bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antimicrobial and antivirulence saponins of Mimusops laurifolia leaves
Authors: Mostafa Hayam M A , Taha Mohamed , El-Gendy Ahmed O , Khairalla Ahmed S , abd El fattah Medhat , Raslan Mai 
Published: June 2023

Abstract
Mimusops laurifolia is a native species restricted to the Red Sea mountains and Gulf of Aden. Its leaves contain saponins with wide range of biological activities. The presented research aimed to prepare saponins-rich extract from n-butanol fraction of M. laurifolia leaves and screen it for promising antimicrobial activities. Minimum inhibitory concentration (MIC) of the prepared saponins against Candida albicans, and their potential anti-pathogenic and antivirulence effects were determined. Different concentrations of the saponins-rich extract were investigated for their antimicrobial potential, particularly against C. albicans, using the agar well diffusion method. To assess the potential antivirulence and antipathogenic effects, we carried out molecular docking of the bioactive saponins against four key enzymes in C. albicans, which are involved in virulence and/or pathogenicity. Different concentrations of the investigated mixture showed notable antifungal activity against C. albicans with an MIC value of 6.4 μg ml−1. Docking analysis of the investigated saponins showed their affinity toward the docked enzymes, particularly saponin 1 with secreted aspartic proteinase 3 and saponin 6 with secreted aspartic proteinase 5. Thereafter, the stability of these two protein-ligand interactions was investigated using molecular dynamics (MD) simulation. The molecular interactions between saponins and the enzymes' active sites were analyzed and discussed.
#2568 LONG-READ SEQUENCING IDENTIFIES NOVEL PATHOGENIC INTRONIC VARIANTS IN GITELMAN SYNDROME
Authors: Viering Daan , Hureaux Marguerite , Neveling Kornelia , Blanchard Anne , Konrad Martin , Bindels René , Schlingmann Karl Peter , Vargas-Poussou Rosa , de Baaij Jeroen 
Published: June 2023

Abstract

Background and Aims
Gitelman syndrome is a salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. It is caused by homozygous recessive or compound heterozygous pathogenic variants in SLC12A3, which encodes the Na+-Cl− cotransporter (NCC). In up to 10% of patients with Gitelman syndrome, current genetic techniques detect only one specific pathogenic variant. This study aimed to identify a second pathogenic variant in introns, splice sites, or promoters to increase the diagnostic yield.

Method
Long-read sequencing of SLC12A3 was performed in 67 DNA samples from individuals with suspected Gitelman syndrome in whom a single likely pathogenic or pathogenic variant was previously detected. In addition, we sequenced DNA samples from 28 individuals with one variant of uncertain significance or no candidate variant. Midigene splice assays assessed the pathogenicity of novel intronic variants.

Results
A second likely pathogenic/pathogenic variant was identified in 45 (67%) patients. Those with two likely pathogenic/pathogenic variants had a more severe electrolyte phenotype than other patients. Of the 45 patients, 16 had intronic variants outside of canonic splice sites (nine variants, mostly deep intronic, six novel), whereas 29 patients had an exonic variant or canonic splice site variant. Midigene splice assays of the previously known c.1670-191C&gt;T variant and intronic candidate variants demonstrated aberrant splicing patterns.

Conclusion
Intronic pathogenic variants explain an important part of the missing heritability in Gitelman syndrome. Long-read sequencing should be considered in diagnostic workflows for Gitelman syndrome, especially in patients with one pathogenic variant.
#3408 A META-ANALYSIS OF VASCULAR ACCESS OUTCOMES IN HEMODIALYSIS PATIENTS OVER 75 YEARS OF AGE
Authors: Ntemka Alexandra , Argyriou Christos , Kyriklidou Parthena , Lazaridis Miltiadis , Georgiadis Georgios 
Published: June 2023

Abstract

Background and Aims
The age of patients with end-stage renal disease is constantly growing, but evidence for the best vascular access for hemodialysis is scarce and controversial for elderly. A meta-analysis was performed in hemodialysis patients over 75 years old to compare the outcomes of different vascular access procedures in the sub-group of elderly ESRD patients ≥ 75 years of age.

Method
A literature search was performed using the electronic databases MEDLINE and SCOPUS up to October 2021. Twelve eligible articles fulfilled the inclusion criteria and were finally selected in the meta-analysis (Table). Three of these studies including ESRD patients &gt;70 years of age were exceptionally included as the mean age was well above 75 years. First step analysis was focused on studies that reported the primary patency rates of autologous vs. prosthetic vascular accesses (5 studies). Second step analysis was focused on articles comparing the results of primary and secondary patency rates of distal (forearm) vs. proximal (upper arm) fistulas in elderly patients (8 studies). All these studies were retrospective cohort studies, none was randomized controlled trial.

