bluuebunny/crossref_metadata_2025_split huggingface dataset:
FC076: Development of a High-Throughput in Vivo Drug Screening Assay Using a FSGS-Like Zebrafish Model
Authors: Schindler Maximilian , Siegerist Florian , Lange Tim , Bach Sophia-Marie , Klawitter Marianne , Gehrig Jochen , Ellinger Bernhard , Gul Sheraz , Endlich Nicole 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Focal segmental sclerosis (FSGS) is a severe histopathological condition which often results in end-stage renal disease. Loss of podocytes and severe changes of podocyte foot process morphology accompanied by proteinuria are the hallmarks of FSGS. Since no therapeutic agents are available until now, further efforts must be made to identify new drugs to treat this disease. The zebrafish larva is a widely used kidney research model as the morphology and function of zebrafish and mammalian glomeruli are very similar. Since our group has already established a FSGS-like zebrafish injury model based on the nitroreductase-metronidazole cell ablation system, we have developed a high-throughput based in vivo drug screening assay.

METHOD
We used a zebrafish screening strain that expresses mCherry and the bacterial enzyme nitroreductase in podocytes. Additionally, a circulating vitamin-D-binding eGFP fusion protein with a size of 78 kDa is expressed and serves as a read-out for proteinuria. Incubation with 80 µM metronidazole for 24 h at 4 days post-fertilization (dpf) induces an FSGS-like phenotype in these larvae. A library of 138 epigenetic drugs were screened and the results are presented herein. Groups of 12 larvae received injury induction as well as drug treatment and were transferred individually into 96-well plates prepared with custom agarose molds. Larvae were oriented laterally and imaged with a high-content screening microscope (Acquifer Imaging Machine). The eGFP signal in the caudal vasculature as well as the glomerular mCherry signal served as readout systems. At 6 dpf, the same larvae and regions were imaged again. Custom written FIJI codes automatically segmented and measured the fluorescence intensities of both readouts and timepoints. For each larva, intensity ratios were determined and the ratios of each treatment group served as the input for statistical analysis.

RESULTS
Treatment for 24 hours with 80 µM metronidazole resulted in a measurable decline of the eGFP signal in the vasculature and of the podocyte mCherry signal compared to the vehicle (DMSO) group. Simultaneous treatment of metronidazole with the 138 drugs in the epigenetics library resulted in beneficial outcomes in varying degrees (9 drugs were positive, 36 compounds were lethal).

CONCLUSION
This new in vivo semi-automated high-throughput compatible drug screening assay allows rapid identification of FSGS protective drugs. Here we screened 138 epigenetic drugs, which led to the identification of 9 potential drugs which have had a beneficial effect on podocytes and/or the glomerular filtration barrier.
FC 100: Echocardiography: A Promising Screening and Monitoring Tool for Central Venous Stenosis in Hemodialysis Patients
Authors: Liao Ruoxi , Wang Hui , Wang Shanshan , Cui Tian-Lei , Fu Ping 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Central venous stenosis (CVS) is a common but underestimated complication of vascular access in hemodialysis (HD) patients. The objective of this study was to compare the diagnostic efficacy of echocardiography and computed tomography angiography (CTA) for CVS in HD patients with access dysfunction.

METHOD
This was a retrospective study. HD patients with access dysfunction admitted to our institute between 1 April 2021 and 31 October 2021 were enrolled. Echocardiography, CTA and digital subtraction angiography (DSA) were performed to assess CVS. Receiver operator characteristic analysis was performed to compare the diagnostic efficacy of echocardiographic parameters and CTA for CVS, with DSA results as the reference standard.

RESULTS
A total of 167 HD patients (70 males, age 63 ± 13 years) were enrolled, among whom 99 (59%) were diagnosed with CVS based on DSA and only 9 presented with significant clinical symptoms of CVS. Among all of the echocardiographic parameters, superior vena cava (SVC) diameter showed the highest efficacy for CVS diagnosis (cut-off value ≤12 mm, specificity 70%, sensitivity 77%), which was equivalent to CTA (AUC 0.79 versus 0.81; P = 0.646) (Figure 1A). Some of the other echocardiographic parameters, including maximal and minimal right atrial volume (RAV), also showed moderated diagnostic efficacy for CVS. The specificity and sensitivity increased when echocardiography and CTA were used to diagnose brachiocephalic vein and SVC stenosis instead of total CVS (Figure 1B). Patients with CVS had a smaller SVC diameter (9.8 ± 3.5 mm versus 13.7 ± 3.3 mm; P &lt; 0.001) and a reduced right RAV [RAV max median 20 (interquartile range 15–27) mL versus 31(24–39) mL; P &lt; 0.001; RAV min 8 (5–10) mL versus 14 (10–17) mL; P &lt; 0.001] compared with non-CVS patients. Spearman's rank correlation showed a significant negative correlation between RAV and hemodialysis vintage.

