bluuebunny/crossref_metadata_2025_split huggingface dataset:
MO551A COST-OFFSET ANALYSIS OF THE ROXADUSTAT DIALYSIS-DEPENDENT GLOBAL PHASE 3 PROGRAM: A CANADIAN HEALTHCARE PERSPECTIVE
Authors: Schneider John , Davies Shawn , Howarth Amanda , Garcia Sanchez Juan Jose , Rao Naveen , Grandy Susan , Bhatt Purav , Wong Deborah , Parackal Anna , Yu K-H , Lai Rachel , Briggs Andrew 
Published: May 2021

Abstract

Background and Aims
Chronic kidney disease (CKD) is a costly public health issue, which affects 13.4% of the population globally. Anaemia is a common complication in patients with CKD resulting in reduced health-related quality of life and high healthcare costs. The objective of this analysis was to estimate the direct medical care cost offsets of the investigational agent roxadustat for the treatment of anaemia in patients with dialysis-dependent (DD) CKD from a Canadian healthcare perspective.

Method
Data from the roxadustat global phase 3 program were used to estimate the incidence of rescue therapy or iron supplementation use (i.e. intravenous iron, erythropoiesis-stimulating agents [ESAs] or red blood cell transfusions) and major adverse cardiovascular events (MACE+) for roxadustat compared with ESAs in DD patients with anaemia of CKD. MACE+ included myocardial infarction, stroke, unstable angina requiring hospitalization, congestive heart failure (CHF) requiring hospitalization, cardiovascular death and other death. Published Canadian cost data were used to estimate event costs. Drug acquisition costs for roxadustat and ESAs were not considered. A hypothetical cohort of 10,000 Canadian adult DD patients (90% undergoing haemodialysis, 10% undergoing peritoneal dialysis) with treatable anaemia was modelled to determine net medical care cost offsets annually and cumulatively compared with ESAs over a 4-year time horizon.

Results
Preliminary results for patients with DD CKD show that, compared with ESAs, roxadustat could produce sizeable net medical care cost offsets resulting from reductions in rescue therapy or iron supplementation use, specifically red blood cell transfusions, and from reductions in MACE+, specifically CHF hospitalizations. For the entire cohort of patients with DD CKD, cumulative medical care cost offsets for roxadustat were an estimated $162,609 for rescue therapy or iron supplementation use and $1,027,070 for MACE+ compared with ESAs.

Conclusion
This analysis provides evidence that treatment with roxadustat in DD patients with anaemia of CKD could result in considerable medical care cost offsets for roxadustat compared with ESAs.
MO552PHARMACOLOGICAL HIF PROLYL HYDROXYLASE INHIBITION IMPROVES EXERCISE ENDURANCE CAPACITY IN CKD MICE
Authors: Takemura Koji , Nishi Hiroshi , Higashihara Takaaki , Nangaku Masaomi 
Published: May 2021

Abstract

Background and Aims
Erythropoietin (EPO) and hypoxia-inducible factor (HIF) stabilizers (prolyl hydroxylase (PH) inhibitors) are efficient therapeutic modalities against anemia in chronic kidney disease (CKD). Compared to EPO and EPO receptor system, extra-renal action of PH inhibitors has still not been fully investigated. Previous reports caution us about the actual misuse of PH inhibitors in doped athletes, but the drug nonhematopoietic effects of PH inhibitors on skeletal muscles remain controversial both in healthy subjects or in patients with CKD.

Method
To study direct pharmacological effects of PH inhibitors on skeletal muscles, one of PH inhibitors, roxadustat, was administered via oral gavage to healthy 8-week-old C57BL6 mice. Plasma EPO levels and HIF-targeted gene expression were analyzed after a single administration. Exercise ability was assessed by treadmill exhaustion test after a single dose or chronic 5-week treatment. Roxadustat was also administered for 2 weeks to CKD mice with 2-week 0.2% adenine diet. Endurance capacity was similarly assessed after 2-week roxadustat treatment.

Results
Even a single administration of roxadustat increased plasma EPO levels and gene expression downstream of HIF in skeletal muscles. Healthy mice treated with roxadustat for 5 weeks showed higher blood haemoglobin (Hb) levels and improved exercise endurance in treadmill exhaustion test, which was blunted by hemodilution procedure. Adenine-fed CKD mice showed lower blood Hb levels and worse endurance capacity compared to control mice. Roxadustat treatment improved endurance capacity in CKD mice without significant increase in blood Hb levels compared to control mice.

