bluuebunny/crossref_metadata_2025_split huggingface dataset:
MO533: Safety of Roxadustat versus Erythropoiesis-Stimulating Agents for Treatment of Anemia in Patients With Chronic Kidney Disease Incident to or not Receiving Dialysis: Pooled Analysis of Four Phase 3 Studies
Authors: Barratt Jonathan , Dellanna Frank , Portoles Jose , Choukroun Gabriel , De Nicola Luca , Reusch Michael , Young James , Dimkovic Nada 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Patients with late-stage chronic kidney disease (CKD) who are non–dialysis-dependent (NDD) or incident to dialysis (ID) (e.g. initiated dialysis within the last 4 months) or dialysis-dependent (DD) represent a vulnerable population at increased risk for morbidity and mortality despite significant clinical advancements in recent years. The safety of roxadustat in patients with NDD or ID-DD CKD requires further elucidation.

METHOD
In this post-hoc exploratory analysis, safety results from eligible patients with anemia of CKD enrolled in four phase 3, randomized, open-label studies [NDD (DOLOMITES) or ID-DD (SIERRAS, HIMALAYAS, ROCKIES)] were pooled and compared roxadustat to an erythropoiesis-stimulating agent (ESA). Endpoints were time to major adverse cardiovascular event [MACE; myocardial infarction, stroke and all-cause mortality (ACM)] and MACE+ (MACE plus congestive heart failure or unstable angina requiring hospitalization), ACM, and treatment-emergent adverse events (TEAEs). MACE and MACE + were evaluated for non-inferiority using hazard ratios (HRs) at 1.8 and 1.3-upper margins, respectively, and 95% confidence intervals (CIs). TEAEs were descriptively summarized.

RESULTS
In total, 2142 patients were evaluated (1083 roxadustat; 1059 ESA; 616 NDD; 1526 ID-DD). Roxadustat was non-inferior to ESA for risk of MACE [HR 0.79 (95% CI 0.61–1.02)] and MACE+ [HR 0.78, (95% CI 0.62–0.98)] with a consistent finding for ACM [HR 0.78 (95% CI 0.57–1.05)]. TEAEs were generally comparable between roxadustat and ESA groups, including any TEAE [incidence rate per 100 patient-exposure years (IR/100 PEY) 56.1 versus 53.5], TEAEs leading to discontinuation of study drug (IR/100 PEY 6.7 versus 5.1) and TEAEs leading to death (IR/100 PEY 6.9 versus 7.4). The most frequent (IR/100 PEY) TEAEs were hypertension (roxadustat 12.8, ESA 12.3), end-stage kidney disease (roxadustat 6.6, ESA 6.1), diarrhea (roxadustat 7.1, ESA 4.8) and hyperkalemia (roxadustat 4.3, ESA 4.8).

CONCLUSION
There was no evidence of an increased risk of cardiovascular events or mortality with roxadustat compared with ESA in patients with anemia who have NDD or ID-DD CKD. Although TEAE development occurred commonly in both the roxadustat and ESA groups, patients infrequently discontinued a study drug because of an adverse event.
MO553: Impact of the Internal Parathyroid Clock on the Regulation of Parathyroid Gene Expression
Authors: Egstrand Søren , Lerche Mace Maria , Morevati Marya , Nordholm Anders , Olgaard Klaus , Lewin Ewa 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Proper rhythms in metabolism, hormone secretion and activity are maintained by a molecular circadian clock. The central clock in central nervous system (CNS) receives light input via retina to regulate timing of activity. Peripheral clocks are found in a number of tissues regulating an estimated 8–10% of all expressed genes[1]. We have previously shown that an internal circadian clock operates in the parathyroid gland (PTG) which is disturbed in a rat model of chronic kidney disease (CKD)[2].
Here, we examined the PTG transcriptome of wildtype mice over 24-h and compared with our novel mouse strain with PTG-specific circadian clock knockdown (by PTG-specific knockdown of core circadian clock gene Bmal1) to investigate the role of the PTG clock.

METHOD
PTG-specific knockdown of Bmal1 was generated by crossing PTHcre-mice with Bmal1flox/flox mice (WT) creating PTHcre; Bmal1flox/flox mice (KD). PTGs of WT and KD were harvested at 4-h interval and 24-h gene expression was examined by RNAseq. Circadian rhythmicity was assessed by cosinor-analysis and JTK_CYCLE algorithm. Cluster analysis was performed using the Mfuzz package in R. The clusterProfiler R package was used for gene ontology enrichment and gene set enrichment analysis (GSEA) with FDR-adjusted P-value at &lt; 0.05.

