bluuebunny/crossref_metadata_2025 huggingface dataset:
#5393 INFLUENCE OF CELLULAR INFLAMMATION ON THE OUTCOME OF KIDNEY TRANSPLANTATION AFTER RECURRENCE OF IGA NEPHROPATHY
Authors: Vázquez Teresa , Rodrigo Emilio , Porras Luis Fernando Quintana , Fructuoso Ana Sanchez , Gomez-Ortega Jose María , Buxeda Anna , Gavela Eva , Castello Maria Isabel Beneyto , Oliva Maria Ovidia Lopez , Hernández Domingo
Published: June 2023

Background and Aims

The recurrence of IgA nephropathy (rIgAN) worsens the prognosis of renal transplantation, representing the third cause of loss in these recipients. Several variables at the time of recurrence, such as worse renal function, greater proteinuria, previous steroid withdrawal, and MEST-C histological findings have been associated with a higher risk of graft loss after recurrence. The presence of clinical or subclinical inflammation has been associated with a higher risk of kidney graft loss, but it is not precisely known how it influences the outcome of patients with rIgAN.

Method

A multicenter retrospective study was carried out including renal transplant recipients with biopsy-proven IgA nephropathy as the underlying disease in which the recurrence of the primary disease had been verified by means of graft biopsy and in which the Banff criteria were available or could be reviewed. Cellular inflammation was defined according to Banff scores as “t” or “i” ≥2. The main endpoint was progression to CKD stage 5 or death censored-graft loss (DCGL).

Results

118 kidney transplant recipients were included with an age of 47 ± 14 years at recurrence, 80% male, with a mean time to biopsy of 65 ± 69 months and a post-transplant follow-up of 118 ± 70 months. After recurrence, 34 (28.8%) transplants were lost after 35 ± 28 months, excluding death. Using univariate Cox regression, the factors related to CKD stage 5 or graft loss were systolic blood pressure (HR 1.039, 95%CI 1.016-1.064, p = 0.001), glomerular filtration rate (HR 0.948, 95%CI 0.922-0.974, p <0.001), the logarithm of proteinuria (HR 15.836, 95% CI 5.504-45.565, p < 0.001), Oxford-C score (HR 3.490, 95% CI 2.137-5.699, p <0.001), interstitial fibrosis (HR 2.173, 95% CI 1.362-3.468, p = 0.001) and cellular inflammation (HR 2.458, 95% CI 1.237-4.884, p = 0.010). After multivariate analysis, cellular inflammation remained significantly related to CKD stage 5 or DCGL (HR 2.338, 95% CI 1.077-5.075, p = 0.032). independently of systolic blood pressure, glomerular filtration rate, the logarithm of proteinuria and Oxford-C score.

Conclusion

In addition to the previously described factors usually related to worse evolution of IgA nephropathy in the native kidney and after post-transplant recurrence, we observed that cellular inflammation influences worse evolution after rIgAN. We suggest to considering the Banff criteria for acute cellular inflammation to better understand the subsequent evolution of patients with rIgAN.
#5504 EXTENDED VALIDATION OF THE IBOX IN REAL LIFE SETTING, DIFFERENT TRANSPLANT SYSTEMS AND CLINICAL TRIALS: THE IBOX EXTENDED TRIAL
Authors: Naser Sofia , Divard Gillian , Raynaud Marc , Naesens Maarten , Segev Dorry , Stegall Mark , Lefaucheur Carmen , Aubert Olivier , Loupy Alexandre
Published: June 2023

Background and Aims

The iBox is a validated prognostication system predicting long-term kidney allograft failure. Recently, it received regulatory endorsement by EMA, for surrogate endpoint for clinical trials. As the iBox system was primarily built using a deep phenotyped cohort, there is a need for proof of validity in extended clinical scenarios, geographic distinct medico-economic cohorts and transplant allocation systems.