Conclusion
Treatment with HIF-PH inhibitor, roxadustat, improves exercise endurance principally via pharmacological erythropoiesis. However, roxadustat shows potential effects independent of erythropoiesis on endurance capacity in CKD.
MO557EFFICIENCY OF FERRIC CARBOXYMALTOSE IN NON-DIALYSIS CKD PATIENTS AND ITS IMPACT ON KIDNEY FUNCTION: A PROSPECTIVE OBSERVATIONAL STUDY
Authors: Roldão Marisa , Escoli Rachele , Gonçalves Hernâni , Lopes Karina 
Published: May 2021

Abstract

Background and Aims
Iron deficiency anemia occurs in the vast majority of patients with chronic kidney disease (CKD). The aim of this study was to investigate the efficacy of ferric carboxymaltose (FCM) iron deficiency anemia’s treatment in non-dialysis CKD patients and to clarify its impact on kidney function.

Method
Prospective observational study of non-dialysis CKD stage 3 to 5 patients, with anemia and iron deficiency treated with FCM from 01 January 2019 to 31 June 2020. FCM was administrated as a single IV infusion of 500mg or 1000mg. Baseline clinical, analytical and demographic data were recorded. FCM efficacy was evaluated by comparing hemoglobin (Hb), serum ferritin and transferrin saturation index (TSAT) 24 ± 8 weeks after the infusion with analytical values at baseline. Renal function was also assessed at baseline and at 24 ± 8 weeks using estimated glomerular filtration rate (eGFR), calculated by CKD-EPI formula. Statistical analysis was executed using SPSS (Version 23 for Mac OSX).

Results
The average age of 71 patients was 77.31 ± 9.68 years, 29 (40.8%) were male, 46 (64.8%) were diabetic and 41 (57.8%) had congestive heart failure. Sixteen (22.5%) patients had CKD stage 3, 41 (57.7%) stage 4 and 14 (19.7%) stage 5. Twenty-five (35.2%) patients were treated with 1000mg of FCM. At baseline, average hemoglobin level (Hb) was 10.16 ± 1.12g/dL, serum ferritin 83.25 ± 96.55µg/L, TSAT 14.48 ± 6.72mg/dL and eGFR 24.21± 13.09ml/min/1.73m2. At 24 ± 8 weeks, Hb showed an increase of 1.31 ± 1.49 g/dL (p=0.001) and TSAT 10.68 ± 10.40% (p=0.001). Serum ferritin showed also an increase of 4.75 ± 180.53µg/L but did not reach statistical significance. The increase in Hb was observed uniformly across all stages of CKD. A Pearson correlation revealed a positive correlation between the variation of Hb and eGFR during the study follow-up period (r=0.310, p=0.008). A subgroup analysis was performed, patients were classified in 2 groups according to FCM dose. At baseline, there was no age, comorbidities or eGFR difference among groups. Patients treated with 1000mg had lower Hb (p=0.03) and serum ferritin (p=0.01). At 24±8 weeks both groups showed increases in Hb (p=0.001) and TSAT (p=0.001). Patients treated with 1000mg showed also a significant increase in ferritin (p=0.004). The Pearson correlation confirmed a positive correlation between the variation of Hb and eGFR in the group of patients treated with 1000mg (r=0.467, p=0.019) but not in the group treated with 500mg.

Conclusion
FCM was effective in the treatment of iron deficiency anemia in non-dialysis CKD stage 3 to 5 patients. In our population, the increase of Hb levels correlated with an improvement in eGFR in patients treated with higher doses of FCM, suggesting a positive impact of FCM on kidney function.
MO562ACUTE IMPACT OF A SINGLE HIGH DOSE OF FERRIC CARBOXYMALTOSE ON ENDOTHELIAL FUNCTION IN CKD NON-DIALYSIS PATIENTS
Authors: Mehedinti Ana-Maria , Iosif Liviu , Stoian Irina , Andreiana Iuliana , Capusa Cristina-Stela , Mircescu Gabriel 
Published: May 2021

Abstract

Background and Aims
Anemia is highly prevalent in CKD, and most frequently is caused by iron deficiency. Intravenous iron therapy is often and efficiently used, even in non-dialysis CKD patients. Still, experimental data suggested that intravenous iron could alter endothelial function, rising concerns related to the possible cardiovascular long-term effects. In this regard, we clinically assessed the acute impact of a high dose of iron ferric carboxymaltose (FCM), a commonly used iron formulation, on endothelial function in CKD iron-naive non-dialysis patients.