RESULTS
A total of 6.85% of all expressed genes were significantly rhythmic in the wildtype PTG, including parathyroid signature genes Casr, Vdr, Klotho, Fgfr1 and Gcm2. Rhythmic genes were divided into nine clusters based on similar expression profile, indicating common regulation. Gene ontology analysis revealed that five clusters showed significant enrichment of genes involved in regulating transcription (cluster 1), mitochondrial ATP synthesis by oxidative phosphorylation (cluster 2), secretion (cluster 3), peptide biosynthesis (cluster 4) and cell cycle (cluster 5) (Figure 1).
KD mice had global dampening of rhythmicity of PTG circadian clock genes as well as parathyroid signature genes compared to WT and significant downregulation of genes involved in mitochondrial ATP synthesis at four consecutive timepoints compared to WT by GSEA analysis (Figure 2A + B). Gene ontology analysis of all downregulated genes across timepoints in KD mice revealed multiple interconnected enriched terms related to mitochondrial ATP synthesis (Figure 2C).

CONCLUSION
Dampened rhythm of PTG circadian clock genes also reduced rhythmicity of parathyroid signature genes and downregulated genes involved in mitochondrial function and ATP synthesis in four separate comparisons. This indicates importance of the internal PTG molecular clock for parathyroid function.
MO554: Roxadustat Improves Renal Osteodystrophy by Dual Regulating Bone Remodeling
Authors: LI Luyao , LI Afang , Zuo LI 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Renal osteodystrophy (ROD) is a complication of chronic kidney disease (CKD) resulting in increased susceptibility to fractures. Therefore, developing effective drugs to prevent and treat ROD is vital. Accumulating evidence suggested stabilization of hypoxia-inducible factor-1α (HIF-1α) could promote bone formation. Roxadustat is a novel HIF stabilizer to treat renal anemia in CKD patients. This study aims to investigate the effects of roxadustat on bone remodeling using a CKD rat model.

METHOD
A total of 24 8-week-old male Sprague–Dawley rats were divided into three groups (n = 8/group): the normal group (Normal), CKD group and CKD + Roxadustat group. For induction of CKD, the diet containing 0.5% (w/w) adenine was given to the rats for the first 4 weeks. Roxadustat (10 mg/kg, by gavage) was given every other day from the third week of CKD induction for 4 weeks. Then blood was collected to test hemoglobin (Hb) concentrations, serum levels of creatinine (Cr), calcium (Ca), phosphorus (P), intact parathyroid hormone (iPTH) and bone turnover markers including bone alkaline phosphatase (BAP), osteocalcin (OCN) and tartrate-resistant acid phosphatase 5b (TRACP-5b). Left femurs were subjected to micro-computed tomography (micro-CT) to evaluate bone mineral density (BMD), bone volume/total volume (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th) and trabecular separation (Tb.Sp). Left tibiae were collected to calculate osteoclast surface/bone surface (Oc.S/BS), osteoclast number/bone surface (N.Oc/BS), osteoblast surface/bone surface (Ob.S/BS) and osteoblast number/bone surface (N.Ob/BS). One-way analysis of variance followed by Tukey HSD post hoc test was used for comparisons. P &lt; 0.05 was statistically significant.

RESULTS
CKD rats exhibited remarkably higher serum Cr, P, iPTH, TRACP-5b levels and obviously lower Hb and serum Ca levels compared with the normal group. Whereas roxadustat treatment significantly decreased iPTH, TRACP-5b and increased Hb, BAP and OCN levels in CKD rats. CKD induced remarkably decreased BMD, BV/TV, Tb.N, Tb.Th and dramatically increased Tb.Sp compared with the normal group. However, roxadustat treatment improved these changes in CKD rats. CKD rats had increased Oc.S/BS, N.Oc/BS, Ob.S/BS and N.Ob/BS compared with the normal group. Roxadustat decreased Oc.S/BS, N.Oc/BS but further increased Ob.S/BS and N.Ob/BS in CKD rats.

CONCLUSION
Roxadustat alleviated bone loss and bone microstructure deterioration of CKD rats by promoting bone formation and inhibiting bone resorption.
MO555: Exosomes From Endothelial Cells to Smooth Muscle Cells Induce Vascular Calcification in Early Chronic Kidney Disease
Authors: Liao Ruoxi , Qin Zheng , Jiang Luojia , Xiong Yuqin , LI Jiameng , Wang Liya , LI Yupei , Han Mei , Su Baihai 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Vascular calcification can occur in the early stages of chronic kidney disease (CKD) and result in a poor prognosis. How the calcification signal in the blood is transduced from endothelial cells in the tunica intima to vascular smooth muscle cells in the tunica media in the early stages of CKD is still unknown. The aim of this study was to explore the role of exosomes in signal transduction in vascular calcification.

