bluuebunny/crossref_metadata_2025_split huggingface dataset:
TO001EFFECTS OF THE BET-INHIBITOR APABETALONE ON CARDIOVASCULAR EVENTS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS AND ACUTE CORONARY SYNDROME, ACCORDING TO PRESENCE OR ABSENCE OF CHRONIC KIDNEY DISEASE. A BETONMACE TRIAL REPORT
Authors: Kalantar-Zadeh Kam , Ray Kausik K , Nicholls Stephen J , Ginsburg Henry N , Buhr Kevin A , Johansson Jan , Kulikowski Ewelina , Toth Peter P , Sweeney Michael , Schwartz Gregory G 
Published: June 2020

Abstract

Background and Aims
Patients with type 2 diabetes (T2D) and acute coronary syndrome (ACS) are at high risk for recurrent cardiovascular (CV) events, particularly in the presence of chronic kidney disease (CKD). Apabetalone (APB) is a novel inhibitor of bromodomain and extraterminal (BET) proteins. Its cardiovascular efficacy and safety were evaluated in a phase 3 trial, BETonMACE.

Method
BETonMACE was a randomized, double-blind, comparison of effects of ABP or placebo (PBO) on major adverse CV events (MACE) defined as CV-death, non-fatal myocardial infarct or stroke, in 2425 pts with T2D and recent ACS. Here we report MACE plus CHF hospitalization in subjects with or without CKD Stage 3.

Results
Baseline characteristics: median age 62 years, 25.6% female, 87.6% white, 90% high intensity statin use, mean LDL-C 70.3 and HDL-C 33.3 mg/dl, median HbA1c 7.3%, and 11% with CKD Stage 3. Overall in the trial, MACE plus CHF hospitalization occurred in 139 (11.5%) patients with ABP and 173 (14.3%) with PBO (HR 0.78, 95% CI 0.63-0.98). In the subgroup with CKD, MACE plus CHF hospitalization occurred in 16 (12.9%) on APB and 41 (25%) on PBO (HR 0.48, 95% CI 0.26-0.89). In the subgroup without CKD, MACE plus CHF hospitalization occurred in 123 (11.3%) and 132 (12.7%) with APB or PBO, respectively (HR 0.89, 95% CI 0.70-1.

Conclusion
Patients with T2D, ACS, and Stage 3 CKD have a very high risk of subsequent MACE plus CHF hospitalization. The BET protein inhibitor ABP may reduce this risk.
TO002REDUCTION IN THE RATE OF EGFR DECLINE WITH SEMAGLUTIDE VS PLACEBO: A POST HOC POOLED ANALYSIS OF SUSTAIN 6 AND PIONEER 6
Authors: Tuttle Katherine , Cherney David , Hadjadj Samy , Idorn Thomas , Mosenzon Ofri , Perkovic Vlado , Rasmussen Søren , Wolthers Benjamin , Bain Stephen C 
Published: June 2020

Abstract

Background and Aims
The SUSTAIN 6 cardiovascular outcomes trial (CVOT) indicated that once-weekly (OW) subcutaneous (s.c.) semaglutide may have beneficial effects on kidney function. SUSTAIN 6 and the more recent PIONEER 6 CVOT (oral semaglutide) had similar designs and subject populations; both evaluated the effects of semaglutide compared with placebo on important macro- and microvascular outcomes. This post hoc analysis of pooled data from the two trials evaluated the effects of semaglutide vs placebo on kidney function, assessed by estimated glomerular filtration rate (eGFR) slope.

Method
Data for 6,480 subjects from SUSTAIN 6 (OW s.c. semaglutide 0.5 and 1.0 mg or placebo, n=3,297; median follow-up 2.1 years) and PIONEER 6 (oral semaglutide once-daily 14 mg or placebo, n=3,183; median follow-up 1.3 years) were pooled into two groups: semaglutide and placebo. Annual change in eGFR was compared between semaglutide and placebo in patients with eGFR data at baseline, both overall and by baseline eGFR subgroup (≥30–&lt;60 or ≥60 mL/min/1.73 m2). Data were analysed using a linear random regression model with individual intercept and time slope. Estimated treatment difference (ETD) between annual rates of eGFR slope (from baseline to timepoint of interest) was calculated at Year 1 and Year 2 (Year 2 data predominantly from SUSTAIN 6); interaction p-values indicated differences between subgroups.

