bluuebunny/crossref_metadata_2025_split huggingface dataset:
#5797 AMINOPEPTIDASE A REGULATES ACUTE ANGIOTENSIN DEPENDENT HYPERTENSION
Authors: Forster Peter , Abedini Yasemin , Müller Tilman , Ye Minghao , Wysocki Jan , Batlle Daniel 
Published: June 2023

Abstract

Background and Aims
Aminopeptidase A (APA) is an enzyme that cleaves a single aspartate residue from the amino-terminus of several renin-angiotensin systems (RAS) peptides. We have shown that genetic deficiency of APA was associated with increased blood pressure and ultrastructural glomerular pathology in mice. Here we studied the effect of this Aminopeptidase on different peptides of the RAS and its effect on acute hypertension.

Method
We developed an in vitro assay based on Aspartate formation by APA to detect which Angiotensin (Ang) peptides are the substrate of this enzyme. The identified Ang peptides were injected to determine their relative effects on systolic blood pressure (SBP) in anesthetized WT mice. The effect of recombinant Aminopeptidase A on Ang I, Ang II and Ang 1-12 mediated SBP increase was further assessed in APA deficiency using global knockout mice (KO), and after systemic injection of recombinant APA.

Results
In the in vitro assay, the rAPA showed significant cleavage activities for Ang II (22427±3353, n = 12), Ang I (21883±1692, n = 3), Ang1-7 (15833±3395, n = 3), Ang1-9 (15773±3395, n = 3) and Ang1-12 (13170±220, n = 3) as evidenced by the formation of aspartate measured as a readout of enzymatic cleavage. When the five angiotensin peptides were injected into WT mice, only Ang I, Ang II and Ang 1-12 caused a substantial increase in SBP (Figure 1, left). In APA KO mice the bolus administration of Ang II showed an exaggerated increase in SBP compared to WT mice (Figure 1, right). The effect of Ang I and Ang 1-12 in APA KO appeared similar (not shown). When Ang I, Ang II and Ang 1-12 were administrated in WT mice preinjected with APA the increase in SBP was markedly reduced (p&lt;0,001, p = 0,0024 and p = 0,0063, respectively).

Conclusion
Aminopeptidase A can cleave the N-terminal aspartate from Ang II as well as from other RAS peptides upstream [Ang 1-12, Ang I (1-10) and Ang 1-9] and downstream of Ang II (Ang 1-7). Aminopeptidase A deficiency is associated with exaggerated SBP response to Ang I, Ang II and Ang 1-12 whereas the recombinant enzyme restores the effect on acute hypertension caused by infusion of these peptides. This suggests that APA could be used to treat hypertension due to RAS overactivity.
#6104 CLINICAL IMPACT OF UNDIAGNOSED HOSPITAL ACUTE KIDNEY INJURY
Authors: Cappadona Francesca , Sangregorio Filippo , Mallia Laura , Zanetti Valentina , Costa Elisa , Picciotto Daniela , Nescis Lorenzo , Viazzi Francesca , Esposito Pasquale 
Published: June 2023

Abstract

Background and Aims
Hospital Acute kidney injury (H-AKI) is associated with an increased risk of complications and mortality. Despite attempts to uniform the diagnosis of AKI and point attention to this condition, in clinical practice, the recognition of AKI is often limited. In this study, we tried to evaluate the impact of underdiagnosed AKI in hospitalized patients.

Method
We collected data of patients hospitalized at IRCSS Policlinico San Martino, Genoa, Italy, between 1/1/2106 and 31/12/2019. We considered clinical data, serum creatinine (sCr), length of hospital stay, death, comorbidities, and primary diagnoses as codified in the hospital discharge form-HDF. Patients with CKD stage 4-5 were excluded.
In the selected patients, we defined and graded AKI according to the KDIGO criteria, by comparing the peak sCr to the lowest sCr during hospitalization under the assumption that the lowest sCr would represent baseline kidney function. Then, we divided this cohort into 3 groups: 1) patients with no AKI at all, 2) AKI calculated by sCR changes and formally codified in HDF (diagnosed AKI), 3) AKI calculated by sCR changes but not codified in HDF (i.e., undiagnosed AKI).
Finally, we compared the clinical characteristics and outcomes of these groups.