Results
Regarding the first step analysis, primary failure rate at 24 months was in favor of AVFs (OR: 0.56, 95% CI: 0.38-0.83, p = 0.003, Fig. 1). Although several studies have shown that AVG patency is not affected by age, this meta-analysis showed patency benefit of AVF in this subgroup of elderly patients ≥75 years of age. In a second step, the 12-month primary failure rate was by far in favor of proximal AVFs (OR: 2.14, 95% CI: 1.53-2.97; p&lt;.00001, Fig. 2). The 12-month secondary patency rate of the forearm AVFs was also inferior compared to the proximal AVF (OR: 1.76, 95% CI: 1.12-2.78; p&lt;.01, Fig. 3) These findings favor the use of proximal AVFs as first choice access in this subgroup of elderly patients, especially when they are late referrals or have low life expectancy.

Conclusion
The question of the right access in elderly ESRD patients does not have an easy answer. The present study shows that patients ≥75 years old should not be excluded from creation of an autologous access, with proximal AVFs having better patency rates.
#3794 AUTOPHAGY PATHWAY ACTIVATION IN IMMUNE-INFLAMMATORY CELLS OF PERITONEAL DIALYSIS PATIENTS
Authors: Granata Simona , Bruschi Maurizio , Pontrelli Paola , Candiano Giovanni , Stallone Giovanni , Gesualdo Loreto , Zaza Gianluigi 
Published: June 2023

Abstract

Background and Aims
The better understanding of the biological pathways related to chronic kidney disease (CKD) may be useful for the identification of new therapeutic targets to improve the management of CKD patients. High-throughput technologies with innovative bioinformatics approaches for data analysis are very useful to achieve this objective.

Method
We reinterrogated our previous gene expression microarray data obtained from peripheral mononuclear cells (PBMCs) of 5 healthy subjects (HS), 9 chronic kidney disease patients with KDOQI stage II-III (CKD) and 10 CKD patients undergoing peritoneal dialysis treatment (PD). Advanced statistical and machine learning methods, including support vector machine learning and partial least squares discriminant analysis, were used for bioinformatics. Western blot and flow cytometry, then, was used to validate these results in an independent study group (10 HS, 10 CKD and 15 PD).

Results
Statistical analysis revealed that the transcriptomic profile of PD was significantly different from HS and CKD. Instead, no significant differences were observed between HS and CKD. A total of 348 genes (p&lt;0.0001, FDR&lt;5%) were able to differentiate PD patients from the other two study groups. Autophagy resulted one of the most up-regulated pathways in PD and the autophagy related 5 (ATG5), a gene encoding for a key protein involved in autophagic vesicle formation, was the top discriminative transcript (as demonstrated also by the VIP score). Western blot for ATG5 and LC3BII, main phagosome proteins, performed on the validation cohort, confirmed the activation of autophagy pathway only in PBMC of PD patients.

Conclusion
Our high-throughput data demonstrated, for the first time, that the autophagy pathway is activated in immune-cells of PD patients. This condition may significantly impact their immune-response and -homeostasis and, probably, it represents the last attempt of these circulating cells to avoid apoptosis.
#3940 RISK OF MAJOR ADVERSE CARDIOVASCULAR EVENTS ACCORDING TO DIALYSIS MODALITY
Authors: Bitar Wisam , Helve Jaako , Haapio Mikko , Rauta Virpi , Honkanen Eero Olavi , Finne Patrik 
Published: June 2023

Abstract

Background and Aims
Among dialysis patients, cardiovascular events are the leading cause of death. Little is known about difference in the frequency of cardiovascular events between various dialysis modalities. Glucose load may contribute to a metabolic burden in peritoneal dialysis (PD). On the other hand, hemodialysis can cause intradialytic hypotension, cardiac stunning, and arrhythmias, which are associated with increased risk of death. We compared risk of major cardiovascular events in patients who started continuous ambulatory PD (CAPD), automated PD (APD) and home HD with in-center HD patients.

Method
We included 968 patients who entered dialysis in the Helsinki-Uusimaa healthcare district in Finland from 2004 to 2017, of whom 162 were on CAPD, 229 on APD, 145 on home HD and 432 on in-center HD at day 90 from the start of dialysis. Patients were followed up for 5 years or until the end of 2019. Major adverse cardiovascular event (MACE) was defined as acute myocardial infarction, stroke or death due to cardiovascular disease. The cumulative incidence of the first MACE was calculated by taking other causes of death into account as competing risk events and censoring at time of kidney transplantation. Cox regression was used to compare risk of MACE between dialysis modalities with adjustment for age, gender, primary renal disease, prior comorbidities (coronary heart disease, left ventricular hypertrophy, heart failure and stroke), and laboratory data (plasma albumin, phosphate and ionized calcium). Imputation was performed to replace missing values of comorbidities and laboratory data.

