bluuebunny/crossref_metadata_2025_split huggingface dataset:
#4158 URINE DERIVED STEM CELL AMELIORATES RENAL FIBROSIS VIA KLOTHO ACTIVATION
Authors: Choi Dae Eun , Lee Kang Wook , Na Ki Ryang , Ham Young Rok , Chang Yoon-Kyung , Lee Eu Jin , Park Heyrim , Jeong Jin Young , Shin Jin Ah 
Published: June 2023

Abstract

Background and Aims
After renal IRI, regeneration and recovery of the renal tubular cell occurs. However, if the renal repair process is maladaptive, it progresses to renal fibrosis. The role of stem cells in kidney regeneration or fibrosis has not been fully elucidated. we evaluated the urine drived stem cells (UDSC) for renal inflammation and fibrosis after renal ischemia reperfusion (IR).

Method
10 week old balb/c nude male mice were used. sham, sham with UDSC, IR, IR with UDSC. UDSC were infused 3 times via tail vain at 6, 7, 8th day after renal IR. Urine NGAL/creatinine (Cr) were checked. The kidneys tissue were harvested at day 14 day. In vitro, TGF-β treated HK2 cell were co-cultured with UDSC. Klotho siRNA silencing was performed in UDSC.

Results
Urinary NGAL/Cr were significantly increased in IR mice after 14 day IR, compared to sham mice. Urinary NGAL/Cr significantly decreased in UDSC treated IR mice, compared to IR mice. In H&E stain, renal tubulo-interstitial injury were significantly decreased in UDSC treated IR mice, compared to IR mice. In masson trichrom stain, renal fibrosis area were were significantly decreased in UDSC treated IR mice, compared to IR mice. The renal expression of TGF-β, α-SMA, and collagne IV were significantly decreased in UDSC treated IR mice, compared to IR mice. The renal expression of Klotho were increased in UDSC treated IR mice, compared to IR mice. in vitro, UDSCs were stem cells that expressed Klotho protein more strongly than other mesenchymal stem cells (MSCs). UDSCs also suppressed fibrosis by inhibiting transforming growth factor (TGF)-β in HK-2 human renal proximal tubule cells in an in vitro model. Klotho siRNA silencing reduced the TGF-β-inhibiting ability of UDSCs.

Conclusion
UDSC attenuate renal fibrosis after renal IR. Klotho-secretion of UDSC play a role in these anti- fibrotic effects.
#4171 DIALYSIS WITHOUT SOCKS: DETECTION OF ULCERS AND AMPUTATIONS IN HEMODIALYSIS
Authors: González-Mariño Rocío Zamora , Hernández Rosa Sánzhez , Jiménez Laura Rodríguez-Osorio , Gúrpide Beatríz Durá 
Published: June 2023

Abstract

Background and Aims
Dialysis patients are at high risk of ischemia and foot ulcers (14.4%) that frequently precede severe complications, including amputations (5.9%), hospitalizations, and mortality. Critical ischemia in this location accounts for 20% of the annual causes of death in hemodialysis, produces pain that is difficult to control and greatly reduces the quality of life. The aim of this work was to analyze the prevalence and factors associated with amputations in hemodialysis patients, and to assess the evolution after amputation.

Method
Carrying out a survey by email sent by the SEN (Spanish Society of Nephrology) and SOMANE (Madrid Society of Nephrology). Retrospective, cross-sectional, multicenter study. The survey sent to all hemodialysis units nationwide. Answered by 47 Centers. The exclusion criteria were oncological-traumatic amputations.

Results

Conclusion
#4292 PATIENT-REPORTED MENTAL HEALTH PROBLEMS, SUICIDE IDEATION, AND CLINICAL OUTCOMES IN ADULTS WITH NON-DIALYSIS CKD: RESULTS OF THE KNOW-CKD STUDY
Authors: Lee Kyu-Beck , Yang Jihyun , Hyun Young Youl 
Published: June 2023

Abstract

Background and Aims
Mental health is important for health and well-being at every stage of life and disease. Mental health problems are common and bothersome in chronic kidney disease (CKD). Mental health problems of CKD are poorly understood and evaluated. To address the importance of mental health in CKD, we analyzed a prospective cohort database from prospective CKD cohort.