Results
In the overall treatment population, the annual rate of eGFR change was 0.60 mL/min/1.73 m2 (95% confidence interval [CI]: 0.31;0.90; p&lt;0.0001) lower with semaglutide vs placebo in Year 1. In the subgroup with an eGFR ≥60 mL/min/1.73 m2 at baseline, the ETD for semaglutide vs placebo at Year 1 was 0.48 mL/min/1.73 m2/year (95% CI: 0.13;0.82). Whereas, at Year 1, the subgroup with eGFR ≥30–&lt;60 mL/min/1.73 m2 had an ETD of 1.07 mL/min/1.73 m2/year (95% CI: 0.46;1.68) (Table). Accordingly, a numerically larger difference in ETD was observed in the eGFR ≥30–&lt;60 mL/min/1.73 m2 vs the eGFR ≥60 mL/min/1.73 m2 subgroup (not statistically significant; pinteraction=0.21).

Conclusion
Semaglutide was associated with a significantly smaller decline in renal function compared with placebo in subjects across stages of impaired kidney function at baseline. Although benefits were observed in the overall population, the findings indicate that the primary benefit may be observed in those with established chronic kidney disease.

Table
Annual eGFR change with semaglutide or placebo and ETD between semaglutide and placebo in pooled SUSTAIN 6 and PIONEER 6 trials
TO003CROSSTALK OF UREMIC TOXINS AND INFLAMMASOME IN CHRONIC KIDNEY DISEASE-RELATED COGNITIVE IMPAIRMENT
Authors: LI LUNG-CHIH , CHEN WEI-YU , Chen Jin Po , Lee Wen-Chin , YANG JENG-LIN 
Published: June 2020

Abstract

Background and Aims
Chronic kidney disease (CKD) is getting prevalent and causes big burden to the health care systems worldwide. CKD-associated cognitive impairment (CI) not only influences the behave function, but also results in longer hospitalization and higher risk of mortality. Inflammation is an important pathogenesis of CKD and plays a crucial role in progression of CKD. In this study, we hypothesized that accumulated uremic toxins, especially indoxyl sulfate (IS) and P-cresyl sulfate (PCS) induce neuroinflammation via activation of NLRP3 inflammasome in the brain tissue of CKD animals. This study aims to delineate the crosstalk between uremic toxins and inflammation in CKD-induced CI.

Method
Eight-week-old male C57B6 wildtype and NLRP3 knockout mice received sham and 5/6 nephrectomy to mimic CKD status. AST-120 (Kremezin), a spherical carbon adsorbent, was given orally to mice to neutralize the accumulated uremic toxins. The Y-maze and Morris water maze (MWM) testes were applied to evaluate cognitive function, including the spatial, short-term and long-term memory in shame, CKD, and AST-120 treated CKD mice. HPLC was used to examine the concentration of IS and PCS in the serum and brain tissues. Western blot and immunohistochemistry stain were used to identify the protein expression of target molecules in the brain tissue.

Results
CKD mice showed impaired spatial, short-term and long-term memory; however, 10% AST-120 attenuated CKD-induced memory impairment (Figure 1). IS, but not PCS, elevated in the brain tissues, especially in the frontal cortex and hippocampus. AST-120 reduced CKD-induced IS elevation in the brain tissue, and also ameliorated NLRP3 inflammasome activation in the astrocytes in the frontal and hippocampus. Finally, NLRP3 deficiency reversed the CKD-induced memory impairment (Figure 2).