Method

10,851 transplant recipients were included from 17 academic medical centers from France, Belgium, Spain, Germany, Finland, United States, Brazil and Argentina. We applied to these cohorts the iBox algorithm that integrates eight independent prognostic factors including the time from transplantation to risk evaluation, functional parameters (eGFR, proteinuria), allograft histological lesions (IFTA, g+ptc, i+t, cg Banff scores), and circulating anti-HLA DSA. We stratified the performances of the iBox according to several real-life scenarios, including: 1) iBox + different eGFR formulas (MDRD186, MDRD175, CKD-Epi); 2) iBox + urinary dipstick; 3) iBox Functional + Structural (absence of DSA measurements); 4) iBox functional + Immunological (absence of histology); 5) iBox in response to treatment in T-cell mediated rejection (TCMR); 6) iBox for in response to treatment antibody mediated rejection (ABMR) clinical trials. The performances of the iBox system were assessed with the discrimination (C-index) and calibration.

Results

The derivation cohort included 4,000 recipients from France, and the international external validation cohort included 6,851 recipients from Europe (France, Belgium, Spain, Germany, Finland n = 4,643), the United States (n = 1,537) and South America (Brazil, Argentina n = 671). The mean recipient age was 50.26 years (14.05) with a median follow-up after evaluations of 5.41 years [IQR: 3.26 to 7]. 1336 patients (12.31%) lost their graft during the study follow-up. The performances of the iBox were confirmed in the different real-life setting with the following C-Index: 1) iBox + different eGFR formulas (MDRD186, MDRD175, CKD-Epi) 0.81; 2) iBox + urinary dipstick 0.80; 3) iBox Functional + Structural (histology) 0.80 (derivation) and 0.84 (validation); 4) iBox functional + Immunological 0.80 (derivation) and 0.83 (validation); 5) iBox in response to treatment in T-cell mediated rejection 0.81; 6) iBox for in response to treatment antibody mediated rejection trials 0.81. The score showed an accurate calibration in every scenario.

Conclusion

The iBoxEXTENDED trial confirms in various medico-economic settings the performances transportability and surrogacy of the iBox system, further reinforcing its use as a surrogate end point for clinical trials including TCMR and ABMR.
#5699 IS GFR DECLINE INDUCED BY SGLT-2 INHIBITOR OF CLINICAL IMPORTANCE?
Authors: Guenes-Altan Merve , Bosch Agnes , Striepe Kristina , Schiffer Mario , Bramlage Peter , Schmieder Roland E , Kannenkeril Dennis
Published: June 2023

Background and Aims

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are associated with better cardiovascular outcome and with nephroprotection independent of diabetes status. However, the use of SGLT2i often cause an initial decline in estimated glomerular filtration rate (eGFR). This study addresses the question whether there is a relationship between vascular improvement and GFR dipping.

Method

We measured GFR (mGFR) and calculated GFR (eGFR) in 65 patients with T2D at baseline and after 12 weeks of treatment with either a combination of Empagliflozin (E) + Linagliptin (L) (n = 34) or Metformin (M) + Insulin (I) (n = 31). mGFR was measured using the gold standard clearance technique by infusion of inulin. In addition, pulse wave velocity (PWV) was obtained at office and under ambulatory conditions. We splitted the study cohort according to the median change of mGFR after 12 weeks and compared the baseline characteristics.

Results

mGFR and eGFR decreased significantly with E+L and with M+I (Ott C et. al. Cardiovasc Diabetol. 2021). However, no correlation was noticed between the change of mGFR and change of eGFR for either treatment cohorts (E+L: p = 0.404; M+I: p = 0.460). We found a significant decrease in office PWV in the E+L group only (8.2±1.6 to 7.8±1.5, p = 0.028) without any change in 24-h PWV. The change of office PWV correlated with the change of mGFR (p = 0.009) in E+L group only and remained significant after adjustment for the change of office systolic BP (p = 0.018). In addition, we observed a correlation between the change of high sensitive C reactive protein (hsCRP) and change in mGFR (p = 0.031).

We identified patients with higher albumin excretion (p = 0.044), higher fasting plasma glucose (p = 0.014) and high hsCRP (p = 0.057) to have a greater decline in mGFR with E+L.