Method
We analyzed 1897 participants from the KNOW-CKD cohort. We evaluated 4 items as indicators of patient-reported mental health: sleep duration, perceived stress, depressive symptoms, and suicidal ideation. To facilitate interpretation of the mental health problems in CKD, we measure a scaled effect size (ES) for the Kidney Disease Quality of Life Short Form (KDQOL-SF) differences among the groups of mental health problems. We investigated the association between patient-reported mental health problems and clinical outcomes of incident end-stage kidney disease (ESKD) all-cause death in non-dialysis CKD.

Results
The mean age was 53 ± 12 years and 62% were male. The participants had mental health problems of inadequate sleep duration (17.4%), subject distress (27.3%), experience of depression (13.2%), and suicide ideation (16.8%), but had not well taken care (psychiatric counselling 1.9%, antidepressant therapy 2.8%). The 4 item indicators of mental health showed large effect size between-groups KDQOL mental component summary (ES = 1.67). In the fully adjusted Cox proportional model, poor mental health (≥2 mental health problems) was associated with high risk of ESKD [HR = 1.46; 95% CI (1.18∼1.08)] and death [HR = 1.55; 95% CI (1.04∼2.32)] compared to good mental health (no mental health problems). Among 4 item indicators of patient-reported mental health, suicide ideation was the most predictive indicator of clinical outcomes.

Conclusion
Mental health problem is common and undertreated in CKD. Poor mental health is associated with high risk of ESKD and death in non-dialysis CKD and the single question of suicide ideation is significantly associated with high risk of ESKD and death. It suggests that the evaluation and management of mental health problem is important to the clinical outcomes in CKD.
#4346 SERUM NONSKELETAL ALKALINE PHOSPHATASE AS A MARKER OF METABOLIC ENDOTOXINEMIA AND PREDICTOR OF ADVERSE OUTCOME IN PATIENTS WITH CKD
Authors: Smout Dieter , Joergensen Hanne , Meijers Björn , Dejongh Sander , Haarhaus Mathias , Cavalier Etienne , Van Craenenbroeck Amaryllis , Evenepoel Pieter 
Published: June 2023

Abstract

Background and Aims
Elevated alkaline phosphatase (ALP) levels are widely recognized as a marker of poor outcomes in chronic kidney disease (CKD). This association remains poorly understood, with arguments pointing to the skeletal and non-skeletal isozyme fractions as being decisive factors. The liver and intestinal isoenzymes of ALP are able to dephosphorylate and thus inactivate a number of substrates which have been implicated in the promotion of inflammation, including the bacterial endotoxin lipopolysaccharide (LPS). Present study aimed to test the hypothesis whether association of total ALP with all-cause mortality is mainly driven by non-skeletal ALP and its link with metabolic endotoxemia and inflammation.

Method
Laboratory parameters of mineral and bone disease, inflammation (C-reactive protein, CRP), and metabolic endotoxemia (Lipopolysaccharide binding protein, LBP) were assessed in 431 CKD patients enrolled in the Leuven Mild-to-Moderate CKD Study between Nov 2005 and Sept 2006. Non-skeletal ALP levels were estimated as residuals of the linear regression of log transformed total and bone-specific ALP. Spearman correlation, multivariate regression, and Cox proportional hazard analyses were performed to investigate the associations between skeletal and non-skeletal ALP, LBP, CRP and mortality. Data were censored at start of renal replacement therapy.

Results
Median age was 63 years, 54% were men, 19% had diabetes, 31% had established cardiovascular disease. At baseline, non-skeletal ALP was associated with inflammatory parameters (CRP: rho = 0.33, P&lt;0.001) and with metabolic endotoxemia (LBP: rho = 0.32, P&lt;0.001). Non-skeletal ALP was a significant predictor of elevated CRP (&gt;3 mg/dL) in multivariate models (odds ratio (OR) per standard deviation (SD) increase 1.97; 95% CI 1.21-3.21; P = 0.006). This association was attenuated by further adjustment for LBP (OR 1.40; 95% CI 0.69-2.80; P = 0.3). During a median follow-up of 8.0 (interquartile range, 2.6-14.7) years 131 patients died. High non-skeletal ALP associated with increased risk of all-cause mortality, even after adjusting for demographics, Framingham risk factors and comorbidities (Hazard ratio (HR) per SD increase 1.28; 95% CI 1.05 – 1.56; P = 0.016). This association was attenuated by further adjustment for LBP (HR 1.22; 95% CI 1.00-1.50; P = 0.051). High bone-specific ALP was not associated with increased risk of all-cause mortality.