CONCLUSION
With equivalent diagnostic power for CVS to CTA, echocardiography has the potential to be used as a screening and monitoring tool for CVS in HD patients with access dysfunction.
FC 102: Daily Phosphorus Intake, its Source and Mortality in Adults on Hemodialysis: The Diet-Hd Study
Authors: Su Guobin , Saglimbene Valeria , Bernier-Jean Amélie , Wong Germaine , Natale Patrizia , Ruospo Marinella , Craig Jonathan , Hegbrant Jorgen , Jesus Carrero Juan , Strippoli Giovanni 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Elevated serum phosphorus is associated with increased mortality in dialysis patients. Since the bioavailability of dietary phosphorus intake (DPI) varies based on its source and might contribute to serum phosphorus differently, the aim of the study is to investigate the association between total DPI and DPI from different sources with mortality in patients treated with hemodialysis.

METHOD
DPI (plant, animal and other sources) was ascertained by the Global Allergy and Asthma European Network food frequency questionnaire within the DIET-HD study, a multinational cohort study of European and South American adults on maintenance hemodialysis. Adjusted Cox regression analyses were conducted to evaluate the association between total and source-specific DPI (both as tertiles and continuous in fraction or in absolute amount) with all-cause and cardiovascular mortality.

RESULTS
A total of 8110 patients were followed for a median of 3.8 years (26 074 person-years). There were 2953 deaths, of which 1160 were cardiovascular-related. The median (interquartile range) DPI was 1388 (961–1994) mg/day, with only 12% (995/8110) of participants consuming the recommend range of DPI (800–1000 mg/day). Each standard deviation (SD, 896 mg/day) increase in total DPI was associated with higher all-cause mortality [hazard ratio (HR) 1.14; 95% confident interval (95% CI) 1.02–1.27] and cardiovascular mortality (1.45; 95% CI 1.08–1.96). Each SD (17%) increase in the fraction of DPI from plant sources was associated with lower all-cause mortality (HR 0.92; 95% CI 0.85–0.99) and marginally in cardiovascular mortality (HR 0.93; 95% CI 0.85–1.01). Each SD (9%) increase in the fraction of DPI from other source [HR: 1.06; 95%CI 1.02–1.10)] was associated with higher all-cause mortality. In contrast, each SD (17%) increase in the fraction of DPI from animal source was not associated either all-cause (HR: 1.02; 95% CI 0.96–1.07) or cardiovascular mortality (HR 1.07; 95% CI 0.98–1.16). Increased absolute amount of DPI from animal or other source were associated with both all-cause and cardiovascular mortality.

CONCLUSION
A higher total DPI is associated with increased all-cause and cardiovascular death. This positive association is driven by the DPI from animal and other sources, while higher DPI fraction from plant associated with reduced all-cause mortality.
FC 117: Clinical Validation of Automated Urinary Chemokine Assays for Non-Invasive Detection of Kidney Transplant Rejection: A Large Prospective Cohort Study
Authors: Van Loon Elisabet , Tinel Claire , Callemeyn Jasper , Coemans Maarten , Van Craenenbroeck Amaryllis , Vaulet Thibaut , Anglicheau Dany , Naesens Maarten 
Published: May 2022

Abstract

BACKGROUND AND AIMS
The urinary chemokines CXCL9 and CXCL10 have been extensively studied as biomarkers for kidney transplant rejection. However, final validation in a sufficiently large, real-world prospective cohort is needed to determine the relation to rejection subtypes and clinical confounders, the context of use and the added benefit for clinical practice.

METHOD
In this single-centre prospective cohort study, we analysed 1559 biopsy-paired urine samples at both indication and protocol time points from 622 kidney transplants performed between April 2013 and July 2019. We quantified urinary CXCL9 and CXCL10 using automated immunoassays and normalized the values to urinary creatinine. In addition to evaluating diagnostic performance for Banff-grade rejection, we also considered rejection as assessed by the molecular microscope.