Method
In this prospective crossover single center study, forty CKD iron-deficient non-dialysis patients [median age 66.5 (56;73) years, 62% female, median estimated glomerular ﬁltration rate 24 (11;36) mL/min, 78% in the very high-risk category according to KDIGO, 90% with hypertension and 40% with diabetes mellitus] were included. The study was approved by Ethics Committee of the UMF “Carol Davila” Bucharest. Pregnancy and breast feeding, anemia of other cause, history of erythropoietin therapy, high-degree inflammation, active malignancies, glomerulonephritis or liver diseases, immunosuppressive therapy, hemoglobin &lt;7g/dl, ferritin &gt; 500 ng/ml and/or transferrin saturation &gt; 50%, baseline flow mediated dilatation (FMD) &lt; 7%, antioxidant supplements and active smoking were exclusion criteria. The effect on endothelial function was clinically assessed by comparing FMD at 15 minutes before and 15 minutes after 2 infusions: first, the comparator (250 mL 0.9% saline), and 24 hours apart, FCM (1000 mg in 250 mL 0.9% saline). FMD was measured using a Doppler ultrasound system according to guidelines recommendations. Wilcoxon paired test was used to test the post- and pre-infusion differences.

Results
Flow mediated vasodilatation and blood pressure at baseline was similar before each intervention. Neither comparator nor FCM infusion had any effect on acute changes in systolic and diastolic blood pressure. Arterial reactivity was not acutely affected after FCM [ΔFCM 0.01 (-0.35;0.15) versus saline solution 0.001 (-0.4;0.5), p=0.9].

Conclusion
A single high dose of ferric carboxymaltose did not acutely impaired endothelial function evaluated by flow mediated vasodilatation, in a CKD non-dialysis cohort.
MO544EFFECT OF DIFFERENT FREQUENCY OF FG-4592 ON CHRONIC KIDNEY DISEASE
Authors: Yin Di , Li Zuolin , Ding Zhao-ying , Liu Bicheng 
Published: May 2021

Abstract

Background and Aims
Hypoxia inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) is a novel small molecule inhibitor in clinical treatment for renal anemia. Several studies have shown that sustained HIF activation may also have deleterious effects, such as tubulointerstitial fibrosis. Here, the potential effects of different treatment frequency of HIF-PHI (FG-4592) on CKD (chronic kidney disease) mice were investigated.

Method
Male C57BL/6J mice were constructed by subtotal nephrectomy of 5/6 to serve as a model for CKD. We then compared four different strategies based on the frequency of FG-4592(intragastric administration, 30mg/kg) over 9 weeks: once a week (qw), twice a week (biw), three times a week (tiw), and every day (qd).
In vitro, HK-2 cells were divided into three groups according to the different administration methods of FG-4592(30μM): FG-4592 for 20h (FG0); FG-4592 for 8h, followed by washing with medium for 12h(FG1); twice FG-4592 for 8h, followed by washing twice with medium for2h(FG2).

Results
Hemoglobin in the biw group, tiw group or qd group was significantly higher than that in vehicle group. EPO, HIF-1α and HIF-2α of tiw group, biw group and qd group were significantly higher than those in vehicle group. Makers of fibrosis and inflammation in qd group were higher than that in vehicle group, while there was no statistical difference in the changes of the above indicators in tiw group and biw group. HIF-1α and HIF-2α were increased in intermittent administration, but the expression of VEGF, makers of fibrosis or inflammation were not affected. In HK2, HIF-1α and HIF-2α were activated by continuous administration of FG-4592. At the same time, the expression of VEGF, inflammatory and fibrosis indicators were increased significantly during continuous administration. In HepG2, EPO was increased in intermittent administration in HepG2 cells without VEGF increasing.