Results
We included 56,820 pts. The incidence of AKI was 24.5% (n = 13,920), evaluating the distribution among the 3 groups, we noticed that a small percentage of AKI was reported in HDF (Fig. 1). Only in 27% of cases in medical wards, 13% in surgical wards, and 19% in Intensive care Units AKI was formally reported in HDF, while in the emergency department, AKI was diagnosed in 78% of cases. Compared with No AKI patients, those with AKI (both diagnosed and undiagnosed) had a higher prevalence of comorbidities (diabetes mellitus, heart failure, atrial fibrillation) and incidence of myocardial ischemia and sepsis (Table 1). Moreover, patients with AKI had a significantly longer hospitalization and major mortality risk, at cox regression (HR 2.6, IC 2.4-2.8, p0.000) and Kaplan Meier (Fig. 2). The mortality risk augmented in all patients with AKI analyzed by both logistic regression univariate (OR 7.1, IC 6.7-7.6, p&lt;0.001) and multivariate analysis corrected by age, gender, and comorbidities (OR 4,5, IC 4,2-4,9, p&lt;0.001). Interestingly, these findings were confirmed also considering only the group of patients with undiagnosed AKI (univariate: OR 5.9, IC 4.2-4.9, p&lt;0.001; multivariate: OR 4.6, IC 4.2-4.9, p&lt;0.001).

Conclusion
Undiagnosed AKI is still very common in hospitalized patients, even if it identifies a category of patients with a high risk of complications and mortality. Proper recognition of H-AKI remains a problem to face.
#6147 BELATACEPT OUTCOMES IN PEDIATRIC KIDNEY TRANSPLANTATION: AN INTERNATIONAL MULTICENTER STUDY
Authors: Hogan Julien , Duneton Charlotte , George Roshan , Anne-Laure Sellier-Leclerc , Dunand Olivier , Baudoin Véronique , Cheyssac Elodie , Garro Rouba 
Published: June 2023

Abstract

Background and Aims
Belatacept is a co-stimulation blocker associated with better long-term outcomes in adult patients compared to CNI based regimens. Data on its use in older children and young adults are lacking. We are the 1st to report outcomes for 45 pediatric kidney transplant recipients converted to belatacept.

Method
45 patients were included from 4 centers (USA and France) between 05/2018 and 12/2021. Patients received an induction with basiliximab (n = 39) or ATG (n = 6). Maintenance immunosuppression included CNI, MMF +/− steroids. Patients’ viral status (EBV, CMV) were monitored monthly and allograft biopsies were performed prior and ∼6 months after starting belatacept. The first 5 belatacept injections were administered at 5 mg/kg/dose (10 mg/kg/dose if early conversion) every 2 weeks, then monthly. CNI were progressively reduced and stopped. MMF doses were also increased at CNI withdrawal.

Results
Median age at conversion was 17.7 y (range 10.3-20.6). 7/45 patients received an early conversion (median: 1 month post-transplant, IQR 0.5-1.2): 6 patients because of delayed graft function and 1 to avoid CNI toxicity (post-transplant diabetes). 38/45 patients were converted after a median of 4.1 years post-transplant (IQR 1.7-6.0). Conversion indication was based on the need for long term CNI avoidance: either because of toxicity (histology, post-transplant diabetes, tremors; n = 13) or sub-optimal creatinine (n = 12) or to improve adherence (e.g. monthly IV-treatment, n = 13). CNI were withdrawn in 42/45 patients by a median of 2.4 months (IQR 1.4-6.0). GFR was stable or improved over a median follow-up time of 1.6 years (IQR 1.1-2.4), Fig 1 A. Rejection episodes were observed in 10/45 patients (22%) after a median of 10.2 months (IQR 6.1-15.8) and included 7 TCMR, 2 ABMR and 1 mixed rejection. None of these patients were converted early (&lt;3 m), 5 had been converted for non-adherence, 4 had pre-existing DSA and 4 had prior history of rejection. Evolution of GFR in rejectors is shown in Fig 1 B. CNI were reintroduced for 6/10 and belatacept stopped for 3/10. Regarding viral complications, 1 severe BKv nephropathy required the discontinuation of belatacept. All patients were EBV+ at conversion (4 were EBV- at the time of transplant). No EBV replication was observed.