RESULTS
The urinary chemokines strongly associated with the inflammation severity in the biopsy, when considering classical semi-quantitative histological scores, but also when considering molecular rejection scores. The diagnostic performance of urinary chemokines alone was moderate for Banff acute rejection, and increased when considering treated rejection or molecular rejection instead (Figure 1). Taking into account confounding factors rather than excluding them, an integrated model of urinary chemokines with eGFR, donor-specific antibodies, time post-transplant and polyoma viremia had a high diagnostic value for acute rejection (N = 150) [ROCAUC 82.6%, 95% confidence interval (95% CI) 78.9–86.2] and added value on top of clinical standard-of-care. The integrated score would help to safely avoid 59 protocol biopsies per 100 patients when the predicted rejection risk is less than 10%.

CONCLUSION
The integration of urinary chemokines and clinical markers allows for personalized noninvasive monitoring of rejection probability and enables to importantly and safely reduce the number of unnecessary biopsies. We expect this study to pave the way for the final implementation of urinary chemokine measurements as noninvasive markers of rejection in routine clinical follow-up after kidney transplantation.
MO084: Resistant Hypertension is Associated With an Increased Cardiovascular Risk Compared to Patients Controlled on a Similar Multi-Drug Regimen
Authors: Leiba Adi , Angel-Korman Avital 
Published: May 2022

Abstract

BACKGROUND AND AIMS
The long-term risk associated with resistant hypertension as compared with other phenotypes of hypertension is still unclear. This has been a result of heterogeneity in the definition of both resistant and non-resistant hypertension. We aimed at assessing the cardiovascular and renal outcomes of resistant hypertension compared with a similarly treated (≥3 medication classes including a diuretic) patients whose blood pressure is under control.

METHOD
This retrospective cohort study utilized the computerized database of Maccabi Healthcare Services (MHS). Over a 10 years follow up, a historical cohort of patients with baseline uncontrolled resistant hypertension were compared to a similar cohort of hypertensive examinees, whose BP was well controlled. Clinical outcomes were assessed using Cox regression multivariable analyses.

RESULTS
—A total of 1487 patients (50% males, mean age at baseline = 68.3 ± 10.4 years) were included in the resistant hypertension cohort and 1343 patients (50% males, 66.2 ± 10.6y) in the controlled hypertension reference group. After adjusting for age, sex, BMI and patients’ comorbidities, uncontrolled resistant hypertension was associated with a hazard ratio (HR) of 1.35 (95% CI: 1.08–1.69) for incidence of ischemic heart disease and 1.51 (1.06–2.16) for secondary cardiovascular events compared to the reference group. It also was associated with an increased risk of stroke or TIA (HR = 1.36; 95% CI: 1.00–1.86). Patients with resistant hypertension had more hospitalization days (mean = 4.2 days versus 3 days per year, P &lt; 0.001), and more emergency room visits during follow-up period (83.3% versus 77%, P &lt; 0.001). Overall, uncontrolled resistant hypertension was associated with a 19% (95% CI: 11–29%) increase in the direct healthcare expenditure during the first year of follow-up.

CONCLUSION
Resistant hypertension is associated with a 35% increased risk of both cardiovascular and cerebrovascular events, when compared with a similarly treated hypertensive patients whose blood pressure is under control. Physicians should overcome therapeutic inertia and add a fourth or a fifth anti-hypertensive medication, even when treating patients who are already on a multi-drug regimen.
MO088: Peridialytic and Intradialytic Blood Pressure Measurements are Not Valid Estimates of 44-Hour Ambulatory Blood Pressure in Patients With Intradialytic Hypertension
Authors: Theodorakopoulou Marieta , Eleni Alexandrou Maria , Iatridi Foteini , Karpetas Antonios , Geladari Virginia , Pella Eva , Alexiou Sofia , Ziakka Stavroula , Papagianni Aikaterini , Sarafidis Pantelis 
Published: May 2022

Abstract

BACKGROUND AND AIMS
In contrast with pre- and post-dialysis blood pressure (BP), intradialytic and home BP measurements are accurate metrics of ambulatory BP load in hemodialysis patients. This study assessed the agreement of peridialytic, intradialytic and scheduled interdialytic recordings with 44-h interdialytic BP in a distinct hemodialysis population, patients with intradialytic-hypertension (IDH).

METHOD
45 patients with IDH (defined as: SBP rise ≥ 10 mmHg from pre- to post-dialysis and post-dialysis SBP ≥ 150 mmHg) with valid 48-h ABPM and 197 without IDH were included in this analysis. With 44-h BP used as reference method, we tested the accuracy of the following BP metrics: Pre- and post-dialysis, intradialytic, intradialytic plus pre/post-dialysis readings and scheduled interdialytic BP (out-of-dialysis day: readings at 8:00 am, 8:00 pm or their average).

