bluuebunny/crossref_metadata_2025_split huggingface dataset:
#5349 CYCLIN D1 AMELIORATES ACUTE KIDNEY INJURY BY IMPROVING FATTY ACID OXIDATION VIA AMPK PATHWAY
Authors: Huang Yuliang , Chen Junzhe , Shao Xiaofei , Li Jinxiang , Tang Ying 
Published: June 2023

Abstract

Background and Aims
Acute kidney injury (AKI) is a life-threatening condition. The absence of oxygen during the acute ischemic phase would disturb energy metabolism and cause kidney tubular epithelial cell damage. Fatty Acid Oxidation (FAO) is the main source of energy production of renal proximal tubular epithelial cells. Timely promoting FAO, increasing supplies of energy, and promoting cell proliferation are essential to improve kidney injury, but there is no clinically recognized effective treatment for this. Cyclin D1(CCND1), a member of the cell cycle family, plays a vital role in cell proliferation. Our previous study found that CCND1 improved AKI accompanied with increased fatty acid oxidation. Therefore, we investigated the role and molecular basis for CCND1 involvement in fatty acid oxidation of AKI.

Method
CCND1 was evaluated in AKI in human kidney proximal tubular epithelial cells (HK-2 cells) and male C57BL/6J mice (wild type). The protective role of CCND1 in AKI was investigated in a mouse model of ischemia-reperfusion AKI treated by ultrasound-microbubble-mediated kidney-specifically transferring CCND1-expressing plasmids in male C57BL/6J mice (wild type). Eight-week-old male C57BL/6J mice (wild type) were subjected to bilateral renal artery occlusion for 30min followed by 24h of reperfusion. We evaluated FAO, proliferation, and autophagy in vitro and in vivo. In addition, we evaluated the concentrations of blood urea nitrogen and creatinine, evaluated kidney ultrastructure and so on.

Results
In vivo studies had shown that activation of CCND1 can prevent AKI-induced lipid accumulation, kidney tubule injury and kidney function declined after ischemia-reperfusion injury. Compared to test control, the treatment significantly (p &lt; 0.05) lowered the concentrations of blood urea nitrogen and creatinine. Kidney specific overexpression of CCND1 promoted FAO, promoted proliferation and reduced apoptosis. Mechanistically, CCND1 activated the AMPK pathway, which increased the expression of phosphorylation AMP activated protein kinase (p-AMPK) and upregulated FAO. On the contrary, inhibiting the expression of CCND1 exacerbated impairment of FAO and disturbed energy metabolism.

Conclusion
Thus, CCND1 improved FAO and reduced lipid accumulation via active AMPK pathway in kidney proximal tubular epithelial cells (PTECs). Hence, reconstruction of the expression of CCND1 may be a novel therapeutic strategy for treating AKI.
#5485 CHRONIC KIDNEY DISEASE NOR STROMAL CELL-DERIVED FACTOR 1Α PEPTIDE (SDF-1A) BIO-FUNCTIONALIZATION ALTER RODENT VASCULAR IN SITU TISSUE FORMATION
Authors: Krebber Merle , Bessseling Paul , Driessen Rob , Söntjens Serge , Janssen Henk , Teraa Martin , Fledderus Joost , Dankers Patricia , Bouten Carlijn , Verhaar Marianne 
Published: June 2023

Abstract

Background and Aims
The systemic pro-inflammatory environment of chronic kidney disease (CKD) could influence neo-tissue formation of in situ tissue engineered vascular access grafts. Here, we studied in-graft tissue formation and inflammation in a rat CKD model. Moreover, we explored graft bio-functionalization with stromal cell-derived factor 1α peptides (SDF-1α), a progenitor cell chemotactic which may improve cell engraftment.

Method
Pristine or SDF-1α bio-functionalized vascular grafts (1,2 mm ID, 2 cm length, 250–300 μm wall thickness) were created from biodegradable, polycarbonate-bisurea (PC-BU) electrospun meshes. Abdominal aorta interposition grafts were implanted in female Sprague Dawley rats (n = 53) that underwent sham surgery or CKD induction by 5/6th nephrectomy. Explanations and analyses were performed after two (n = 25) or twelve (n = 9) weeks.