Conclusion
Selected pediatric kidney recipients benefit from long-term CNI toxicity avoidance, but selection criteria need to be refined to avoid rejection under costimulation blockade.
#6818 UNVEIL THE IMMUNE CELL LANDSCAPE IN AGEING KIDNEYS WITH AKI AND CKD
Authors: Liao Chia-Te 
Published: June 2023

Abstract

Background and Aims
Immunosenescence, or aging process of the immune system, leads to either defective immune response or increased systemic inflammation. Previous studies have shown that kidney immune system may coordinate the process of kidney inflammation, resolution, or progressive fibrosis in kidney diseases. However, the exact role of individual immune cell type has not been systematically characterized, especially in the context of ageing kidneys.

Method
Firstly, we induced acute and chronic aristolochic acid nephropathy (AAN) in 15-month-old mice. At different stages of AAN (Steady state, acute inflammation, recovery from acute injury, and chronic fibrosis), mice were then sacrificed, and kidneys were harvested for further processing. We flow-sorted kidney CD45+ immune cells (live cells) and applied to 10 x Genomics platform for single cell isolation and cDNA library construction. Illumina NovaSeq 6000 system was used for RNA sequencing. Finally, we performed downstream bioinformatics analysis through CellRanger and Seurat pipelines.

Results
Utilizing AAN mouse model, we successfully conducted flow sorted kidney immune cells single-cell RNA sequencing (scRNAseq) from 15 M/O kidneys with AKI and CKD. We clearly identified 25 distinctive immune cell types, representing distinctive lymphoid and myeloid populations (Figure 1a). We showed dynamic change of immune cell compositions upon different phases of AAN (i.e., CCR2+ monocytes and proliferative macrophages increased during acute inflammation, activated T cells expanded during recovery phase, CD206+CCL8+ macrophages enriched within the fibrotic kidneys) (Figure 1b). By analysis of differentially expressed genes (DEG), we identified 30 top-ranked genes, which uniquely enriched in specific cell subset (Figure 1c).

Conclusion
We have successfully unveiled the immune cell landscape in ageing kidneys with AKI and CKD. Our preliminary data has demonstrated that distinct immune cell subsets at different phases of injury may have unique roles. Future work will focus on the cell-cell interactions and immune cell activation/differentiation.
#3790 BASELINE BLOOD PRESSURE CONTROL IN THE NURTURE CKD COHORT STUDY
Authors: Lucas Bethany , Cockwell Paul , Fraser Simon , Kalra Philip A , Wheeler David C , Taal Maarten 
Published: June 2023

Abstract

Background and Aims
Blood pressure (BP) control is one of the most important therapeutic interventions in chronic kidney disease (CKD) and reduces cardiovascular morbidity, mortality and progression to end stage kidney disease. The optimal BP target for patients with CKD is debated, with several guidelines making different recommendations. This analysis of the UK multicentre NURTuRE CKD cohort study assessed achievement of BP targets and investigated associations with achieved BP.

Method
2996 participants with CKD stages G3-4 or G1-2 plus albuminuria &gt;30 mg/mmol were enrolled from 16 nephrology centres in the UK from 2017 to 2019. Medical history, demographic, biometric and laboratory samples were collected at baseline. BP was measured according to a standard operating procedure. Three measurements differing by &lt;10% were recorded and the mean value used for analysis. BP control was assessed against the following guidelines: National Institute for Health and Clinical Excellence (NICE), Kidney Disease Improving Global Outcomes (KDIGO) 2012 and 2021 guidelines.