Conclusion
Taken together, our studies demonstrated that FG-4592 administration 2-3 times a week can effectively improve renal anemia without side effects on inflammatory and fibrosis.
MO576ASSOCIATION OF BONE MATERIAL STRENGTH WITH BONE DENSITY IN PATIENTS WITH END-STAGE RENAL DISEASE
Authors: Johnsson Matilda , Qureshi Abdul Rashid Tony , Jankowska Magdalena , Lindholm Bengt , Haarhaus Mathias 
Published: May 2021

Abstract

Background and Aims
Patients with end-stage renal disease (ESRD) have an increased risk of skeletal complications, including an increased fracture risk, which is only partially identified by determination of bone mineral density (BMD). Experimentally, the complex bone-and mineral disorders in ESRD cause disturbances of bone material properties, but these have not been studied in vivo. Determination of bone material strength index (BMSi) by reference point indentation (RPI) is a novel method to determine bone material quality in vivo and can identify patients at increased fracture risk, even in the presence of normal BMD. We determined BMSi in ESRD patients and investigated its association with BMD and serum markers of mineral metabolism.

Method
15 Adult patients with ESRD, scheduled for a living-donor kidney transplantation, were included in this cross-sectional study. Laboratory analyses included calcium, phosphate, PTH 1-84 and alkaline phosphatase. BMSi was determined by RPI with the OsteoProbe RUO in the tibia. Bone mineral density was measured by dual X-ray absorptiometry.

Results
Patients with bone mineral strenght index above median had higher bone mineral density of the right hip and total body than patients below median (p = 0.04). Alkaline phosphatase was lower in patients with BMSi below the median (47 (35-71) U/L vs. 103 (53-318) U/L, p = 0.009). There was a trend towards a significant relationship between length and BMSi (p = 0.09).

Conclusion
We identified for the first time an association of BMSi with BMD and alkaline phosphatase in patients with ESRD. Our findings of an association of BMSi with BMD are in accordance with findings in other populations with increased fracture risk.
MO577EXPANDING THE POTENTIAL BENEFITS OF FERRIC CITRATE FOR IMPROVING IRON-DEFICIENCY ANAEMIA AND MINERAL BONE DISORDER PARAMETERS IN NON-DIALYSIS-DEPENDENT CHRONIC KIDNEY DISEASE PATIENTS: A META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS
Authors: Putra Boby Pratama , Putra Felix Nugraha 
Published: May 2021

Abstract

Background and Aims
Most of non-dialysis-dependent chronic kidney disease (NDD-CKD) patients will suffer from iron-deficiency anaemia (IDA) also mineral and bone disorders (CKD-MBD) as consequences of CKD progression. Ferric citrate (FC) is an iron-based phosphate binder that based on previous studies showed efficacies in improving IDA and CKD-MBD parameters although the results were still inconclusive. This study aims to establish the overall efficacies of FC in improving IDA and CKD-MBD parameters in NDD-CKD patients.

Method
We did comprehensive searching using predefined keywords in online databases of Pubmed, EMBASE, ScienceDirect, and The Cochrane Library, to include all relevant studies from 2000-2020. We included all randomized controlled trials (RCTs) accessing the efficacies of FC in improving IDA and CKD-MBD parameters compared with standard care (SC) in NDD-CKD patients. The CKD-MBD parameters analysed in this study are changes in serum phosphorus (P), serum calcium ions (Ca), alkaline phosphatase (ALP), intact fibroblast growth factors-23 (iFGF-23), C-terminal fibroblast growth factors-23 (cFGF-23), and intact parathyroid hormone (iPTH), while the IDA parameters analysed are changes of haemoglobin (Hb), serum iron (Fe), transferrin saturation (TSAT), and ferritin. Bias risk was accessed by using the revised Cochrane Risk-of-bias (RoB-2) tool. Analysis was performed to provide standard mean difference (SMD) with 95% confidence interval (CI) using random-effect heterogeneity test.

Results
We included six RCTs with total of 1,082 participants met our inclusion criteria. The FC significantly improve CKD-MBD parameters of P (SMD = -0.84. 95% CI = -1.21 to -0.07, p&lt;0.00001, I2 = 74%), iFGF-23 (SMD = -0.43. 95% CI = -0.73 to -0.13, p = 0.005, I2 = 73%), cFGF-23 (SMD = -0.74. 95% CI = -1.12 to -0.35, p = 0.0002, I2 = 78%), and iPTH (SMD = -0.23. 95% CI = -0.40 to -0.06, p = 0.008, I2 = 0%), while the improvement of Ca (SMD = 0.16. 95% CI = -0.07 to 0.38, p = 0.17, I2 = 0%) and ALP (SMD = 0.03. 95% CI = -0.22 to 0.28, p = 0.81, I2 = 14%) are not statistically significant compared with the SC group. The FC also significantly improve IDA parameters of Hb (SMD = 1.10. 95% CI = 0.06 to 2.14, p = 0.04, I2 = 97%), TSAT (SMD = 1.18. 95% CI = 0.67 to 1.69, p&lt;0.00001, I2 = 72%), and ferritin (SMD = 1.10. 95% CI = 0.34 to 1.86, p = 0.004, I2 = 87%) compared with the SC group, unless the improvement of Fe is not statistically significant (SMD = 1.34. 95% CI = -0.28 to 2.95, p = 0.11, I2 = 97%).