Results
At two weeks, survival and graft patency were 100%. Explant cellularity and collagen content were not significantly different between sham and CKD rats and were not influenced by SDF-1α. Endothelial cell coverage (RECA+) and smooth muscle cell presence (αSMA+) were visually similar irrespective of disease or bio-functionalization. Elastin+ (p = 0,11), pan-(CD68+, p = 0,08) and anti-inflammatory macrophage (CD163+, p = 0,52) surface area, as well as (anti-)inflammatory gene expression were not significantly different between groups. The twelve-week CKD-group was taken out of experiment prematurely due to rapid disease progression. In addition, preliminary death due to vascular rupture occurred in four animals (n = 2 pristine and n = 2 SDF-1α) in the twelve-week sham animals. While patent, all remaining sham explants at twelve weeks (n = 9) showed severe vascular dilatation and calcifications (Von Kossa+). No differences in inflammatory and neo-tissue markers were found between twelve-week sham pristine and SDF-1α grafts or between explants over time.

Conclusion
CKD did not significantly alter inflammation or tissue formation of in situ tissue engineered vascular grafts. Additionally, SDF-1α bio-functionalization did not significantly alter cell engraftment or tissue formation. Mechanical stability of the graft appears to be the primary driver of neo-tissue formation. Future emphasis on in vitro to in vivo translation should be on the fine balance between tissue formation on one hand and fiber resorption on the other hand.
#5551 THE TROPONIN LEVEL AND ITS INFLUENCE ON RENAL AND CARDIOVASCULAR EFFECTS IN RENAL TRANSPLANT RECIPIENTS
Authors: Heleniak Zbigniew , Naik Marcel , Osmanodja Bilgin , Eleftheriadis Georgios , Schmidt Danilo , Debska-Slizien Alicja , Halleck Fabian , Budde Klemens 
Published: June 2023

Abstract

Background and Aims
Cardiovascular (CV) morbidity and mortality are highly prevalent in renal transplant recipients (RTRs). As such, assessments of CV status using troponin concentrations could help to identify patients at risk for death or CV events and as a predictor for deterioration of graft function. The aim of the study was to investigate the biomarker troponin for the prediction of adverse renal and cardiovascular outcomes in stable RTRs.

Method
305 stable RTRs with a median age of 53 years, (60.6% male) transplanted between 1994 and 2018 were enrolled in the study. General characteristics are shown in Table 1. At baseline, troponin, NT-pro BNP, carotid-femoral pulse wave velocity (cfPWV) and pulse pressure (PP) were measured. Troponin was measured during a routine baseline visit in stable RTR without cardiac symptoms. The median troponin concentration (11 ng/l) was used as cut-off. Patients were divided into two groups high (≥11 ng/l) and low (&lt;11 ng/l) troponin and followed for 54 months. During this time CV events (stroke, myocardial infarction, peripheral artery thrombosis) death, graft loss and deterioration of renal graft function (increasing creatinine ≥30%) or proteinuria (urine protein creatinine ratio UPCR ≥500 mg/g) were monitored.

Results
At baseline, significant differences were observed between groups in terms of creatinine, eGFR, troponin, UPCR, PP, and PWV. In the group with baseline troponin ≥11ng/l, more patients had coronary artery disease/peripheral obliterans artery disease (CAD/POAD), heart failure (HF), and diabetes. Baseline troponin correlated only weakly with age (R = 0.47), cfPWV (R = 0.41), eGFR (R = −0.52). During follow-up, patients with high troponin experienced more frequently an increase in creatinine ≥30% (32.9% vs 13%), doubling creatinine (11.2% vs 3.1%), an increase in UPCR (22.4% vs 9.2%), graft loss (16.1% vs 1,8%), death (13.3% vs 0%), and CV events (6.3% vs 4.9%).