Conclusion

First, eGFR may not be an appropriate parameter to assess the true change in renal function after receiving E+L in a single patient. Second, after E+L medication a high decrease in mGFR goes in parallel with vascular improvement and less inflammation thereby reflecting the pleiotropic pharmacologic effects of SGLT 2 inhibitors.
#5721 HEPATITIS B VIRUS REACTIVATION IN KIDNEY TRANSPLANT RECIPIENTS TREATED WITH BELATACEPT
Authors: Schwarz Chloe , Morel Antoine , Matignon Marie , Grimbert Philippe , Rondeau Eric , Ouali Nacera , Francois Helene , Mesnard Laurent , Petit-Hoang Camille , Rafat Cédric , Dahan Karine , Luque Yosu
Published: June 2023

Background and Aims

Hepatitis B virus (HBV) reactivation in kidney transplant recipients may be associated with liver failure and graft loss, especially in anti-HBc antibody (HBcAb)-positive HBs antigen (HBsAg)-negative patients. Belatacept, a selective costimulation blocker, has been used in kidney transplantation for some time and has been associated with reactivation of other viruses as BK or CMV. However, there are few data on HBV reactivation among kidney recipients treated with belatacept.

Method

We performed a retrospective study in two French kidney transplantation centres including all transplant recipients receiving belatacept. Among HBcAb-positive patients, we analyzed HBV reactivation rate, outcomes and risks factors.

Results

135 patients treated with belatacept were included, and 32 were HBcAb-positive. Seven patients reactivated HBV (21.9% of HBcAb-positive patients), including 5 HBsAg-negative patients (16.7%); reactivation occurred 54.8 (± 70.9) months after transplantation. There was no significant difference in survival between patients that reactivated HBV and patients that did not: 5-year patient survival of 100% (28.6; 100) and 83.4% (67.6; 100), respectively (p = 0.363) and 5-year graft survival of 100% (28.6; 100) and 79.8% (61.7; 100), respectively (p = 0.335). No factor, including HBsAb positivity and antiviral prophylaxis, was statistically associated with the risk of HBV reactivation.

Conclusion

Compared to the few studies that exist in this area, the HBV reactivation rate was high in patients treated with belatacept in our study. Our findings suggest that systematic antiviral prophylaxis for anti-HBc antibody (HBcAb)-positive HBs antigen (HBsAg)-negative patients should be considered and that there should be close monitoring of HBV serology and viral load in these patients to detect early HBV reactivation.
#5797 AMINOPEPTIDASE A REGULATES ACUTE ANGIOTENSIN DEPENDENT HYPERTENSION
Authors: Forster Peter , Abedini Yasemin , Müller Tilman , Ye Minghao , Wysocki Jan , Batlle Daniel
Published: June 2023

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<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

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<0.001) and multivariate analysis corrected by age, gender, and comorbidities (OR 4,5, IC 4,2-4,9, p<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<0.001; multivariate: OR 4.6, IC 4.2-4.9, p<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

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 (<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

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

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 >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 <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 >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 <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

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 >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

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

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

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<0.001], systolic blood pressure[(157.8 ± 20.5) vs.(141.5 ± 16.8), P<0.001], diastolic blood pressure [(85.2 ± 14.9) vs.(78.5 ± 10.2), P<0.001], heart rate[(78.1 ± 9.0) vs.(74.5 ± 6.9), P<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<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.
#5446 A COHORT OF DIALYSIS PATIENTS WITH LOW PREVALENCE OF UPPER ARM FISTULAS
Authors: Cuna Simona , Fonto Giulia , Lefons Luisa , Ria Paolo , Protopapa Paolo , Napoli Marcello , Barbarini Silvia
Published: June 2023

Background and Aims

International guidelines encourage the use of distal native fistula (AVF) which is the best first-line vascular access (VA). But, despite these indications, all over the world, except for Japan, the prevalence of upper arm fistula (UAF) is dramatically increasing. Previous surveys in our department included about 50% of Haemodialysis patients (HP) and showed prevalence of UAFs less then 5%–very low, if compared with those of our country, reported by DOPPS 5 study. We decided to analyse 100% of HP in our department, in order to confirm or exclude the low prevalence of UAF.

Method

Puglia, southern east of Italy, has 1.4 millions inhabitants, of which 1365 need dialysis; 1295 on haemodialysis in 17 different centers and 70 on peritoneal dialysis. The department is organized on a Hub and Spoke model for VA management (Fig. 1). Hub performs simple and complex AVFs, Graft, PTA of non matured or stenotic fistulas, PTA of central stenosis, and surgical rescue of thrombosed or stenotic fistulas. Our four spokes perform mainly simple distal forearm fistula (DFF). In December 2021 we collected datas of VA prevalence of all 1295 HP. The AVFs were classified, according to their anatomical site, in DFF, mean-proximal forearm fistula (MPFF) and UAF.