Results
2992 participants had a baseline BP measurement and of these 59% were male, 53% were ≥65 years, 87% were of white ethnicity and 31% had diabetes. Median eGFR was 33.8 (24.0 to 46.6) ml/min/1.73m2. The mean systolic BP for the cohort was 139 ± 20 and diastolic 80 ± 12 mmHg. The characteristics of patients with a higher mean systolic BP included: ≥65 years, male sex, black ethnicity, diabetic, body mass index &gt;30 kg/m2, a history of atherosclerotic cardiovascular disease, lower eGFR values and higher albuminuria category. Conversely, mean systolic BP was not associated with index of multiple deprivation quintiles, health literacy by the single-literacy item screener and smoking status. Achievement of BP targets is shown in Table 1. Of 2723 with centrally calculated urine albumin creatinine ratio (ACR) and BP data available, only 1036 participants (38.0%) met the NICE guideline recommended BP. For the KDIGO 2012 guideline, 794 participants (29.2%) achieved recommended BP control. For KDIGO 2021, only 420 participants (15.4%) met the standard of systolic BP &lt;120mmHg. For those in the highest risk albuminuria category (A3) only 143 (18.6%) and 96 (12.5%) of participants met the KDIGO BP recommendations for 2012 and 2021, respectively.

Conclusion
BP control in the NUTuRE-CKD cohort at baseline was suboptimal when compared to all three major guidelines. Subgroups at highest risk of adverse outcomes demonstrated poorer BP control. Given the importance of BP control in people with CKD, further research into BP management approaches and barriers to achieving optimal control is required. Priority should be given to developing a patient-centred approach to reduce BP more effectively.
#4080 NOVEL EXTRACORPOREAL TREATMENT FOR SEVERE NEONATAL JAUNDICE: A MATHEMATICAL MODELING STUDY WITH ALLO-HEMODIALYSIS
Authors: Maheshwari Vaibhav , Ferris Maria , Filler Guido , Kotanko Peter 
Published: June 2023

Abstract

Background and Aims
Neonate hyperbilirubinemia usually resolves within 3–5 days without complications however, severe neonatal jaundice (SNJ) is associated with long-term neurocognitive impairment, cerebral palsy, auditory neuropathy, deafness, or death. Globally, at least 481,000 term/near-term neonates are affected by SNJ annually, with 114,000 neonates dying and an additional 63,000 neonates surviving with kernicterus [1,2]. Phototherapy and exchange transfusions prevent/treat SNJ, but these modalities are scarce in some low and lower-middle income countries, where SNJ prevalence is increased due to higher prevalence of glucose-6-phosphate dehydrogenase deficiency, blood group incompatibilities, late referrals, and delayed diagnosis. We aimed to explore a model for allo-hemodialysis (alloHD), a novel potential modality to treat SNJ rapidly and effectively in neonates, possibly avoiding exchange transfusions.

Method
With alloHD, the neonate's blood flows through hollow fibers of a 0.075 m2 miniature low flux hemodialyzer (pore size 1.2 to 2.2 nm), while the blood of a healthy adult (“buddy”) flows counter-currently through the dialyzer, thus serving as the “dialysate”. Our mathematical model simulates the bilirubin kinetics in alloHD, with neonate and buddy blood flow rates at 15 and 30 mL/min, respectively. In the neonate model, bilirubin conjugation was assumed to be zero, resulting in excess unconjugated bilirubin that binds to albumin and causes SNJ. Bilirubin production rate in neonate and buddy were set to 6 and 3 mg/kg/day, respectively [3]. Buddy bilirubin conjugation rate was calculated to obtain normal steady state bilirubin levels. We only simulated unconjugated bilirubin because the conjugated form is easily excreted. Simulations are performed with neonate and buddy albumin levels of 31 g/L and 43 g/L, respectively.

Results
Model simulations suggest that 3- to 6-hour alloHD session can reduce neonatal bilirubin levels by &gt;30% (Fig. 1, left panel). Due to the high bilirubin conjugation capacity of an adult's healthy liver, the buddy's bilirubin level increases only transiently during the alloHD session (Fig. 1, right panel).