Conclusion
1. Age, arterial stiffness, and eGFR only have a weakly impact on troponin in stable RTR. 2. Higher troponin is associated with poor outcomes and might be useful not only for the identification of patients with high-risk CV events but also for the deterioration of allograft function.
#5611 ASSOCIATION BETWEEN LOSS OF IMMUNE CHECKPOINT PROGRAMMED CELL DEATH PROTEIN 1 AND ACTIVE ANCA-ASSOCIATED RENAL VASCULITIS
Authors: Tampe Björn 
Published: June 2023

Abstract

Background and Aims
Immune checkpoint inhibitors (ICIs) have made an important contribution on the survival of patients with certain cancers. ICIs interrupt co-inhibitory signalling pathways mediated by programmed cell death protein 1 (PD-1), programmed cell death protein-ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen (CTLA-4) that result in the elimination of cancer cells by stimulating the immune system. Immune-related adverse events have also been described and attributed to an enhanced immune system activation. Recent observations have suggested dysregulation of immune checkpoints in active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Therefore, we here aimed to analyze abundance of immune checkpoint molecules PD-1/PD-L1 and its implications in ANCA-associated renal vasculitis.

Method
We here analyzed intrarenal PD-1 and PD-L1 by immunostaining in a total number of 15 kidney biopsies with ANCA-associated renal vasculitis in correlation with glomerular and tubulointer-stitial lesions. For independent validation, publicly available datasets were analyzed for PD-1 expression (encoded by PDCD1).

Results
We here observed a predominant tubulointerstitial expression of PD-1 that is decreased in ANCA-associated renal vasculitis. Moreover, loss of tubulointerstitial PD-1 correlated with active ANCA-associated renal vasculitis. Consistent to the observed association with active glomerular and tubulointerstitial lesions, we identified that interstitial PD-1 correlated with tubular and/or glomerular PD-L1 positivity. Finally, PD-1 was associated with decreased local synthesis of complement factor B. Interestingly, we did not observe a correlation between PD-1 and complement C5 or its C5a receptor. Combined with our observations, this may implicate a link between im-paired PD-1/PD-L1 signalling, complement factor B, and active ANCA-associated renal vasculitis.

Conclusion
These findings could be of relevance because experimental data have already been described that PD-1 agonism can be used therapeutically to attenuate autoimmunity in multiple disease models. Furthermore, targeted therapy against complement C5/C5a receptor and factor B are both available and currently evolving in the treatment of AAV. Therefore, this pilot study expands our current knowledge and describes a potential interplay between immune checkpoints and the alternative complement pathway in active ANCA-associated renal vasculitis.
#6522 CYSTATIN C-BASED ESTIMATED GLOMERULAR FILTRATION RATE AND RISK OF STROKE IN THE GENERAL POPULATION
Authors: Xiao Fei , Liao Jinlan 
Published: June 2023

Abstract

Background and Aims
Previous results on the association between estimated glomerular filtration rate (eGFR) and strokes are mixed. Most studies derived the eGFR from serum creatinine, which is affected by non-kidney determinants and possibly has biased the association with stroke risks. We hypothesized that eGFR was independently associated with the risk of stroke in the general population. Herein, we investigated the linear and nonlinear associations of the cystatin C-based eGFR (eGFRcys) with the risk of total stroke and its subtypes in the UK Biobank participants.

Method
In this cohort study, we included 462,307 UK Biobank participants (94.5% Whites, 54% women, aged 56±8 years) free of stroke at enrollment. The eGFRcys and eGFRcr were calculated with serum cystatin C and creatinine, respectively. Outcomes of interest were the incidences of total stroke and subtypes. We investigated the linear and nonlinear associations using Cox proportional hazards models and restricted cubic splines, corrected for regression dilution bias.

Results
During averaged follow-up of 10.11 years, 4,427 incident strokes occurred, among which 3,447 were ischemic and 1,163 were hemorrhagic. After adjustment of confounders, the regression dilution-corrected hazard ratios (95% confidence intervals) for every 10 ml/min/1.73 m2 decrement in eGFRcys were 1.10 (1.06-1.12) for total stroke and 1.11 (1.08-1.15) for ischemic stroke. A similar pattern was observed with eGFRcr although the association was weaker. When either eGFR was below 75 ml/min/1.73 m2, the risks of total and ischemic stroke increased exponentially as eGFR decreased. However, when eGFRcys was above 75 ml/min/1.73 m2, the risks did not significantly differ but seemingly decreased as eGFRcys exceeded 105 ml/min/1.73 m2. A U-shape relationship was witnessed if eGFRcr was used instead. There was null association between eGFR and hemorrhagic stroke.