Conclusion
In patients with CKD not yet on dialysis, increased non-skeletal ALP (as opposed to skeletal ALP) is associated with inflammation and increased risk of all-cause mortality. These associations are at least partly driven by metabolic endotoxemia.
#4375 LANOSTEROL SYNTHASE RS2254524 POLYMORPHISM MODULATES SALT SENSITIVITY AND RENAL EXPRESSION IN A NOVEL MICE MODEL, LSSV643L/V643L
Authors: Citterio Lorena , Faienza Sipontina , Messaggio Elisabetta , Zagato Laura , Lanzani Chiara Livia , Simonini Marco , Manunta Paolo 
Published: June 2023

Abstract

Background and Aims
The blood pressure (BP) response to different salt intakes (salt sensitivity-SS), shows variability among individuals, with more frequency in hypertensives compared to the general population. Elevated levels of the Endogenous Ouabain (EO) have been associated with hypertension (HT) and SS. We characterized the missense variation rs2254524 (Val642Leu; C&gt;A) of the Lanosterol Synthase gene (LSS) coding for an enzyme in steroid biosynthesis, since AA patients on a low-salt diet showed a greater reduction in BP compared to the LSS CC, with only CC having an increase in plasma EO. Moreover, AKI incidence following cardiovascular surgery was greater among those with the LSS rs2254524 AA genotype than in those with the CC genotype. We aim at dissecting the functional correlation between LSS polymorphism, EO, SS-HT, and renal function.

Method
We generated by CRISPR-Cas9 a knock-in mouse model carrying the Lss V643L (LssV643L/V643L), homologous to V642L to dissect the functional correlation between LSS polymorphism, EO and salt-sensitive hypertension, and kidney expression. Male mice were fed with a normal-salt diet (0.5% NaCl), high-salt diet (4% NaCl), or low-salt diet (&lt;0.03% Na) and BP was measured every two days by the tail-cuff system.

Results
LssV643L/V643L mice were viable, healthy, and undistinguishable phenotypically from WT. At baseline, the Lss AA affected kidney weight that was significantly enlarged at 3 (p = 0.02) and 12 months of age, compared to WT (kidney p = 0.04; liver p = 0.003). The Lss V643L mutation did not affect EO and SBP at 3 and 12 months, per se, but affects SBP responsiveness to salt intake. Indeed, we observed an increased SBP upon a high-salt diet only in LssV643L/V643L mice 12 months old compared to the control diet (p = 0.01). Moreover, the 12-month-old LssV643L/V643L mice in high-salt diet showed cardiac hypertrophy and showed a higher incidence of heart fibrosis. At 12 months, in the adrenal gland of LssV643L/V643L mice, Lss mRNA level was reduced upon high-salt diet (p = 0.03), while RNA-seq analysis of renal differentially expressed genes revealed a different regulation of multiple Slc genes, both in control and high-salt diet, but also of Cbr2, and Arhgap26.

Conclusion
The new LssV643L/V643L mouse model resembles the SS-HT phenotype together with EO non-responsiveness observed in HT patients, thus providing a good model of SS-HT. Our results reveal a role of Lss gene in the regulation of BP upon salt stimulus, and its influence at renal level at 3 and 12 months of age.
#4425 EZH2 PROMOTES RENAL INTERSTITIAL FIBROSIS THROUGH DOWNREGULATION OF PHOSPHOENOLPYRUVATE CARBOXYKINASE 1 MEDIATED GLUCONEOGENESIS
Authors: Bai Yanfang , Wu Ming , Ye Chaoyang , Chen Dongping 
Published: June 2023

Abstract

Background and Aims
Renal fibrosis is the common pathological pathway of various chronic kidney diseases progressing to the end stage of renal failure. The methyltransferase enhancer of zeste homolog 2 (EZH2) has been identified as a therapeutic target to inhibit renal interstitial fibrosis. However, the mechanism underlying the role of EZH2 in renal fibrosis is not completely understood.