Conclusion
Our modeling suggests that a single alloHD session can lower neonatal bilirubin levels effectively. In principle, this bilirubin reduction should lower the risks associated with SNJ, especially kernicterus and possibly avoiding exchange transfusions. Future modeling scenarios will incorporate the improved neonatal liver function over time and additional alloHD schedules.
#4477 IDENTIFICATION OF DIFFERENTIALLY EXPRESSED GENES AND PATHWAYS IN NON-DIABETIC CKD AND DIABETIC CKD BY INTEGRATED BIOINFORMATICS ANALYSIS
Authors: Barrios Clara , Julia Jan , Gomez Jessica , Marquez Eva , Ribas Andres , Sans Laia , GarcÍa Eva RodrÍguez , Crespo Marta , Riera Marta 
Published: June 2023

Abstract

Background and Aims
Chronic kidney disease (CKD) is a complex genetic-based disease with multiple unclarified molecular pathways involved. Dapagliflozin have shown a clear improvement in the progress of renal function and CV risk in both diabetic and non-diabetic populations. However, we do not really know the molecular pathways that this drug modulates. To overcome this global objective we have first seek similarities and differences in genes and molecular pathways implicated in Non-diabetic (Non-DM) CKD (considering Autoimmune-CKD and Hypertension-CKD) and type2 diabetic nephropathy (DN).

Method
Expression datasets were compiled from databases (ArrayExpress and Gene Expression Omnibus). Differential expression analysis (DEA) and Gene Set Enrichment Analysis (GSEA) were carried out; each cohort was compared with controls, and between them as direct comparison (Non-DM CKD vs. DN).

Results
Non-DM CKD and DN share many similarities when compared to controls. However, some quantitative differences come up in terms of genes and pathways (see Figure 1 for examples). (1) Hypertension-CKD is clearly closer to DN than Autoimmune-CKD in both glomeruli and tubulointerstitium both in gene and pathway analysis. (2) Extracellular matrix remodelling and immune system activation (innate and adaptive) are processes involved in Non-DM CKD and DN but show a higher activation in DN. (3) Metabolic modulations, regarding metabolic acidosis, reprograming and dyslipidaemia, are more present in DN tubulointerstitium than Non-DM CKD subcohorts, tubulointerstitium specifically. (4) Genes related to complement activation are found overexpressed in DN glomeruli compared to CKD/subcohorts, which then translate to a complement system activation rise in the GSEA analysis.

Conclusion
We raise a series of core genes that may be potential targets for the study of Dapagliflozin mechanism of action.
#5420 A MODULAR INTRACELLULAR HIERARCHICAL-RESPONSIVE NANOCARRIER ENABLES DUAL TARGETING FOR HIGH THERAPEUTIC EFFICACY IN KIDNEY DISEASE
Authors: Zeng Tao , Li Aiqing 
Published: June 2023

Abstract

Background and Aims
Single-loaded nanocarrier that can improve targeting capability and drug toxicity compared with free drugs demonstrates a promising strategy for disease treatment. Due to the heterogeneity of the injured cells during the disease progression, dose-induced drug resistance, and instability of nanocarriers in the blood circulation, it is challenging to achieve dual targeting to different injured cell subsets as well as reducing drug dosage but obtaining efficient treatment. In addition, developing nanocarriers is a complex and time-consuming process; there is a desire to develop a universal nanocarrier for various diseases, especially complex ones. Here, we have successfully designed a modular nanocarrier capable of co-delivery drugs. Meanwhile, the effective dosage was reduced to one-tenth of single-loaded nanocarriers.