METHOD
Exosomes were isolated from normal phosphate- and high phosphate-stimulated human umbilical vein endothelial cells (HUVECs) by superspeed centrifugation. We used transmission electron microscopy, molecular size analysis and Western blot analysis of exosome markers to identify exosomes (Figure 1). VSMC calcification was assessed by Alizarin Red Staining and Western blot. Proteomics analysis and miRNA microarray analysis were carried out to detect the differences in exosomal proteins and miRNAs. The results were analysed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis.

RESULTS
Fluorescence microscopy verified that VSMCs took up exosomes from HUVECs. Exosomes isolated from high phosphate-stimulated HUVECs (HP-HUVEC-exos) induced VSMC calcification (assessed by Alizarin Red Staining), increased osteopontin expression and increased alkaline phosphatase activity (Figure 2). Proteomics analysis showed different protein expressions including STAT1, STAT3, HDAC1, PARP1, WDR5 et al. MiRNA microarray analysis showed different miRNA levels including miR-223–3p, miR-6776–5p, miR-6851–5p, miR-2116–3p, miR-6849–5p et al. (Figure 3). Target GO analysis showed that both miRNA and protein difference focused on some biological processes (RNA splicing, mRNA processing, RNA targeting), molecular function (cadherin binding, cell adhesion molecule binding, ubiquitin-like protein ligase binding) and cellular component (focal adhesion, cell-substrate junction, spliceosomal complex). KEGG analysis revealed that both miRNA and protein differences were focused on pathways associated with the cell cycle, virus infection and protein processing in the endoplasmic reticulum.

CONCLUSION
Exosome-mediated miRNA and protein transfer from endothelial cells to VSMCs may induce vascular calcification via RNA processing, protein processing and cell adhesion.
MO558: Chronic Kidney Disease and Gastroparesis: What is the Association?
Authors: Sandoval Terra Campos Guelli Mariana , Correa Tulio , Silva Isabella , Zampier Daniela , Costa Leticia , Dias Lorena , Guidoreni Angela 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Chronic kidney disease (CKD) can predispose individuals to multiple extrarenal manifestations, such as anemia, bone disease, heart disease and electrolyte disorders. In addition, some patients with CKD can present with gastrointestinal (GI) symptoms, but the pathogenesis of this condition is still unclear. Symptoms of gastroparesis include early satiety, pyrosis, epigastric pain, nausea and vomiting, which may lead to caloric and electrolyte deficiencies as well as significant weight loss. Therefore, the aim of this study was to analyze the association between CKD and gastroparesis.

METHOD
A systematic literature review was conducted following the PRISMA guidelines. Papers were selected searching PubMed/Medline, SciELO and LILACS databases using the terms (chronic kidney disease OR CKD) and (gastroparesis OR gastric emptying) in January 2022. The inclusion criterion was limited to observational studies that evaluated the association between CKD and gastroparesis. There were no language or publication date restrictions.

RESULTS
Among the 111 papers initially identified, 14 were eligible for this review after full texts were read. Dysmotility-like dyspeptic complaints and delayed gastric emptying can be prevalent in CKD patients. Gastric hypomotility appears to be an important factor in the generation of GI symptoms in patients with CKD. Different pathophysiological mechanisms, such as electrolyte imbalance, gastric mucosal edema and direct toxicity of uremic retention molecules can play a role in inducing gastroparesis in patients with CKD. Serum levels of several polypeptide hormones involved in the modulation of GI motility [e.g. gastrin, cholecystokinin (CCK) and neurotensin] and the regulation of hunger and satiety (e.g. glucagon, CCK) were significantly altered as a consequence of renal insufficiency and may play a major role in gastrointestinal dysmotility. Patients with CKD showed impaired gastric myoelectrical activity in response to food and high levels of GI hormones. Delayed gastric emptying contributes to malnutrition, which may potentially have a broad impact in the prevention and treatment of CKD and its complications. Gastric emptying tests are valuable in identifying occult gastroparesis in high-risk patients and may guide the selection of prokinetic therapy, which can significantly increase levels of serum albumin and improve general prognosis. Electrogastrography is an interesting noninvasive technique to evaluate gastric motility in patients with severe chronic renal failure.