Conclusion
IS is the major uremic toxin that causes CI in CKD mice via activating NLRP3 inflammasome pathway in the brain tissue. However, AST-120 effectively ameliorates CKD-induced CI.
TO008COMPARATIVE TRANSCRIPTOME AND CO-EXPRESSION NETWORK ANALYSIS REVEALED A POTENTIAL ROLE OF C1QB AND INTERFERON TYPE 1 PATHWAY IN CIRCULATING IMMUNE CELLS OF KIDNEY TRANSPLANTS PATIENTS WITH CHRONIC ANTIBODY MEDIATED REJECTION
Authors: Santoro Gloria , Granata Simona , Pontrelli Paola , Rossi Mattia , Gambaro Giovanni , Grandaliano Giuseppe , Zaza Gianluigi 
Published: June 2020

Abstract

Background and Aims
Chronic antibody-mediated rejection (CAMR) is a multifactorial pathological condition that can affect more that 40-50% of kidney allografts. Its clinical evolution is often silent, and this can delay its diagnosis. Although many advances in understanding the biological mechanisms underlying its onset/development, at the moment, no reliable non-invasive diagnostic biomarkers are available in clinic.

Method
We enrolled 29 patients with biopsy-proven CAMR, 29 stable transplant recipients (controls). Subsequently, the microarray profile of mRNA isolated from peripheral blood mononuclear cells (PBMCs) from 10 randomly selected CAMR patients and 10 controls was evaluated by Agilent technology. For the bioinformatics analysis we employed several statistical algorithms (including ANOVA and Kruskal-Wallis tests adjusted for multiple-tests) and a Weighted Gene Correlation Network Analysis (WGCNA) to select genes biologically associated in co-expressed networks.

Results
935 genes resulted differentially expressed between the two study groups, demonstrating the large biological impact of this pathological condition on circulating immune-inflammatory cells. After WGCNA co-expression analysis, a group of genes (enclosed in a single co-expression module, 13 genes) resulted highly discriminating CAMR versus controls (p&lt;.5.2 e-7, FDR&lt;1%). This module included: Interferon-induced transmembrane proteins (IFITM) 2, 3, 4, confirming previous results by our group. However, the top discriminative gene was C1QB (Complement component 1, q subcomponent, B chain, p &lt;000.1), a key element involved in the classical complement pathway. ELISA confirmed the microarray results on the entire patients’ cohort.

Conclusion
Our study confirmed the role of the type 1 interferon pathway in CAMR and underlined its capability to promote C1QB expression. These effects could contribute to better define the role of innate immunity in CAMR. Finally, C1QB, if validated in a large cohort of patients, could represent a new valuable molecular diagnostic biomarker for this complication.
TO010A NEW IMMUN-TOXICOLOGICAL TEST TO DETECT POLYSULFONE HYPERSENSITIVITY IN HEMODIALYSIS PATIENTS
Authors: Beige Joachim , Wendt Ralph , Rüssmann Despina , Ringel Karl-Peter 
Published: June 2020

Abstract

Background and Aims
Incompatibility of dialysis procedure due to hypersensitivity against dialyzer material which currently is mainly based on polysulfone and derivatives can not be assessed by routine laboratory tests. Although the frequency of such symptoms is suspected to be low (below 2%) such resembles an important clinical problem because dialysis procedures are frequently accompanied by symptoms of non-tolerability with reasons not being entirely clear while circulatory reasons are suspected to play a major role.

Method
To enlighten the role of polysulfone hypersensitivity, we adapted known standardized material immune-toxicological tests (lymphocyte transformation test, basophil degranulation test) to the specific conditions of dialysis and polysulfone material sensitivity. We developed a method of polysulfone micronisation and measured humoral immune response of isolated patient´s lymphocytes when incubated with polysulfone dispersion.

Results
39 samples from 103 patients with suspected polysulfone hypersensitivity showed positive results for type 1 (n=19), type 4 (n=18) or both type (n=2) reactions. There were no significant differences in the level of stimulation measured for DI, SI and lymphogenesis before and after dialysis (average delta -0.4; -0.28; - 1.74, p = 0.71; 0.34; 0.37) and with different dialyzer materials (Tab. 1). Patients with pos. type 4 results (LTT and lymphogenesis) showed highly correlated results in either LTT or lymphogenesis test (Fig. 1, R=0.87, p&lt;0.0001). 8 out of 8 samples from patients with repeated test on different PS showed positive results on either PS. One patient tested positive on PS showed no hypersensitivity with another non-PS (PMMA) material.