Method
The dual-loaded drug-targeting nanoparticles consist of four main modules, including a chemical material, an antibody, and two drugs. First, we constructed a mesoscale spherical nanoparticle with a particle size of 400 nm from PLGA and wrapped drug A inside it. Next, the foot cell-specific antibody Nephrin is used as the target material and modified on the nanoparticle surface by the ph-sensitive short peptide. Finally, drug B is coupled to the antibody to obtain the final dual-targeting dual-drug nanoparticles. The dual-targeting dual-drug nanoparticles were injected into mice via the tail vein to evaluate their toxicity to organs and the immune system and compared with free drug. We explored the targeting and mechanisms of dual-targeting nanoparticles by organ imaging, Immunofluorescence, and other experimental methods. In mice, we established the model of acute kidney injury, puromycin aminonucleoside nephropathy (PAN), and ccRCC to compare the protective effects and mechanisms of dual targeting nanoparticles in different concentrations.

Results
Dual targeting nanoparticles loaded with different drugs demonstrated the ability of dual targeting of glomeruli and tubules. In treating acute kidney injury, the nanocarriers were encapsulated with rapamycin and dexamethasone acetate; for puromycin nephropathy, the drugs were changed to rapamycin and captopril; and in the treatment of kidney cancer models, gefitinib and glutathione were chosen as targeted antitumor drugs. For different diseases, the lesions were treated significantly with different drug combinations. We observed a reduction of tubular injury in the acute kidney injury model, a recovery of the foot process of podocytes in the puromycin nephropathy model, and a reduction of cancer foci in the renal cancer model. These results show that dual drug-loaded nanomaterials have an excellent ability to cope with complex situations.

Conclusion
Dual drug delivery system can flexibly adapt the treatment of various diseases by changing particle size, surface antibodies, and drugs.
#5434 EFFICACY OF SACUBITRIL/VALSARTAN IN MAINTENANCE HEMODIALYSIS PATIENTS WITH HEART FAILURE WITH PRESERVED EJECTION FRACTION
Authors: Fu Sha , Wang Xiaohong , Song Qirong , Chen Junzhe , Tang Ying 
Published: June 2023

Abstract

Background and Aims
Growing evidences have confirmed the effect of Sacubitril/Valsartan (SV) on hypertension and heart failure espacially EFrHF in general population. However, data on ARNI treatment in maintenance hemodialysis (MHD) patients with EfpHF are lacking. The present study was conducted to assess the efficacy and safety of sacubitril-valsartan in patients with HFpEF undergoing MHD.

Method
End-stage kidney disease (ESKD) patients undergoing MHD for more than 3 months with New York Heart Association (NYHA) class II–IV heart failure ejection fraction of 50% or higher, and elevated levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP) were assigned to receive sacubitril-valsartan. Patients were followed up regularly after medication treatment. The alterations in clinical and biochemical parameters before and after taking sacubitril-valsartan (generally 50–200mg b.i.d) were investigated, and safety was also assessed.

Results
120 patients were recruited in this study. Compared with baseline levels, NT-proBNP levels [7540.5 (3575.7–18373.0) vs. 4649.0 (2259.0–8187.0), P&lt;0.001], systolic blood pressure[(157.8 ± 20.5) vs.(141.5 ± 16.8), P&lt;0.001], diastolic blood pressure [(85.2 ± 14.9) vs.(78.5 ± 10.2), P&lt;0.001], heart rate[(78.1 ± 9.0) vs.(74.5 ± 6.9), P&lt;0.001], total cholesterol [4.7 ± 1.1 vs. 3.9 ± 1.3, P = 0.01] and Low Density Lipoprotein [2.4 ± 0.9 vs. 2.2 ± 1.1,
P = 0.04] were markedly decreased after treatment with sacubitril-valsartan. The results of KCCQ scores[53.4 ± 16.1vs. 61.4 ± 15.7, P&lt;0.001] and NYHA classification [P = 0.01] showed obviously improvement after a median follow-up of 13 months. None of the patients showed adverse drug reactions.

Conclusion
Sacubitril/valsartan treatment improves significantly quality of life, symptoms of heart failure, NT-ProBNP and NYHA functional class in patients with HFpEF undergoing hemodialysis. Sacubitril/valsartan was safe and well tolerated.