CONCLUSION
The studies suggest that patients with CKD are at higher risk of developing gastroparesis and dysmotility-like dyspeptic complaints. Nevertheless, more studies are needed to provide high-quality evidence.
MO566: Relationship Between Cholesterol Intake and Development of Chronic Kidney Disease: A Community-Based Prospective Cohort Study
Authors: Park Joonbyung , Kim Hyoungnae , Noh Hyunjin , Seok Jeon Jin , Hyo Kwon Soon , Lee Haekyung , Cheol Han Dong 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Globally, the incidence and prevalence of CKD have been increased. Also, CKD DALYs and death due to CKD have been increased (DALYs: The disability-adjusted life-year).[1] CKD puts a lot of mental and economic burden on an individual’s life and lowers the quality of life.[2] As CKD progress, kidney-specific risk factor for cardiovascular events and disease are increased.[3] Dyslipidemia is generally known to be associated with the development and progression of chronic kidney disease.[4] However, it is unclear whether limiting cholesterol intake helps prevent CKD. Recent studies have reported that there is no association between cholesterol intake and cardiovascular disease.[5] The aim of our study is to analyze the relationship between cholesterol intake and the development of CKD in a general population.

METHOD
We included 9226 subjects without CKD from the Korean Genome and Epidemiology Study. The amount of daily cholesterol intake was assessed by food frequency questionnaire. The primary outcome was the development of CKD, which was defined as an estimated glomerular filtration rate (eGFR) of &lt; 60 mL/min/1.73 m2 and/or proteinuria (≥1+).

RESULTS
The mean age was 55.7 ± 8.8 years and 39.6% of subjects were men. The cholesterol intake was only significantly correlated with serum HDL cholesterol but not with total and non-HDL cholesterol. Moreover, this significant relationship was disappeared after adjusting for daily fat intake. During median follow-up duration of 11.4 years, 778 (8.5%) CKD events occurred. In multivariable Cox analysis, serum total cholesterol was significantly associated with incident CKD (hazard ratio [HR] 1.005, 95% confidence interval [CI]: 1.003–1.007; P &lt; 0.001). However, cholesterol intake was not associated with incident CKD both in subjects with dyslipidemia (HR: 1.001; 95% CI: 1.000–1.002; P = 0.205) and without dyslipidemia (HR: 0.999; 95% CI: 0.997–1.000; P = 0.134).

CONCLUSION
Cholesterol intake was not correlated with serum cholesterol levels with considering fat intake. In addition, cholesterol intake was not associated with increased risk of CKD in the general population. Therefore, it may not be necessary to limit cholesterol intake to prevent CKD in this population.
MO570: Effects of Dark Chocolate on Inflammation and Oxidative Stress in Patients With Chronic Kidney Disease on Hemodialysis
Authors: Mafra Denise , M. Ribeiro Marcia , Fanton Susane , R. Paiva Bruna , G. Baptista Beatriz , Alvarenga Livia , Cardozo Ludmila 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Patients with chronic kidney disease (CKD), especially on hemodialysis (HD), have a high prevalence of cardiovascular mortality, with oxidative stress (OE) and inflammation as the main contributors. Persistent inflammation from the early stages of CKD is caused by several factors, including increased production of reactive oxygen species (ROS), leading to OE, which in turn induces inflammation by activating the nuclear factor-kB pathway, causing the overproduction of inflammatory cytokines such as tumour necrosis factor-alpha (TNF-α) and interleukins (IL). Dark chocolate is rich in polyphenols, which have antioxidant, anti-inflammatory and cardioprotective properties, and it could be an alternative nonpharmacological to mitigate inflammation and complications of CKD. Therefore, this study aimed to evaluate the effects of dark chocolate on oxidative stress and inflammation in patients with CKD on HD.

METHODS
This is a longitudinal clinical trial performed with 46 patients with CKD on a regular dialysis program (3 dialysis sessions per week). A group received 40 g of dark chocolate during HD sessions, totaling 120 g per week, for 2 months, and a group did not receive any intervention. Plasma levels of TNF-α and IL-6 were evaluated using the ELISA method. Thiobarbituric acid reactive substances were performed to evaluate lipid peroxidation as malondialdehyde (MDA). Routine parameters were also analyzed using commercial kits. Changes in parameters were evaluated between the pre- and post-treatment.

RESULTS
Thirty-five patients performed the chocolate group (18 men, 53.4 ± 12.9 years old and 43.2 ± 30 months on HD) and 11 patients (7 men, 46.7 ± 10.9 years old and 55.2 ± 18.7 months on HD) the control group. Although TNF-α plasma levels did not reduce significantly after chocolate, the levels were increased in the control group (Table 1 and Fig. 1). The potassium plasma levels were reduced (from 5.9 ± 0.8 to 5.5 ± 0.8 mg/dL, P &lt; 0.05) and phosphorus plasma levels did not change in the chocolate group (5.9 ± 1.7 to 5.8 ± 1.6 mg/dL). In the control group, both parameters did not change after 2 months.