Results
Of all 968 patients, 195 (20%) experienced a MACE during the entire follow-up and 62 (6.4%) during the first year of follow-up. The cumulative incidence of first MACE was similar in in-center HD and CAPD patients and higher than that in APD and home HD patients (Figure 1). Without adjustments, the hazard ratio of MACE was 0.83 [95% CI 0.56–1.2] for CAPD, 0.49 [95% CI 0.31–0.77] for APD and 0.42 [95% CI 0.23–0.78] for home HD in comparison to in-center HD. After adjustment for possible confounders, the hazard ratio of MACE was 1.1 [95% CI 0.70–1.6] for CAPD, 0.88 [95% CI 0.53–1.5] for APD and 0.80 [95% CI 0.41–1.6] for home HD and not statistically significantly different in comparison to in-center HD.

Conclusion
We observed a lower risk of MACE among patients who entered APD or home hemodialysis compared to in-center hemodialysis, but after adjusting for potential confounding factors, the difference diminished and was no longer statistically significant.
#4503 ESTIMATING DELAY IN TIME TO KIDNEY FAILURE OR DEATH FOR TREATMENT EFFECTS ON PROTEINURIA IN IGA NEPHROPATHY
Authors: Mercer Alex , Carroll Kevin , Conley Leah , Hendry Bruce , Pitcher David , Gale Daniel , Barratt Jonathan 
Published: June 2023

Abstract

Background and Aims
Reduction in proteinuria is associated with lower risk of kidney failure (KF) in IgA nephropathy (IgAN) (Thompson et al, 2019). In phase 3 randomized controlled trials in IgAN patients, a treatment effect on proteinuria reduction is typically evaluated as a mean percent change in proteinuria from baseline at 6-9 months. In this study, we aim to estimate the delay in time to KF or death associated with treatment effects of 40% and 50% reduction of proteinuria at this timepoint.

Method
In this study, we used individual patient level data from the UK National Registry of Rare Kidney Disease (RaDaR) IgAN cohort. Adult IgAN patients (n = 535) with a urine protein-creatinine ratio ≥100 mg/mmol (0.88 g/g) ≥6 months from diagnosis (time point defined as baseline) and eGFR ≥30 mL/min at baseline (study population mean = 61 ml/min/1.73 m2 [SD 26]) were included. Predicted risk of KF (eGFR &lt;15 mL/min, initiation of dialysis, transplantation)/doubling serum creatinine/death associated with treatment effects reducing proteinuria by 40% and 50% at 9 months were calculated from IgAN trial level analysis data (Thompson et al, 2019). Accelerated failure time modelling was used to analyse time to KF/death during follow up in the RaDaR IgAN study population, and to estimate the effect that changes in hazard ratio had on median survival time and 5-year survival rates. Weibull, Log-Logistic and Log-Normal distributions were applied with the fitted survivor function reported from the model with the lowest AIC.

Results
Treatment effects reducing proteinuria by 40% and 50% in IgAN patients predict a 59% and 67% lower risk of KF/death, respectively. A 59% reduction in risk, is estimated to extend the median time to KF/death by 6.3 years, from 8.6 years (95% CI 7.8, 9.5) to 14.9 years (95% CI 13.6, 16.4), while the corresponding extension in median time to KF/death estimate for a 67% reduction in risk is 8.5 years (from 8.6 years [95% CI 7.8, 9.5] to 17.1 years [95% CI 15.6, 18.8]) (Figure 1). Five-year KF/death free survival rate increased from 75% to 89% and 91%, for 59% and 67% reduced risk in KF/death, respectively.

Conclusion
Therapeutic interventions that reduce proteinuria and the risk of KF can confer important and clinically meaningful extensions in the time patients are alive and free from KF.
#4787 VITAMIN D AND PARATHYROID HORMONE PREDICT INCIDENT MAJOR ADVERSE CARDIAC EVENTS IN PATIENTS STARTING HAEMODIALYSIS: A REAL-WORLD ANALYSIS
Authors: Mcdowell Garry , Downey Robert , Buckley Benjamin , Austin Philip , Lip Gregory , Rao Anirudh 
Published: June 2023

Abstract

Background and Aims
Despite its advantages, haemodialysis (HD) is associated with increased cardiovascular mortality and morbidity, with some studies reporting 48% higher mortality, within 2 years of starting treatment. HD patients are known to suffer from vitamin D deficiency which has been linked to excess CV mortality and morbidity. We aimed to investigate the prognostic significance of vitamin D in predicting incident Major Adverse Cardiovascular Events (MACE) within 5 years of commencing HD.