Conclusion
The ferric citrate shows potential benefits for improving iron-deficiency anaemia and CKD-MBD parameters in NDD-CKD patients. Nevertheless, further trials are needed to establish the efficacies.
MO578OSTEOCALCIN AND VASCULAR CALCIFICATION IN HEMODIALYSIS PATIENTS: AN OBSERVATIONAL COHORT STUDY
Authors: Keryakos Hesham Kamal Habeeb , Salama Ahmed , Okaily Nagwa , Boulis Mariam 
Published: May 2021

Abstract

Background and Aims
Vascular calcification contributes to morbidity and mortality in patients with ESRD on maintenance hemodialysis. to study the relationship between osteocalcin and vascular calcification.

Method
160 patients with ESRD on maintenance hemodialysis and 60 age-and sex-matched healthy controls were recruited. Serum vitamin K2 and osteocalcin both intact and undercarboxylated were measured. Transthoracic echocardiography was done for valvular calcification and thickening, and carotid duplex was done for carotid intimal medial calcification and thickening.

Results
Hemodialysis patients have higher median serum vitamin K2 (p&lt;0.001), higher undercarboxylated osteocalcin (p&lt;0.001). Only older age, duration of hypertension, and duration of established cardiovascular disease are associated with carotid media-intimal calcification. Old age is a strong predictor of carotid media intimal thickening. Female sex is associated with valvular thickening.

Conclusion
Functional vitamin K deficiency is present in maintenance hemodialysis patients and serum osteocalcin is not associated with cardiovascular calcification.
MO583IN VITRO AND EX VIVO EXPERIMENTS OF VASCULAR CALCIFICATION
Authors: Holmar Jana , Noels Heidi , Jankowski Joachim , Orth-Alampour Setareh 
Published: May 2021

Abstract

Background and Aims
Vascular calcification (VC) is one major complication in patients with chronic kidney disease whereas a misbalance in calcium and phosphate metabolism plays a crucial role. The mechanisms underlying VC have not been entirely revealed to date. Therefore are the studies aiming at the identification and characterization of the mediators/uremic toxins involved in VC ongoing and highly relevant. However, currently many different protocols being used in the studies of vascular calcification processes. This complicates the comparison of study outcomes, composing systematic reviews, and meta-analyses. Moreover, the reproducibility of data is hampered, and the efficiency in calcification research through the lack of a standardized protocol is reduced. In this study, we developed a standardized operating protocol for in vitro and ex vivo approaches to aiming at the comparability of these studies.

Method
We analysed in vitro and ex vivo experimental conditions to study VC.
Vascular smooth muscle cells (HAoSMCs) were used for in vitro experiments and aortas from Wistar rats were used for ex vivo experiments.
The influence of the following conditions was studied in detail:
• Phosphate and calcium concentrations in calcifying media.
• Incubation time.
• Fetal calf serum (FCS) concentration.
The degree of calcification was estimated by quantification of calcium concentrations that were normalized to protein content (in vitro) or to the dry weight of the aortic ring (ex vivo). Additionally, the aortic rings were stained using the von Kossa method.
Optimal conditions for investigating medial vascular calcification were detected and summarized in the step-by-step protocol.

Results
We were able to demonstrate that the degree and the location of VC in vascular smooth muscle cells and aortic rings were highly dependent on the phosphate and CaCl2 concentration in the medium as well as the incubation time. Furthermore, the VC was reduced upon increasing fetal calf serum concentration in the medium.
An optimized protocol for studying vascular calcification in vitro and ex vivo was developed and validated. The final protocol (Figure 1) presented will help to standardize in vitro and ex vivo approaches to investigate the processes of vascular calcification.

Conclusion
In the current study, we developed and validated a standardized operating protocol for systematic in vitro and ex vivo analyses of medial calcification, which is essential for the comparability of the results of future studies.