Results

The average age of 1295 HP was 69 ± 14,65% yo (65% males and 21% diabetics) and 458 of them (35%) where more than 75 yo. The prevalence of DFF, MPFF, UAF, GRAFT and CVC was 63.5%, 10.1%, 3%, 0.7%, 22.5% respectively (fig. 2). Patients aged ≥75 years, women and diabetics showed a higher prevalence of CVC and a lower prevalence of DFF.

Conclusion

Data collected on all patients confirm the low prevalence of UAF detected in the previous surveys -which involved only a part of haemodialysis patients. Zero upper arm fistulas is an utopian goal, but it seems possible to reduce the prevalence of proximal fistulas to 5% or less as the Japanese experience has showed.
#5524 THE ROLE OF C5AR VERSUS C3 IN THROMBOTIC MICROANGIOPATHY, ISCHEMIC KIDNEY NECROSIS, AND ACUTE KIDNEY INJURY INDUCED BY CHOLESTEROL CRYSTAL EMBOLISM
Authors: Zhao Danyang , Mammadova-Bach Elmina , Anders Hans-Joachim
Published: June 2023

Background and Aims

Certain thrombotic microangiopathies (TMA) respond to inhibition of complement factor C5, which abrogates formation of the membrane attack complex and hence impairs host defense. Inhibition of C5a receptor (C5aR) avoids this safety problem and still controls autoimmune systemic vasculitis. We speculated that targeting C5aR could be sufficient also in TMA, e.g., related to cholesterol crystal embolism (CCE).

Method

We induced experimental TMA in C3-/-, C5aR-/- or wildtype mice by injecting CC into the left kidney artery of mice and analyzed thrombotic angiopathy, drop in measured glomerular filtration rate (GFR), and ischemic necrosis 24 hours after CCE.

Results

In wildtype mice, CC injection caused diffuse TMA followed by a consistent drop of GFR compared to baseline and ischemic kidney necrosis. Genetic deficiency in C3 convertase profoundly attenuated TMA and hence GFR drop and ischemic kidney necrosis indicating a key role of the complement system in CCE-related TMA. Genetic deficiency of C5aR attenuated TMA, GFR drop and ischemic necrosis to the same extent indicating that C5aR provides the main contribution of the complement system to the pathogenesis of TMA.

Conclusion

We conclude that targeting the C5a/C5aR axis could be sufficient to attenuate also TMA for which a better safety profile would be expected as compared to C5 inhibition.
#5661 EARLY COMPENSATORY INCREASE IN SINGLE-KIDNEY EGFR AFTER UNILATERAL NEPHRECTOMY IS ASSOCIATED WITH A LOWER LONG-TERM RISK OF EGFR DECLINE
Authors: Van Der Weijden Jessica , Mazhar Faizan , Fu Edouard , Van Londen Marco , Evans Marie , Berger Stefan P , de Borst Martin , Carrero Juan Jesus
Published: June 2023

Background and Aims

The healthy kidney has reserve capacity, allowing for an increase in single-kidney GFR (ΔskGFR) in the remaining kidney after nephrectomy. We evaluated whether higher ΔskGFR, as a reflection of renal resilience, is associated with a lower long-term risk of eGFR decline in individuals undergoing unilateral nephrectomy.

Method

We included 1777 participants from the observational SCREAM project who underwent radical unilateral nephrectomy in Stockholm during 2006–2021. We calculated the ΔskGFR using the eGFR (CKD-EPI 2009) at 3 months post-nephrectomy eGFR minus 50% of the pre-nephrectomy eGFR and evaluated its pre-nephrectomy determinants (age, sex, eGFR, comorbidities) with multivariable linear regression. Follow-up started at 3-months post-nephrectomy, and Cox regression was used to explore the association between Δsk-GFR and the subsequent risk of CKD progression (defined as composite of a decline >30% relative to three months post-nephrectomy eGFR or initiation of kidney replacement therapy), adjusting for age, sex and pre-nephrectomy eGFR.