Method
A retrospective cohort study was performed using electronic medical records from a global federated research network from the US (TriNetX). The TriNetX network was searched on 31st January 2023. The cohorts commenced HD post-diagnosis of End-Stage Kidney Disease. Data censoring for MACE was invoked prior to the index event of HD. Vitamin D (25-hydroxyvitamin D and 1,25 dihydroxy Vitamin D) concentrations were the first reported result within 3 months of starting HD. Cohorts were grouped according to biomarker-specific thresholds and 1:1 propensity-score matched for age, gender, and co-morbidities (hypertension, diabetes mellitus and smoking status). Logistical regression produced odds ratios with 95% CI for 5-year MACE. MACE was defined, a priori, as a composite of ischaemic heart disease, angina pectoris, acute myocardial infarction, heart failure, AF, stroke, and all-cause mortality. All statistical analysis was performed on the TriNetX online platform.

Results
The results are shown below. There was no association between outcome and PTH at 55 pg/ml threshold. Only results that reached statistical significance (p&lt;0.05) are shown. Patients with a 25-OH Vitamin D concentration &lt;24 ng/ml or 1,25-diOH Vitamin D at &lt;35 pg/ml had significantly more events, as shown below.

Conclusion
Circulating plasma levels of cholecalciferol and calcitriol are predictive of CV outcomes in patients commencing HD; however, the risk profile is different between low levels of active and inactive vitamin D. As the incident HD population are at increased risk of CV mortality and morbidity, cholecalciferol and calcitriol should be included in assessing overall risk.
#5352 INCIDENT ACUTE KIDNEY INJURY AND THE RISK OF DEMENTIA: THE STOCKHOLM CREATININE MEASUREMENTS (SCREAM) PROJECT
Authors: Xu Hong , Xu Yang , Garcia-Ptacek Sara , Bruchfeld Annette , Eriksdotter Maria , Carrero Juan Jesus 
Published: June 2023

Abstract

Background and Aims
Preclinical studies suggest that acute kidney injury (AKI) leads to biochemical and pathological changes in the brain. However, whether developing AKI associates with the risk of dementia is not well explored. We here aimed to evaluate the association between developing AKI and the subsequent risk of dementia in general population.

Method
We included all adults with age ≥65 years, free from dementia diagnosis and with known kidney function in Stockholm during 2006-2019. The exposure was AKI (time varying): prevalent history of AKI was ascertained by clinical diagnoses, and new/incident AKI events during observation by both clinical diagnoses and transient creatinine elevations according to KDIGO criteria. The outcome was dementia diagnosis, first via confirmed cases in the Swedish registry of cognitive/dementia disorders (SveDem) and enriched with cases identified by two issued diagnoses of dementia in outpatient care or initiation of specific anti-dementia medications. We considered death, migration, and end of follow-up as censoring events and also explored risk associations with specific dementia subtypes. The association between developing AKI and study outcomes was evaluated through time-varying multivariate Cox regression, accounting for recurrent AKI events through weighted cumulative exposure metrics.

Results
We included 354,612 individuals with median 76 years (55% women). During median follow-up of 8.1 (IQR: 3.7, 12.1) years, there were 48,624 (14%) persons suffering at least one episode of AKI, and 47,765 (13%) diagnoses of dementia were recorded. The rate of dementia cases was 37.13 per 1000 person-year (95% CI 36.06-38.22) after developing AKI, which was approximately 2 times higher than the rate observed during the periods without AKI (18.47 [18.3-18.64]). After multivariable adjustment, developing AKI was associated with a 48% higher risk of having dementia [adjusted HR 1.48 (95%CI 1.43-1.53)]. This pattern was consistent for the dementia subtypes: the HRs for Alzheimer's dementia, Parkinson's disease dementia, and vascular dementia were 1.14 (1.07-1.21), 1.90 (1.37-2.65) and 1.24 (1.15-1.33) higher, respectively, after developing AKI. Among persons with recurrent AKIs, each additional AKI event was associated a 4% higher risk of dementia (adjusted HR: 1.04, 95% CI: 1.03-1.05). We observed similar results across subgroups of sex, baseline kidney function, history of hypertension, diabetes, and cardiovascular disease.