Conclusion
The risks of total stroke and ischemic stroke increased exponentially when the eGFR fell below 75 ml/min/1.73 m2.
#6667 EFFECTIVENESS AND SAFETY OF APIXABAN, RIVAROXABAN AND WARFARIN IN PATIENTS WITH ADVANCED CKD AND ATRIAL FIBRILLATION: A NATIONWIDE US COHORT STUDY
Authors: Fu Edouard , Desai Rishi , Paik Julie , Kim Dae , Zhang Yichi , Mastrorilli Julianna , Cervone Alexander , Lin Joshua 
Published: June 2023

Abstract

Background and Aims
Head-to-head data comparing the effectiveness and safety of oral anticoagulants in patients with atrial fibrillation (AF) and advanced CKD or on dialysis are lacking. We compared the effectiveness and safety of apixaban, rivaroxaban and warfarin in patients with AF and CKD stages 3 to 5, including those on dialysis.

Method
We conducted a new-user, active-comparator, cohort study using data from two nationwide U.S. claims databases, Medicare and Optum Clinformatics® Data Mart Database (01/01/2013–03/31/2022). We included patients with nonvalvular AF and CKD who newly initiated warfarin vs. apixaban (N = 169,702), or rivaroxaban vs. apixaban (N = 129,396). CKD stages were determined based on a validated claims-based algorithm. The primary outcome was a composite of ischemic stroke or major bleeding to represent the net benefit of treatment. Secondary outcomes included the individual components of the primary outcome and all-cause death. We used 1:1 propensity score matching to adjust for 80 confounders. Adjusted hazard ratios (aHRs) were estimated with Cox regression analyses and absolute rate differences per 1000 person years (aRDs) with generalized linear regression in the propensity score matched sample.

Results
Compared with apixaban, warfarin and rivaroxaban were associated with a higher risk of the composite endpoint, regardless of CKD stage. Comparing warfarin vs. apixaban, the aHRs were 1.5 (1.3–1.6), 1.4 (1.0–1.9) and 1.3 (1.2–1.5) for CKD stages 3, 4, and 5/dialysis, respectively (p-value for heterogeneity 0.31); corresponding aRDs were 27.2 (20.4, 30.0), 32.9 (−4.3, 70.2), and 36.9 (21.7, 52.2) (p-value for heterogeneity 0.51). Comparing rivaroxaban vs. apixaban, the aHRs were 1.5 (1.4–1.7), 1.7 (1.4–2.2) and 1.3 (0.9–1.8) (p-value for heterogeneity 0.38) for CKD stages 3, 4, and 5/dialysis, respectively; corresponding aRDs were 27.1 (12.3, 41.8), 53.2 (29.8, 76.6), and 20.7 (−28.9, 70.2) (p-value for heterogeneity 0.16). The higher rate of the primary endpoint for warfarin and rivaroxaban was driven by a higher risk of bleeding, with similar rates of ischemic stroke.

Conclusion
In patients with AF and CKD, apixaban was associated with a net benefit compared with rivaroxaban or warfarin, which was primarily driven by lower rates of bleeding. Benefits were consistent across severity of CKD.
#6883 PROTECTIVE ROLE OF THE PODOCYTE IL-15 / STAT5 PATHWAY IN EXPERIMENTAL FOCAL AND SEGMENTAL GLOMERULOSCLEROSIS
Authors: Niasse Aissata , Louis Kevin , Lenoir Olivia , Mesnard Laurent , Hadchouel Juliette , Luque Yosu 
Published: June 2023

Abstract

Background and Aims
During glomerular diseases, podocyte-specific pathways can modulate the intensity of histological disease and prognosis. The therapeutic targeting of these pathways could thus improve the management and prognosis of kidney diseases. The Janus Kinase/ Signal Transducer and Activator of Transcription (JAK/STAT) pathway, classically described in immune cells, has been recently detailed in intrinsic kidney cells. We previously evidenced a protective role for a podocyte-expressed immune receptor such as the common gamma chain (ΓC) during glomerulonephritis (1). We also found that STAT5, a transcriptional factor classically described and activated downstream ΓC in T cells is upregulated in podocytes during glomerulonephritis.