Method
Unilateral ureteral obstruction (UUO), unilateral ischemia-reperfusion injury (UIRI) mouse models were established. PCR, cleavage under targets and tagmentation (CUT&Tag) and Western blotting was performed to evaluate the expression of EZH2 and phosphoenolpyruvate carboxykinase 1 (PCK1).

Results
By using EZH2 inhibitor 3-DZNeP and Ezh2 conditional knockout mice, we confirmed the pro-fibrotic effect of EZH2 in unilateral ureteral obstruction (UUO). Through RNA sequence and cleavage under targets and tagmentation (CUT&Tag) sequence analysis, we found that the phosphoenolpyruvate carboxykinase 1 (PCK1), a critical enzyme in gluconeogenesis, is negatively regulated by EZH2 in fibrotic kidneys, which was further confirmed by quantitative PCR, CUT&Tag and Western blotting. We further showed that deletion or inhibition of EZH2 inhibited renal fibrosis and enhanced PCK1 expression and activity in unilateral ischemia-reperfusion injury (UIRI) and folic acid induced mouse nephropathy. Moreover, the dysregulated production of renal glucose and lactate in mouse UUO kidneys was restored after EZH2 inhibition by 3-DZNeP. Finally, inhibition of PCK1 by 3-mercaptopropionic acid (3-MPA) abrogated the anti-fibrotic effect of 3-DZNeP in UUO kidneys.

Conclusion
We conclude that EZH2 promotes renal interstitial fibrosis through inhibition of PCK1 mediated gluconeogenesis.
#4466 EXPLAINABILITY OF A DEEP LEARNING BASED CLASSIFICATION MODEL FOR ANCA-ASSOCIATED GLOMERULONEPHRITIS
Authors: Trejo Maria Wester , Sadeghi Maryam , Singh Shivam , Kronbichler Andreas , Hruskova Zdenka , Puéchal Xavier , Goebel Georg , Bajema Ingeborg 
Published: June 2023

Abstract

Background and Aims
The histopathological classification for ANCA-associated glomerulonephritis (ANCA-GN) is a well-established tool to reflect the variety of patterns and severity of lesions that can occur in renal biopsies of patients with ANCA-associated vasculitis. As with many fields, medicine saw a rapid emergence of Artificial Intelligence (AI) and Deep learning (DL) approaches. In the field of digital pathology AI can now serve as decision-support for pathologists, with the potential for gains in productivity and time-saving. It was demonstrated previously that AI can aid in identifying histopathological classes of renal diseases, e.g. of diabetic nephropathy. Although these models reach high prediction accuracies, their black box structure makes them very non-transparent. The disadvantage is that the networks’ decisions are not easily interpretable by humans and it is not clear what information in the input data underlies their decisions. This necessitates the use of Explainable AI (XAI), so that decisions made by AI models become accessible for validation by a human expert.

Method
Renal biopsy slides of 80 patients with ANCA-GN from 3 European centers, who underwent a diagnostic renal biopsy between 1991 and 2011, were included. On the scanned slides glomeruli were labelled as ‘normal’, ‘sclerotic’, ‘crescentic’ or ‘abnormal - other’. We developed a DL-based computational pipeline, which detects and classifies the glomeruli. We investigated the explainability of our model, using XAI techniques to shed light on the decision-making criteria of our trained DL classifier using saliency maps. These maps were analyzed by pathologists to compare the decision-making criteria of humans and the DL model.

Results
Our DL model shows a prediction accuracy of 93% for classifying glomeruli. The saliency maps from our trained DL models help us to better understand the decision-making criteria of the DL black box.