Conclusion
In this region-representative cohort, participants who experienced AKI were at increased risk of receiving a diagnosis of dementia.
#5635 SYSTEMIC OXALOSIS: AN OVERVIEW OF THE FINDINGS AND PREVALENCE IN PRIMARY HYPEROXALURIA
Authors: Deesker Lisa , Garrelfs Sander , Groothoff Jaap 
Published: June 2023

Abstract

Background and Aims
Systemic oxalosis is a severe co-morbidity that may arise in patients with primary hyperoxaluria type 1 (PH1). It is caused by precipitation of calcium oxalate crystals in organs besides the kidneys, as a result of high endogenous oxalate production. In this study, we aimed to provide an overview of the prevalence, features, screening modalities and factors that play a role in developing systemic oxalosis as cohort studies are currently lacking.

Method
A retrospective registry study was conducted using data from the OxalEurope registry, one of the largest registries of patients with PH1. All patients with primary hyperoxaluria and data on systemic oxalosis were identified. Data was analyzed using descriptive statistics, Chi-square tests, Mann-Whitney U tests and Kaplan Meier analyses.

Results
A total of 159 out of 291 (55%) screened PH1 patients were diagnosed with systemic oxalosis. In addition, 110 patients were recorded having no signs of systemic oxalosis at follow-up, however screening was not performed. Sixty-two patients had already developed systemic oxalosis at moment of diagnosis and systemic oxalosis was most often found in patients with ESKD (95%). The eyes, bones and heart are most frequently affected, nevertheless deposits occurred in many organs, as shown by obduction. Fundus photography (n = 16), X-ray (n = 43), and echocardiography (n = 59) are the modalities used most often to screen respectively the eyes, bones and heart. Patients who developed systemic oxalosis had significantly higher upper plasma oxalate levels (median 22 versus 175 umol/L, p&lt;0.001). Furthermore, patients with systemic oxalosis had a significant higher mortality rate compared to patients without systemic oxalosis (48 out of 142 versus 10 out of 212, p&lt;0.001), which difference persisted after correcting for ESKD (p&lt;0.001). Kaplan Meier analysis (Figure 1) showed that pediatric patients with ESKD tended to developed systemic oxalosis more frequently than adults (p&lt;0.001).

Conclusion
This is the first research to systematically study and report systemic oxalosis in patients with primary hyperoxaluria type 1. Systemic oxalosis is prevalent among PH1 patients, especially when ESKD is present, and may lead to significant morbidity and mortality. Patients with systemic oxalosis have a higher mortality rate and pediatric patients may develop systemic oxalosis more frequently than adults. Given the high incidence and possible implications, we would like to make an appeal on screening all patients with systemic oxalosis. Future research should focus on reliable screening modalities for early signs of systemic oxalosis.
#6737 ESTIMATED GLOMERULAR FILTRATION RATE BY FIVE DIFFERING MEASURES, RACE, GENETIC RISK AND PREDICTION OF CARDIOVASCULAR DISEASE AND MORTALITY
Authors: Tang Lei , Zeng Xiaoxi , Fu Ping 
Published: June 2023

Abstract

Background and Aims
Estimated glomerular filtration rate (eGFR), a significant measurement of chronic kidney disease (CKD), is associated with adverse health outcomes in the general population but whether its utility differs by race and genetic risk remains unclear. The current study aims to investigate the performance of CKD staging and risk prediction in cardiovascular disease and mortality based on five eGFR measures among people of different ethnic groups and genetic background.

Method
In this prospective cohort study, we included 431,126 participants from the UK Biobank, deriving hazard ratios and 95% confidence intervals from multivariable adjusted Cox proportional hazards models. C statistic and net reclassification improvement (NRI) were utilized for comparing the predictive benefit of eGFR measures when added to the traditional cardiovascular risk factors.

Results
Over a median of 13.4 (IQR 12.7-14.9) years of follow-up, 27,757 (6.4%) participants died from any cause, of which 3272 (0.8%) died primarily from CVD. 39,522 (9.2%) incident composite CVD hospitalization and 911 (0.2%) ESRD occurred. Two new eGFR equations refitted without race provided lower estimates in Black population but higher in other ethnic backgrounds than the corresponding old ones. The relative risk of adverse outcomes was generally greater in Blacks and participants with low genetic susceptibility to impaired kidney function. The superiority of cystatin C-based eGFR measures in risk prediction did not differ by race and genetic risk.

Conclusion
Eliminating the use of racial categories in eGFR calculation help enhance the access to specialist care and intervention at the early stage of CKD for Black population. Cystatin C-based eGFR measures can be extensively used in risk assessment in clinical practice.