RESULTS
In patients with IDH, peri-dialytic and intradialytic BP metrics showed at best moderate correlations, while averaged-interdialytic-SBP/DBP exhibited strong correlation (r = 0.882/r = 0.855) with 44-h SBP/DBP. Bland-Altman plots showed large between-method difference for peri- and intradialytic BP, but only + 0.7 mmHg between-method difference and good 95% limits-of-agreement for averaged-interdialytic-SBP. The sensitivity/specificity and κ-statistic for diagnosing 44-h SBP ≥ 130 mmHg were low for pre-dialysis (72.5%/40.0%, κ-statistic = 0.074) and post-dialysis (90.0%/0.0%, κ-statistic = −0.110), intradialytic (85.0%/40.0%, κ-statistic = 0.198) and intradialytic plus pre/post-dialysis SBP (85.0%/20.0%, κ-statistic = 0.043). Averaged-interdialytic-SBP showed high values of sensitivity/specificity (97.5%/80.0%) and strong agreement (κ-statistic = 0.775). In ROC-analyses, the peri- and intradialytic BP metrics showed bad performance with low Area-Under-the-Curve values; scheduled interdialytic SBP/DBP had the largest AUC (0.967/0.951), along with the highest sensitivity(90.0%/88.0%) and specificity(100.0%/90.0%) for detecting elevated 44-h BP.

CONCLUSION
In patients with IDH, averaged-scheduled-interdialytic but not pre- and post-dialysis, nor intradialytic BP recordings show reasonable agreement with ambulatory BP. Interdialytic BP recordings only could be used for hypertension diagnosis and management in these subjects.
FC 131: Kidney Injury Molecule-1-Mediated Small Extracellular Vesicles Uptake is Crucial for Renal Tubulointerstitial Inflammation
Authors: Chen Jun , Tang Tao-Tao , LI Zuolin , Wang Cui , Shen Anran , Liu Bicheng , LV Linli 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Tubular epithelial cells (TECs) exposed to hypoxia during kidney injury communicate with interstitial inflammatory cells and contribute to tubulointerstitial inflammation. However, whether injured TECs communicate under hypoxia in an autocrine or paracrine manner and contribute to tubulointerstitial inflammation has yet to be identified moieties. The purpose of this study is to explore the role of small extracellular vesicles(sEVs) secreted by hypoxic TECs in the development of renal tubulointerstitial inflammation and the mechanism of sEV-mediated TEC communication.

METHOD
Ischemia reperfusion induced kidney injury (IRI) models were established to explore the conditions of hypoxia induced Inflammation as well as tubular kidney injury molecule-1(KIM-1) expression and sEV production. In vitro, hypoxic TEC-derived sEVs (Hypo-sEVs) were applied to culture TECs to explore sEV-mediated tubule communication. Besides, inflammatory cytokine generation was analyzed in hypoxic TECs with silence of KIM-1 and Rab27a. To investigate the mechanism of sEV internalization, uptake efficiency of the recipient TECs was evaluated in conditions of KIM-1 overexpression. Phosphatidylserine (PS) on the surface of Hypo-sEVs was further assayed by nanoflow cytometry (NanoFCM). sEVs isolated from hypoxic TECs with or without labeling were transferred to IRI mice to detect its localization and the consequences on tubulointerstitial inflammation.

RESULTS
In IRI mice, hypoxia induced tubule injury as evidenced by tubule HIF-1α and KIM-1 expression as well as tubulointerstitial inflammation were observed. Impressively, we noticed the colocalization of sEV marker (CD63) with KIM-1, which suggested increased sEV production in injured tubules or uptake of sEVs by damaged tubules through KIM-1. Intriguingly, KIM-1 expression also correlated with CD3 + and CD68 + inflammatory cells infiltration. In vitro, stable HIF-1α and KIM-1 expression was detected in hypoxic TECs with significant inflammatory cytokine expression. Notably, increased sEV release was noticed in hypoxic TECs, while hypoxia induced inflammation could be ameliorated when KIM-1 and Rab27a were silenced. Importantly, the inflammatory response of hypoxic TECs induced by exogenous Hypo-sEVs could be partly relieved when KIM-1 was knock down by siRNA transfection. Besides, PS could readily be detected in Hypo-sEVs by NanoFCM suggesting that sEVs may accelerate TEC inflammation via recognizing PS by KIM-1. Correspondingly, Hypo-sEVs localized to tubules with KIM-1 expression and amplified tubulointerstitial inflammation in IRI mice.