Conclusion
This is the first methodological report showing plausible in-vitro results of patients samples concerning polysulfone intolerance. On the first superficial view, a “false-negative” rate of 60% looks rather disappointing, because all samples derived from patients with suspicion of PS hypersensitivity. However, due to the clinical variability of intolerance symptoms and the high prevalence of any problems after HD initiation, mainly of circulatory origin after initiating extracorporeal circuit, this rate may obviously express the true frequency of isolated PS material hypersensitivity in suspected patients. Alternative pathophysiological pathways of material sensitivity like complement activation, remain to be elucidated and incorporated into a comprehensive future testing panel. Further clinical and laboratory research is needed to define true polysulfone hypersensitivity and to enlighten the field of hypothetic subclinical material incompatibility in patients with impaired dialysis tolerability.
TO013ADSORPTION THERAPY AND SEPTIC SHOCK: A RETROSPECTIVE STUDY COMPARING COUPLED PLASMA FILTRATION-ADSORPTION AND CYTOSORB
Authors: Di Maso Vittorio , Grecò Domenico , Cozzi Martina , Bedina Elisa , Gerini Ugo , Olivo Elisa , Leonardi Sabina , Giudici Fabiola , Berlot Giorgio , Bianco Francesco 
Published: June 2020

Abstract

Background and Aims
Septic shock is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Excessive release of cytokines and other inflammatory mediators is a key mechanism and cytokines adsorption therapies are applied in this context to restore a balanced immune homeostasis. Different adsorption techniques are available but there are no studies comparing these different adsorption approaches. The aim of this retrospective observational study was to compare Coupled Plasma Filtration Adsorption (CPFA) and CytoSorbTM in terms of hemodynamic and clinical response, mortality and renal function recovery.

Method
A retrospective observational study was designed enrolling all patients admitted to ICU with a diagnosis of septic shock treated with blood adsorption, either CPFA or CytoSorbTM, from January 2015 to December 2017. Primary endpoints of the study were the assessment of changes in NE dosage, MAP values, SOFA score and PCT levels before and after blood adsorption. Secondary endpoints ICU length of stay (LOS), mortality at 30, 60 and 90 days from adsorption initiation; renal outcome at 30 and 90 days from adsorption initiation.

Results
The study included 28 patients (14 CPFA, 14 CytosorbTM). Adsorption treatment was associated with a significant (p=0.03) improvement in hemodynamics with a Norepinephrine/Mean Arterial Pressure ratio (NE/MAP) of 0.64 (0.14-2.6) pre-treatment vs 0.11 (0.0-0.32) post-treatment regardless of the applied technique. Furthermore, a significant (p&lt;0.001) procalcitonin (PCT) post treatment reduction was demonstrated with a comparable effect in the two groups (p=0.32) (Fig.1). No difference has been found in SOFA score changes (p=0.06) and again without any difference between groups (p=0.17). Overall Survival (OS) rate at 30 days was comparable between groups being 64.3% in CPFA and 78.6% in CytoSorbTM group (p=0.34). Finally, a complete recovery of kidney function at 30 and 90 days has been obtained in respectively 90% and 100% of survived patients without any difference between groups (p=1.00) (Fig.2).