Conclusion
AI and DL play an increasingly important role in (nephro)pathology. To ultimately enable safe implementation of these models in clinical practice, validation of their decisions is needed. To achieve this, we used XAI techniques, which showed great potential for illuminating the decision-making criteria of the DL black box.
#4473 PREVALENCE OF POST-COVID-19 CONDITION IN PATIENTS WITH CHRONIC KIDNEY DISEASE, ON DIALYSIS AND LIVING WITH A KIDNEY TRANSPLANT
Authors: Bouwmans Pim , Malahe Reshwan , Messchendorp Lianne , Vart Priya , Sanders Jan-Stephan , Gansevoort Ronald , De Vries Aiko , Abrahams Alferso C , Bemelman Frederike , Vervoort Hanneke , Hilbrands Luuk , Dam Marc Ten , Dorpel van den René , Reinders Marlies , Hemmelder Marc 
Published: June 2023

Abstract

Background and Aims
The prevalence of post-COVID-19 condition (PCC) is estimated to be 13% in healthy individuals. We analyzed the prevalence and disease burden of PCC in patients with chronic kidney disease (CKD) G4/5, dialysis patients and kidney transplant recipients (KTR).

Method
Patients participated in the RECOVAC study, in which SARS-CoV-2 antibodies were measured in CKD G4/5, dialysis patients and KTR after the second and third COVID-19 vaccination in the Netherlands. A questionnaire was sent to 4868 participants one year after initial vaccination asking for the presence of long-lasting symptoms after diagnosis in COVID-19 positive patients, or since the start of the pandemic in COVID-19 negative patients. PCC was defined according to the WHO clinical case definition. Blood samples at one month after the second and third vaccination were analysed with anti-RBD IgG ELISA. COVID-19 diagnosis was assessed by questionnaire or positive anti-nucleocapsid IgG antibodies. Logistic regression analysis was used to compare the presence of one or more long-lasting symptoms between COVID-19 positive and negative patients. In COVID-19 positive patients, we likewise identified predictors of PCC by backward selection and estimated the association between log-transformed antibody levels and PCC.

Results
2747 patients were included, of which 222 patients with CKD G4/5, 390 dialysis patients and 2135 KTR. PCC was present in 25%, 16%, and 21% of CKD G4/5 patients, dialysis patients and KTR with high or very high symptom burden in 57%, 61% and 71%, respectively. In COVID-19 negative patients, long-lasting symptoms were present in 15%, 13% and 18%, respectively. COVID-19 positive patients (n = 1004) were at higher odds of having one or more long-lasting symptoms compared with COVID-19 negative patients (n = 1743) (OR: 1.33 [1.09–1.61], p = .005). Predictors of PCC were chronic lung disease (adjusted OR 2.04 [1.18#x2013;3.50], p = .01) and hospital/ICU admission (adjusted OR 5.03 [3.22-7.86], p &lt; .001). Log anti-RBD IgG antibody level was negatively associated with PCC (adjusted OR: 0.79 [0.66#x2013;0.94], p = .008).

Conclusion
Patients with CKD G4/5, dialysis patients and KTR are at risk for PCC with a high symptom burden, especially if antibody levels after COVID-19 vaccination are low.
#4478 HIF-1α REGULATED LNCRNA-ATP6V0E2-AS1 MEDIATES HYPOXIA-INDUCED MITOPHAGY IN RENAL TUBULAR CELLS
Authors: LI Chi-Yuan 
Published: June 2023

Abstract

Background and Aims
Mitophagy activation is crucial for hypoxia signaling in acute kidney injury (AKI). Selective removal of damaged mitochondria is mediated through a concerted function of coding and non-coding RNA expressions. Insights on HIF-1α signaling in lncRNA-regulated mitophagy mechanism are not known. The study aims to investigate the role of hypoxia-inducible factor 1α (HIF-1α) regulated long non-coding RNA (lncRNA) ATP6V0E2-AS1 in acute kidney injury (AKI) by examining its effect on mitophagy.

Method
Mitophagy proteins (PINK1, p-PARKIN, LC3) were determined through western blot analysis. Immunofluorescence studies of PINK1 mitochondrial translocation and LC3/TOMM20 localization were determined using confocal analysis. HIF-1α interaction with lncRNA-ATP6V0E2-AS1 through promoter binding activity was evaluated through chromatin immunoprecipitation analysis. RNA interaction between lncRNA-ATP6V0E2-AS1 and PINK1 was analyzed by dual-luciferase reporter assay.