Results

Mean (SD) age was 68 ± 11 years, 40% of patients were female, 92% had a kidney cancer diagnosis and mean (SD) pre-nephrectomy eGFR was 75 ± 19 mL/min/1.73m2. Median (IQR) Δsk-GFR was 11 (7–20) mL/min/1.73m2. Pre-nephrectomy determinants of Δsk-GFR were age (St.Β = −0.20, P≪0.001) and pre-nephrectomy eGFR (St.Β = 0.14, P<0.001). During a median follow-up of 4 years (maximum 15 years), 178 participants developed CKD progression. The group with a Δsk-GFR above the median value (11 mL/min/1.73m2) had a 42% lower risk of CKD progression (adjusted HR: 0.58, 95% CI: 0.42 – 0.80), compared to those with a lower Δsk-GFR (Figure).

Conclusion

A larger compensatory increase in single-kidney eGFR early after unilateral nephrectomy, suggesting better renal resilience, was associated with a lower risk of CKD progression during long-term follow-up. Evaluation of Δsk-GFR could help identify patients at higher risk of progressive kidney function decline.
#6300 CHANGES IN ECHOCARDIOGRAPHIC INDICES FOLLOWING KIDNEY TRANSPLANTATION: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Betsikos Achilleas , Theodorakopoulou Marieta , Korogiannou Maria , Marinaki Smaragdi , Papagianni Aikaterini , Boletis John , Tsioufis Costas , Sarafidis Pantelis
Published: June 2023

Background and Aims

Cardiovascular disease is the leading cause of death in ESKD and uremic cardiomyopathy contributes significantly to the increased cardiovascular risk in these patients. Kidney transplantation is associated with improved survival compared to dialysis. This systematic review and meta-analysis (CRD42022371202) aims to assess the changes in echocardiographic indices in patients before and following kidney transplantation

Method

We included studies in adult subjects with echocardiographic assessments before (baseline) and following kidney transplantation (>1 month follow-up). The primary outcome measure was left-ventricular mass index (LVMI). Literature search involved PubMed, Web-of-Science and Scopus databases, manual search of article references and grey literature.

Results

From 6463 records initially retrieved, 35 studies with a total of 2692 participants were included in the final quantitative meta-analysis. From 30 studies (2211 patients) reporting the primary outcome, LVMI was significantly decreased after kidney transplantation compared to pre-transplantation values [WMD -21.16 g/m2, 95%CI(-27.21, -15.12), I2 = 88%, P<0.001]. In subgroup analysis, higher differences were evident among 6 studies (N = 163) evaluating LVMI<6 months after kidney transplantation [WMD -41.54 g/m2, 95%CI (-51.31, -31.78), I2 = 13%, P<0.001] and lower differences among 24 studies (N = 2048) evaluating LVMI >6 months after kidney transplantation [WMD -16.64 g/m2, 95%CI(-22.79, -10.49), I2 = 88%, P<0.001]. In sensitivity analyses, patients receiving kidney from living kidney donors (WMD; -76.90 g/m2, 95%CI (-122.13, -31.67), I2 = 88%, P<0.001) and those on hemodialysis before KTx [WMD;-33.76 g/m2, 95%CI (-51.51, -16.00), I2 = 92% P<0.001] presented higher LVMI reductions following transplantation.

Conclusion

Kidney transplantation is associated with significant reductions in LVMI compared to the pre-transplantation levels. This could be another factor contributing to the lower cardiovascular risk observed in KTRs compared to dialysis patients.
#6485 UNI-494 LOWERS URINARY B2-MICROGLOBULIN LEVELS IN RATS
Authors: Reddy Guru , Gupta Pramod , Khare Atul , Gupta Shalabh
Published: June 2023

Background and Aims

Mitochondrial dysfunction in renal cells play a critical role in the pathophysiology of acute kidney injury (AKI) and chronic kidney disease (CKD). The proximal tubule is the primary sensor and effector in CKD progression and AKI. The measurement of urine Β2-microglobulin (Β2M) is a sensitive assay for proximal tubule injury. Nicorandil, a selective mitochondrial ATP-sensitive potassium channel activator, may be a promising AKI treatment, but its clinical use is limited by serious gastrointestinal side effects and rapid absorption and elimination. UNI-494, a novel nicorandil prodrug designed to improve its pharmacologic properties, may increase the short half-life and improve the safety profile of nicorandil. This study presents the efficacy data on the effects of UNI-494 in a rat ischemia-reperfusion (I/R) model, evaluating biomarkers of renal injury.