Conclusion
These data confirmed the effectiveness of adsorption in terms of short-term clinical improvement independently from the applied technique, supporting the role of both these adjunctive therapies in septic shock treatment. CPFA and CytosorbTM have comparable effects in terms of hemodynamic improvement, clinical outcome, mortality and recovery of kidney function from septic shock AKI.
P0003ADHERENCE BENEFITS OF ADV7103, AN INNOVATIVE PROLONGED-RELEASE ORAL COMBINATION PRODUCT, IN PATIENTS WITH DISTAL RENAL TUBULAR ACIDOSIS
Authors: Bertholet-Thomas Aurélia , Guittet Catherine , Manso-Silván Maria Asunción , Navas Serrano Victor , Granier Luc André , Cochat Pierre 
Published: June 2020

Abstract

Background and Aims
Distal renal tubular acidosis (dRTA) is a rare disorder leading to impaired net acid excretion by the kidney inducing hyperchloremic metabolic acidosis and hypokalemia. The therapeutic effect of the standard of care is of short duration and requires multiple day and night administrations; it is also often accompanied by gastrointestinal discomfort and poor palatability impacting medication adherence. ADV7103, the first advanced therapy for dRTA, consists of a combination of prolonged-release potassium citrate and prolonged-release potassium bicarbonate granules providing round-the-clock alkali and potassium coverage with twice daily administration. Long-term adherence with ADV7103 is reported, along with acceptability of the product.

Method
B22CS is a multicentre, open-label long-term extension study, evaluating safety, tolerability, acceptability and efficacy of ADV7103 in adult and paediatric patients with dRTA. Adherence was assessed at each study visit up to 24 months, based on accountability of study drug retrieval, laboratory results, and interview of the patients in a diary and expressed as the proportion of patients that presented adherence lower than 50%, between 50% and 74%, between 75 and 90%, and higher than to 90%. Treatment acceptability as well as quality of life of the patients and their parents were assessed using a 100-mm visual analogue scales (VAS).

Results
Table 1 shows the evolution of compliance between Month 6 and Month 24. Overall, of the 29 patients remaining in the study after 24 months, 18 (62%) had adherence rates &gt;90%, 5 (17%) had adherence rates of 75-90%, 6 (21%) had adherence rates of 50-74%, and there were no patients with adherence &lt;50%. Adherence was good in all age groups, with rates of ≥75% in 100% of adults, 63% of adolescents 85% of children, and 67% of infants and toddlers.
Compared to the alkalising treatments they had before the study, more than 80% of the patients perceived both the improvement of the formulation and of the number of daily doses at scores ≥ 75 mm. The overall improvement of quality of life reported by the patients was of 89 ± 19 mm and that reported by their parents was of 90 ± 14 mm after 24 months of treatment.

Conclusion
Adherence to treatment was maintained at a high level throughout the 24 months of the study confirming the good acceptance of ADV7103 therapy.
P0004REDUCED EXPRESSION OF PROXIMAL ACID-BASE TRANSPORT PROTEINS IN KIDNEY TRANSPLANT PATIENTS WITH METABOLIC ACIDOSIS
Authors: Wiegand Anna , Daryadel Arezoo , Imenez da Silva Pedro Henrique , Gaspert Ariana , Wuthrich Rudolf Peter , Wagner Carsten , Mohebbi Nilufar 
Published: June 2020

Abstract

Background and Aims
Metabolic acidosis (MA) is a frequent complication of chronic kidney disease and an independent risk factor for kidney disease progression and mortality. MA is highly prevalent after kidney transplantation (12%-58%)(1). However, there are scarcely any data available on the underlying pathomechanisms and in particular molecular mechanisms involved in metabolic acidosis after kidney transplantation. Thus, we wanted to investigate the expression of key acid base transport proteins in kidney biopsies of kidney transplant recipients with and without metabolic acidosis.

Method
We evaluated 22 kidney transplant biopsies including 9 biopsies from kidney transplant recipients (KTR) with MA, nine biopsies from KTRs without MA (control) and four biopsies from KTRs with MA that were consequently subjected to alkali therapy (Alkali therapy). Immunofluorescence staining was used to identify key renal acid-base transport proteins. Additionally, six control kidneys were analyzed. Immunofluorescence staining was used to identify key renal acid-base transport proteins along the nephron. In addition, RNA extraction and full RNA sequencing analysis of all biopsies –where available- was performed.

