervals (CIs). TEAEs were descriptively summarized. Results: In total, 2142 patients were evaluated (1083 roxadustat; 1059 ESA). Roxadustat was comparable to ESA for risk of MACE (HR 0.79, 95% CI 0.61–1.02), MACE+ (HR 0.78, 95% CI 0.62–0.98), and all-cause mortality (HR 0.78, 95% CI 0.57–1.05). TEAEs were comparable between roxadustat and ESA groups, including any TEAE [incidence rate per 100 (IR/100) patient-exposure years 56.1 vs. 53.5], TEAEs leading to study drug discontinuation (IR/100 patient-exposure years 6.7 vs. 5.1), and TEAEs leading to death (IR/100 patient-exposure years 6.9 vs. 7.4). Conclusion: There was no evidence of increased risk of cardiovascular events or mortality with roxadustat compared with ESA in patients with anemia who have NDD or ID-DD CKD. Although TEAEs occurred commonly in both the roxadustat and ESA groups, patients infrequently discontinued the study drug because of an adverse event. Clinical Trial Registration Numbers: DOLOMITES, 1517-CL-0610 [NCT02021318]; HIMALAYAS, FGCL-4592-063 [NCT02052310]; SIERRAS, FGCL-4592-064 [NCT02273726]; and ROCKIES, D5740C00002 [NCT02174731]

Vasculoprotective Effects of Dietary Cocoa Flavanols in Patients on Hemodialysis: A Double-Blind, Randomized, Placebo-Controlled Trial

Background and objectives: Hemodialysis (HD) per se entails vascular dysfunction in patients with ESRD. Endothelial dysfunction is a key step in atherosclerosis and is characterized by impaired flow–mediated dilation (FMD). Interventional studies have shown that cocoa flavanol (CF)–rich supplements improve vascular function. Aim of this study was to investigate the effect of flavanol–rich bioactive food ingredients on acute and chronic HD–induced vascular dysfunction in ESRD. Design, setting, participants, & measurements: We conducted a randomized, double–blind, placebo–controlled trial from 2012 to 2013. Fifty-seven participants were enrolled, ingested CF-rich beverages (900 mg CF per study day), and were compared with those ingesting CF-free placebo. This included (1) a baseline cross–over acute study to determine safety and efficacy of CF and (2) a subsequent chronic parallel group study with a 30-day follow-up period to study effects of CF on HD–mediated vascular dysfunction entailing (3) an acute substudy during HD in flavanol-naive patients and (4) an acute on chronic study during HD. Primary and secondary outcome measures included changes in FMD and hemodynamics. Results: CF ingestion was well tolerated. Acute ingestion improved FMD by 53% (3.2±0.6% to 4.8±0.9% versus placebo, 3.2±0.7% to 3.3±0.8%; P<0.001), with no effects on BP or heart rate. A 30-day ingestion of CF led to an increase in baseline FMD by 18% (3.4±0.9% to 3.9±0.8% versus placebo, 3.5±0.7% to 3.5±0.7%; P<0.001), with reduced diastolic BP (73±12 to 69±11 mmHg versus placebo, 70±11 to 73±13 mmHg; P=0.03) and increased heart rate (70±12 to 74±13 bpm versus placebo, 75±15 to 74±13 bpm; P=0.01). No effects were observed for placebo. Acute ingestion of CF during HD alleviated HD–induced vascular dysfunction (3.4±0.9% to 2.7±0.6% versus placebo, 3.5±0.7% to 2.0±0.6%; P<0.001). This effect was sustained throughout the study (acute on chronic, 3.9±0.9% to 3.0±0.7% versus placebo, 3.5±0.7% to 2.2±0.6; P=0.01). Conclusions: Dietary CF ingestion mitigates acute HD–induced and chronic endothelial dysfunction in patients with ESRD and thus, improves vascular function in this high-risk population. Larger clinical trials are warranted to test whether this translates into an improved cardiovascular prognosis in patients with ESRD

Vasculoprotective Effects of Dietary Cocoa Flavanols in Patients on Hemodialysis: A Double-Blind, Randomized, Placebo-Controlled Trial

Background and objectives: Hemodialysis (HD) per se entails vascular dysfunction in patients with ESRD. Endothelial dysfunction is a key step in atherosclerosis and is characterized by impaired flow–mediated dilation (FMD). Interventional studies have shown that cocoa flavanol (CF)–rich supplements improve vascular function. Aim of this study was to investigate the effect of flavanol–rich bioactive food ingredients on acute and chronic HD–induced vascular dysfunction in ESRD. Design, setting, participants, & measurements: We conducted a randomized, double–blind, placebo–controlled trial from 2012 to 2013. Fifty-seven participants were enrolled, ingested CF-rich beverages (900 mg CF per study day), and were compared with those ingesting CF-free placebo. This included (1) a baseline cross–over acute study to determine safety and efficacy of CF and (2) a subsequent chronic parallel group study with a 30-day follow-up period to study effects of CF on HD–mediated vascular dysfunction entailing (3) an acute substudy during HD in flavanol-naive patients and (4) an acute on chronic study during HD. Primary and secondary outcome measures included changes in FMD and hemodynamics. Results: CF ingestion was well tolerated. Acute ingestion improved FMD by 53% (3.2±0.6% to 4.8±0.9% versus placebo, 3.2±0.7% to 3.3±0.8%; P<0.001), with no effects on BP or heart rate. A 30-day ingestion of CF led to an increase in baseline FMD by 18% (3.4±0.9% to 3.9±0.8% versus placebo, 3.5±0.7% to 3.5±0.7%; P<0.001), with reduced diastolic BP (73±12 to 69±11 mmHg versus placebo, 70±11 to 73±13 mmHg; P=0.03) and increased heart rate (70±12 to 74±13 bpm versus placebo, 75±15 to 74±13 bpm; P=0.01). No effects were observed for placebo. Acute ingestion of CF during HD alleviated HD–induced vascular dysfunction (3.4±0.9% to 2.7±0.6% versus placebo, 3.5±0.7% to 2.0±0.6%; P<0.001). This effect was sustained throughout the study (acute on chronic, 3.9±0.9% to 3.0±0.7% versus placebo, 3.5±0.7% to 2.2±0.6; P=0.01). Conclusions: Dietary CF ingestion mitigates acute HD–induced and chronic endothelial dysfunction in patients with ESRD and thus, improves vascular function in this high-risk population. Larger clinical trials are warranted to test whether this translates into an improved cardiovascular prognosis in patients with ESRD