CONCLUSION
Two months of dark chocolate intervention seem to modulate the TNF-α plasma levels (inflammation marker) in patients with CKD on hemodialysis. It is important to emphasize that dark intervention in this study did not increase the phosphorus plasma levels in patients with CKD on HD.
MO575: Possible Benefits of a Low Protein Diet in Older CKD Patients at Risk of Malnutrition: A Pilot Randomized Controlled Trial
Authors: Vettoretti Simone , Caldiroli Lara , Armelloni Silvia , Mattinzoli Deborah , Ikehata Masami , Molinari Paolo , Alfieri Carlo , Messa Piergiorgio , Castellano Giuseppe 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Current guidelines do not clarify whether older patients with advanced chronic kidney disease may benefit of low protein diet if they are at risk of malnutrition. We compared the effects of normo-calorie/normo-protein (NP) and normo-calorie/low protein diet (LP) on nutritional status and metabolic complications related to the progression of kidney damage in these patients.

METHOD
This pilot study had an open label randomized-controlled design (ClinicalTrials.gov Id: NCT05015647). Thirty-five patients were treated for six months with two different diets (LP = 17) and (NP = 18). Malnutrition was assessed by Malnutrition Inflammation Score and International Society of Renal Nutrition and Metabolism criteria. Renal function was assessed by creatinine and cystatin C based eGFR.

RESULTS
At the end of the study, Malnutrition Inflammation Score was improved in both LP and NP groups (respectively: 3 ± 3 versus 6 ± 1.5, P = 0.020 and 3 ± 2.5 versus 6 ± 2, P = 0.012), and prevalence of protein energy wasting syndrome decreased only in LP. LP group had higher eGFRcys-C (17 ± 6 versus 12 ± 4 mL/min/1.73 m2; P &lt; 0.05), lower serum urea (105 ± 65 versus 138 ± 30 mg/dL; P &lt; 0.05) and lower PTH (68 ± 10 versus 99 ± 61 ng/L; P &lt; 0.05) than NP. Serum and urinary phosphorous did not change while FGF23-intact and FGF23 c-terminal increased in both groups (FGF23-intact in LP: 70[48;98] versus 126[90;410] pg/mL, P &lt; 0.01 and in NP: 86[57;194] versus 143[119;186] pg/mL, P &lt; 0.01; FGF23 c-terminal in LP: 77[30.3;112] versus 111[63;384] RU/mL, P &lt; 0.01 and in NP: 142[56.6;175] versus 157[76.7;281] RU/mL, P &lt; 0.01).

CONCLUSION
LP diet has a favorable impact on nutritional status as much as NP diet with possible greater benefits on the progression of kidney disease and some of its metabolic complications.
MO577: The Role of Nutritional Therapy in CKD: Low Protein Diet VERSUS Mediterranean Diet, A Multicentric Study
Authors: Gembillo Guido , Calabrese Vincenzo , Siligato Rossella , Longhitano Elisa , Metro Daniela , Santoro Domenico 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Nutritional therapy exerts a positive role for the prevention, progression and treatment of chronic kidney disease (CKD) and cardiovascular diseases. An individualized, stepwise approach is essential to guarantee high adherence to nutritional patterns and to reach therapeutical goals. Which is the best dietary regimen is still a matter of discussion.

METHOD
We performed an observational, multicentric study on 75 non-diabetic patients with CKD stage III-IV with a one-year follow-up (Table 1). We compared two of the most used dietary regimens for CKD patients: low protein diet (LPD) and the Mediterranean diet (MD).

RESULTS
Our results showed a significant renal function preservation in LPD compared with the MD cohort patients. An unadjusted model with a general linear model for repeated measures demonstrated a MD significant effect on creatinine clearance compared with LPD with an estimate marginal mean of −9.98 mL/min (95% CI: −15.6 to −4.3). Adjusted model for age, BMI and sex confirmed this significance in between-group in the joint mean difference (9.34, 95%CI: −15.44 to −3.24) (Fig. 1).

CONCLUSION
An adequate dietary strategy is of pivotal importance in the treatment of chronic diseases like CKD. Our study aimed to bring more evidence in the contest of nutritional therapy, demonstrating that beside the central importance of the MD for selected patients, LPD seems to have superior therapeutical benefits on kidney function preservation.