Method

49 male Sprague-Dawley rats were randomly assigned to 4 groups to evaluate the in vivo efficacy of UNI-494 in a bilateral renal (I/R) model. Group 1, the Sham group, consisted of 10 subjects while groups 2–4 each had 13. Group 1 received no treatment, Group 2 a vehicle, Group 3 10mg/kg of UNI-494, and Group 4 20mg/kg of UNI-494. Treatments were administered as a single dose on Day 0, 1 hour prior to modeling. Body weights were measured on Days -1, 0, and 1. Urine Β2M levels and urinary albumin-to-creatinine ratio (UACR) samples were collected within 24 hours after the surgery using the metabolic cages. Serum blood urea nitrogen (BUN) and creatinine samples were collected on Day -1 (pre-modeling) and 24 hours after modeling. T-tests were used to evaluate statistical differences between groups.

Results

Β2M levels were significantly lower for the 20 mg/kg UNI-494 dose group compared to the vehicle group, and Β2M content in both UNI-494 dose groups (10 and 20 mg/kg) was significantly lower compared to the vehicle group (Fig. 1). Β2M levels and content were lower for the 20 mg/kg UNI-494 dose group than for the 10 mg/kg dose group (Fig. 1). There was no difference in body weight changes between the UNI-494 dose groups and the vehicle group. There were no statistically significant differences among all groups for serum creatinine and BUN pre-modeling and in UACR.

Conclusion

Lower levels of urine Β2M levels in the higher UNI-494 dose group compared to the other groups indicate that UNI-494 may have a renoprotective effect. Additionally, the lower levels of Β2M in the higher dose group compared to the lower dose group indicate a dose-response trend. Our study results are consistent with previously published data with nicorandil in a similar rat model of I/R. This potential renoprotective effect should be further investigated.
#2513 EFFECT OF HEMODIALYSIS WITH MEDIUM CUT-OFF VERSUS HIGH-FLUX MEMBRANES ON ENDOTHELIAL FUNCTION OF CHRONIC KIDNEY DISEASE PATIENTS
Authors: Armani Rachel , Carvalho Aluizio , Vercia Monique , Bortolotto Luiz Aparecido , Canziani Maria Eugênia
Published: June 2023

Background and Aims

Endothelial dysfunction (ED) is considered a marker of vascular complications, especially in patients with chronic kidney disease (CKD). Inflammation and the uremic state contribute to ED in hemodialysis (HD) patients. Recently, the medium cut-off (MCO) HD membrane has been proposed to efficiently remove inflammatory cytokines and higher molecular weight uremic toxins. This study aimed to compare the effect of dialysis with medium cut-off (MCO) or high-flow (HF) membranes on the endothelial function of patients on chronic HD.

Method

A prospective, randomized, crossover study in which 32 patients with CKD were dialyzed for 12 weeks with each membrane, including a 4-week washout period between treatments. Endothelial function was assessed by flow-mediated dilation (FMD) using brachial artery ultrasound at weeks 1, 12, 16, and 28.

Results

The population consisted of 59% men, 52.7±13.4 years, 16% non-black, on HD for 8.8(4.1-15.1) years, 72% with arteriovenous fistula). Hypertension was the most common etiology of CKD and 34% of patients had previous cardiovascular disease. Table 1 shows clinical and demographic characteristics of all subjects. The Patients were grouped, regardless of treatment sequence, into MCO or high flow groups, since no drag (p = 0.634) or sequence (p = 0.998) effects were observed in the FMD assessment. The ANOVA model with repeated measures showed no effects of treatment (p = 0.426), time (p = 0.972) or interaction (p = 0.413) in the comparison of FMD, between the MCO and high flow groups.

Conclusion

Dialysis performed with MCO, or HF membranes did not influence endothelial function in patients undergoing chronic HD.