Results
In the proximal tubule, we observed reduced immunostaining for the sodium bicarbonate cotransporter NBCe1 (SLC4A4) in the MA group compared to the control and alkali group, whereas the alkali group demonstrated the strongest staining of all three groups. In the distal nephron, expression of the chloride/bicarbonate exchanger Pendrin (SLC26A4) and the B1 subunit of the V-ATPase (ATP6V1B1) were markedly stronger in the alkali and control group compared to the MA group.
Expression of other acid base proteins such as Renal ammonia transporter RhCG (SLC42A3), Carbonic Anhydrase II, Glutamate dehydrogenase, anion exchanger AE1 (SLC4A1) and the B2 subunit of the V-ATPase (ATP6V1B2) showed no difference among all groups. Interestingly, the B2 subunit was absent in the proximal tubule in transplant biopsies of all groups.
In kidney biopsies of transplant recipients with metabolic acidosis RNA abundance of NBCe1, CAII and Pendrin was lower while RhCG and B1 RNA counts were not different when compared to recipients without metabolic acidosis.

Conclusion
Our data demonstrate altered protein and mRNA expression of several key acid base transporters in kidney biopsies of transplant recipients with metabolic acidosis. Treatment with alkali may have the potential to reverse or prevent these changes in renal allografts after transplantation.
P0031AURINE METABOLOMICS: AN EMERGING TOOL FOR DISSECTING BIOLOGICAL ABERRATIONS UNDERLYING RENAL DYSFUNCTION IN BARDET-BIEDL SYNDROME
Authors: Zacchia Miriam , Marchese Emanuela , Caterino Marianna , Ruoppolo Margherita , Capasso Giovambattista 
Published: June 2020

Abstract

Background and Aims
Bardet Biedl Syndrome (BBS) is a rare genetic disorder characterized by a wide range of organ dysfunction, including kidney disease. The severity of renal dysfunction is highly variable in this setting, ranging from tubular defects to the end stage renal disease, with poor genotype-phenotype correlation. Proteomics and metabolomics are powerful tools able to contribute to the better understanding of molecular basis of disease conditions. Our previous studies demonstrated that the urinary proteomic pattern of BBS patients differed from that of healthy subjects, with a set of deregulated proteins including cell adhesion and extracellular matrix organization proteins (1). The present study aims to characterize urine metabolomic profile of BBS patients, in order to identify both 1) potential disease biomarkers and 2) aberrant metabolic pathways underlying renal disease

Method
To this end, in the pilot study urine samples have been collected from 14 adult BBS patients and have been compared with healthy volunteers, using an untargeted strategy. In the confirmation study, 24 BBS patients with wide range of kidney dysfunction have been enrolled, and additional control groups, besides healthy subjects, were included: 1) age-gender-matched chronic kidney disease patients by other causes and 2) obese individuals.

Results
Several metabolites were de-regulated in BBS patients compared with normal subjects (lactic acid, glycolic acid,3-Hydroxypropionic acid, pyruvic acid, 3-hydroxyisobutyric acid, 2-ethyl-3-hydroxy-propionic acid, succinic acid, fumaric acid, erythropentonic acid, 2-hydroxyglutaric acid, 4-hydroxyphenyllactic acid, 3,4-pyridinedicarboxylic acid, retinoic acid, 4-hydroxyphenylacetic acid, palmitic acid, 9-Hexadecenoic acid, oleic acid and 9-Octadecenoic acid). The clusterization performed by MetaboAnalyst tool, revealed a possible deregulation of different metabolic pathways, including glycolysis, TCA cycle, pyruvate metabolism, lipids biosynthesis and glutamate metabolism (p-value &lt;0.01) (figure 1); some of these pathways were described as de-regulated in other ciliopathies (2). In the confirmation study (on-going studies) some metabolites, including lactic acid and intermediates of Krebs cycle, correlated with kidney dysfunction only in the BBS group.

Conclusion
These findings suggest that urine metabolomic fingerprint of BBS patients is different from that of healthy subjects and indicate a possible deregulation of several metabolic pathways; some urinary molecules correlated with kidney dysfunction only in BBS patients, suggesting the specificity of these results.