CONCLUSION
Our studies demonstrate that KIM-1 expressed by injured tubules mediates sEVs uptake via recognizing PS, which participates in TEC communication and augment of tubulointerstitial inflammation induced by hypoxia.
FC 132: Deficiency of Proximal Tubular Cyclin-Dependent Kinase 12 Exacerbates Kidney Injury Through DNA-Damage Response
Authors: Zhang Yilin , Wang Bin , Liu Bicheng 
Published: May 2022

Abstract

BACKGROUND AND AIMS
Acute kidney injury (AKI) is a frequent, serious condition characterized by acute tubular necrosis involving the destruction of tubular epithelial cells. Recent studies have shown that DNA damage contributes to renal tubular cell death during kidney injury. Cyclin-dependent kinase 12 (CDK12) is a member of the cyclin-dependent kinase family that phosphorylates the carboxy-terminal domain of RNA polymerase II and selectively regulates transcription of DNA-damage response (DDR) genes. CDK12 inhibitor was reported to play an important role in a variety of cancers. So far, the functions of CDK12 deficiency in the pathogenesis of AKI have not been studied.

METHOD
Here, we established a cisplatin-induced AKI mouse model with CDK12 knockdown mice and created stable in vitro models with CDK12 knockdown tubular epithelial cells. Cisplatin nephrotoxicity was induced by intraperitoneal injection of cisplatin (20 mg/kg). After 2 days following cisplatin treatment, blood and kidney tissues were harvested. Renal function and histology were evaluated. DDR, tubular apoptosis, cell proliferation were evaluated by immunofluorescence assays, real-time PCR, flow cytometer and western blot analysis.

RESULTS
Here we found that CDK12 was downregulated in the renal tubular epithelial cells of AKI patients and murine AKI models and associated with kidney functions. RNA-sequencing of kidney cortex demonstrated increased transcripts involved in DDR and tubular apoptosis signaling pathways and decreased transcripts cell proliferation pathways, in knockout versus control mice. Moreover, more severe AKI occurred in tubular cell-specific knock-down of CDK12 mice (CDK12RTEC+/–) than age- and sex-matched wild type mice, as evidenced by increased levels of serum creatinine (Scr), blood urea nitrogen (BUN) and tubular injury score. Mechanistically, CDK12 deficiency accelerated cisplatin-induced DDR, mitochondrial apoptosis and abrogates cell proliferation of renal tubular cells in these mice. Similar results were observed after the human renal tubular epithelial cell line HK-2 cells exposure to CDK12 siRNA stimulation. In contrast, lentivirus-mediated CDK12 overexpression protected against DDR and mitochondrial apoptosis while attenuating renal dysfunction, morphological damage and renal tubular cell death in cisplatin-induced AKI models. Moreover, representative Integrative Genomics Viewer (IGV) profiles demonstrated a minimal impact of gene length-dependent elongation defects, a substantial proportion of which participate in the DDR and cell proliferation.

CONCLUSION
Thus, proximal tubule-specific deficiency of CDK12 exacerbates acute kidney injury and tubular apoptosis, likely due to affecting the expression of genes involved in the DDR and mRNA processing.
What is a Good School, and Can Parents Tell? Evidence on the Multidimensionality of School Output
Authors: Beuermann Diether W , Jackson C Kirabo , Navarro-Sola Laia , Pardo Francisco 
Published: May 2022

Abstract
To explore whether schools’ causal impacts on test scores measure their overall impact on students, we exploit plausibly exogenous school assignments and data from Trinidad and Tobago to estimate the causal impacts of individual schools on several outcomes. Schools’ impacts on high-stakes tests are weakly related to impacts on important outcomes such as arrests, dropout, teen motherhood, and formal labour market participation. To examine if parents’ school preferences are related to these causal impacts, we link them to parents’ ranked lists of schools and employ discrete-choice models to infer preferences for schools. Parents choose schools that improve high-stakes tests even conditional on peer quality and average outcomes. Parents also choose schools that reduce criminality and teen motherhood and increase labour market participation. School choices among parents of low-achieving students are relatively more strongly related to schools’ impacts on non-test-score outcomes, while the opposite is true for parents of high-achieving students. These results suggest that evaluations based solely on test scores may be misleading about the benefits of school choice (particularly for low-achieving students), and education interventions more broadly.