Method
Using a mice model with a podocyte-specific deletion of Stat5, we analyzed the role of STAT5 in two experimental models of glomerular diseases.

Results
Here, we show, for the first time, that STAT5 is activated in human podocytes in focal and segmental glomerulosclerosis (FSGS). Additionally, podocyte-specific Stat5 inactivation aggravates the structural and functional alterations in a mouse model of FSGS (Figure 1). This could be due, at least in part, to an inhibition of autophagic flux and an alteration of mitochondrial function. Finally, Interleukin 15 (IL-15), a classical activator of STAT5 in immune cells, increases STAT5 phosphorylation in human podocytes and its administration alleviates glomerular injury in vivo by maintaining autophagic flux in podocytes.

Conclusion
In conclusion, activating podocyte STAT5 with commercially available IL-15 represents a potential new therapeutic avenue for FSGS.
#2496 ASSOCIATION OF ABNORMALITIES IN ELECTROCARDIOGRAPHY AND ECHOCARDIOGRAPHY WITH THE OCCURRENCE OF CARDIOVASCULAR DISEASE IN CHRONIC KIDNEY DISEASE
Authors: Hirabayashi Ken , Fujii Hideki , Kono Keiji , Yamatani Satoshi , Shimizu Mao , Watanabe Kentaro , Sakamoto Kazuo , Goto Shunsuke , Nishi Shinichi 
Published: June 2023

Abstract

Background and Aims
In chronic kidney disease (CKD), the incidence of cardiovascular disease (CVD) increases along with CKD progression. Although coronary artery disease (CAD) is one of the most critical CVDs, it is difficult to identify CAD because its symptom is usually atypical in CKD. Consequently, appropriate screening tests for CVD are important in this population. Electrocardiography (ECG) and transthoracic echocardiography (TTE) are commonly performed in daily clinical practice, and we researched whether these abnormalities are risk factors for CVD including CAD in patients with advanced CKD.

Method
This study included patients with CKD stage G4-5 who were admitted to our hospital from 2010 to 2019. Depending on the presence of ECG and/or TTE-indicated abnormalities, the study patients were divided into four groups: those without both ECG and TTE abnormalities (group A: ECG-, TTE-), those with only ECG abnormalities (group B: ECG+, TTE-), those with only TTE abnormalities (group C: ECG-, TTE+), and those with both ECG and TTE abnormalities (group D: ECG+, TTE+). The clinical characteristics, the occurrence of CVD events, their prognosis, and the prevalence of positive screening tests for CAD were compared among the four groups. CVD events were defined as CVD death and non-fatal CVD events.

Results
The number of study patients was 607, and they were divided into four groups as follows: 333 in group A, 106 in group B, 76 in group C, and 92 in group D, respectively. The median observational period was 21 months. The incidence of CVD events was highest in group D: 45 patients (13.5%) in group A, 25 patients (23.6%) in group B, 19 patients (25.0%) in group C, and 37 patients (40.2%) in group D, respectively. Multivariate analysis showed that the hazard ratios (HR) for CVD events was significantly higher in group C and D compared to group A as reference (HR: 1.620 in group B, p = 0.116; HR: 2.848 in group C, p = 0.001, and 4.111 in group D, p&lt;0.001, respectively). Furthermore, group D had a higher positive rate of screening tests for CAD compared to the other three groups.