Results
Hypoxia upregulated PINK1, p-PARKIN, LC3 expressions, and mitophagosome in HK-2 cells. Overexpression and knockdown studies of hypoxia-regulated lncRNA-ATP6V0E2-AS1 significantly regulated PINK1/p-PARKIN expressions, subsequent PINK1 mitochondrial co-localization, and mitophagosome formation. shHIF-1α knockdown in HK-2 cells reveals that HIF-1α mediates PINK1/p-PARKIN mitophagy regulation under hypoxic conditions. In detail, HIF-1α binds to the promoter of lncRNA-ATP6V0E2-AS1 and down-regulates its expression under hypoxia. Deficiency of both HIF-1α and lncRNA-ATP6V0E2-AS1 reverted shHIF-1α mediated suppression of PINK1 expression and mitophagosome formation. Further, ATP6V0E2-AS1 post-transcriptionally regulates PINK1 expression by RNA-RNA interaction.

Conclusion
Altogether, our study shows novel findings on the HIF-1α mediated lncRNA-ATP6V0E2-AS1 in hypoxia-induced mitophagy regulation in the renal tubular cells. Thus, downregulated ATP6V0E2-AS1 expression with subsequent mitophagy activation is critical for hypoxia-induced mitophagy regulation through HIF-1α/ATP6V0E2-AS1/PINK1 axis.
#4500 IMPLEMENTATION OF A NEW GENERATION DIGITAL STETHOSCOPE FOR ARTERIOVENOUS FISTULA MONITORING IN HEMODIALYSIS PATIENTS
Authors: Carullo Nazareno , Presta Pierangela , Musolino Michela , Fabiano Giuseppe , Bianco Maria Giovanna , Oliva Giuseppe , Armeni Annarita , Chiarella Salvatore , Andreucci Michele , Fiorillo Antonio , Bolignano Davide , Pullano Salvatore , Coppolino Giuseppe 
Published: June 2023

Abstract

Background and Aims
The management of complications of arteriovenous fistula (AVF) for hemodialysis, principally stenosis, remains a major challenge for clinicians with a substantial impact on health resources. Stenosis not infrequently preludes to thrombotic events with the loss of AVF functionality. A frequent monitoring with physical examination is at the basis for an appropriate clinical care. It includes a regular inspection, palpation and auscultation of the arm. A normally functioning AVF, when listened by a stethoscope, has a continuous systolic-diastolic low-frequency murmur while with stenosis the frequency of the murmur increases and the duration of diastolic component decreases, disappearing in severe stenosis. These evidences are strictly subjective and dependent from operator skill and experience. New generation digital stethoscopes are able to record sound and subsequently dedicated software allows to extract quantitative variables (amplitude and frequency) that characterize the sound in an absolutely objective and repeatable way. The aim of our study was to analyze with an appropriate software listenable sound from AVFs taken by a commercial digital stethoscope and to investigate the potentiality to develop an objective new monitoring system to detect stenosis.

Method
Between September 2022 and January 2023, we screened forty-eight patients from two hemodialysis centers in Catanzaro (Italy). Patients were screened from two blinded experienced examiners for recognized criteria for stenosis by doppler ultrasound (DUS). We recorded the sound coming from the AVFs using a 3M™ Littmann® CORE Digital Stethoscope 8570 (Figure 1-A), in standardized sites: on the anastomosis chamber, at a distance of 5 and 10 cm from it, on the site of stenosis and immediately after. The sound waves were transformed into quantitative variables (amplitude and frequency) using a sound analysis software.

Results
Based on doppler evaluation, 14/48 patients (29%) were classified as stenotic of which three were hemodynamically significant. The sounds detected in the stenosis sites had a significant higher average frequency compared to non-stenotic sites (Figure 1-B). Characteristics of sound waves were significant different for stenotic and non-stenotic patients in term of average power, mean amplitude and mean frequency. Analysis of waves permitted us to determine peculiar shape for stenosis and another for normal AVF (Figure 1-C,D).

Conclusions
The analysis of sound waves by a digital stethoscope permitted us to distinguish between stenotic and no stenotic AVFs. The standardization of this technique and the introducing of data in a deep learning algorithm could allow an objective and fast method for a frequent monitoring of AVF.