Conclusion
In patients with advanced CKD, ECG and TTE abnormalities were significantly associated with the occurrence of CVD events. Additionally, those with both ECG and TTE abnormalities may be at high risk for the presence of CAD.
#2524 RESOLVIN D1 ATTENUATES SEPSIS INDUCED ACUTE KIDNEY INJURY TARGETING MITOCHONDRIA AND NF-κB SIGNALING PATHWAY
Authors: Wang Liya , LI Jiameng , Su Baihai 
Published: June 2023

Abstract

Background and Aims
Acute kidney injury is a highly common and multifactorial renal disease resulting in significant morbidity and mortality, especially sepsis-induced acute kidney injury. There is no effective therapy available to treat or prevent sepsis-induced acute kidney injury. One of the specialized pro-resolving mediators, Resolvin D1 exhibits special anti-inflammatory effects in several inflammatory disease models, but there is little evidence about the effect and mechanism of Resolvin D1 in sepsis-induced acute kidney injury. To explore the renal protective role of RvD1 in SI-AKI and to further explore the inherent pathophysiological mechanism, especially the role of mitochondrial function and NF-κB signaling pathway, in vitro and in vivo experiments were conducted.

Method
We conducted experiments to explore the effect and mechanism of Resolvin D1 in sepsis-induced acute kidney injury. In vitro, human proximal tubular epithelial cells were used to test the apoptosis ratio, cell viability and reactive oxygen species level. In vivo, C57BL/6 mice were injected with lipopolysaccharide to establish a sepsis-induced acute kidney injury model. Renal function and structure, apoptosis ratio of kidney cells, mitochondrial structure and function and related protein and gene levels were assessed.

Results
In vitro, the resolvin D1-treated group showed higher cell viability and lower reactive oxygen species levels and apoptosis ratios than the LPS group. In vivo, Resolvin D1 can not only improve renal function and mitochondrial function but also reduce the apoptosis ratio, while mediating mitochondrial dynamics and inhibiting NF-κB pathway.

Conclusion
Resolvin D1 has a good renoprotective effect by maintaining mitochondrial dynamics and inhibiting the NF-κB pathway. This provides an important basis for us to further develop the clinical therapeutic value of RvD1 in acute renal injury in sepsis.
#2556 BIOLOGICAL EFFECTS OF A SHORT PERIOD OF NORMOTHERMIC MACHINE PERFUSION IN MARGINAL KIDNEYS: RESULTS OF A PROTEOMICS ANALYSIS
Authors: Neri Flavia , Bruschi Maurizio , Candiano Giovanni , Granata Simona , Furian Lucrezia , Zaza Gianluigi 
Published: June 2023

Abstract

Background and Aims
Renal normothermic machine perfusion (NMP) is an organ preservation method based on the circulation of a warm (35–37°C) perfusion solution through the renal vasculature to deliver oxygen and nutrients. However, the biological effects of this technique on the marginal kidneys are uncertain. We consequently used mass spectrometry to define the proteomic profile of kidney tissue and urine from eight organs, considered unsuitable for transplantation, reconditioned for 120 min using a Kidney Assist device.

Method
Biopsies were taken during the pre-implantation histological evaluation (T-1), at the start of back table preparation (T0), and after 60 and 120 min of perfusion (T60, T120). Urine was collected at T0, T30, T60, and T120. Multiple algorithms, support vector machine (SVM) learning and partial least squares discriminant analysis (PLS-DA) were used to select the most discriminative proteins during NMP.

Results
Statistical analysis revealed the upregulation of 169 proteins and the downregulation of 196 in kidney tissue during NMP. Machine learning algorithms recognized the top 50 most discriminative proteins, five of which were concomitantly upregulated (LXN, ETFB, NUDT3, CYCS and UQCRC1) and six downregulated (CFHR3, C1S, CFI, KNG1, SERPINC1, and F9) in the kidney and urine after NMP. Functional analysis showed that the most upregulated proteins were involved in the oxidative phosphorylation system and ATP synthesis, whereas the downregulated proteins were involved in the complement system and coagulation cascade. Results were, then, validated by classical and highly conservative biomolecular lab techniques.

Conclusion
Our proteomic analysis revealed that even brief periods of NMP induce substantial metabolic and biochemical changes in marginal organs, which supports the use of this promising technique in the clinic.