bluuebunny/crossref_metadata_2025_split huggingface dataset:
#5359 DETECTING NEONATAL AKI BY SERUM CYSTATIN-C
Authors: Xin Xu , Nie Sheng , Hou Fan Fan 
Published: June 2023

Abstract

Background and Aims
Serum creatinine is not a sensitive biomarker for acute kidney injury (AKI) in neonates. Unlike creatinine, cystatin-C (Cys-C) does not cross the blood placental barrier and the serum level in the neonates is not significantly impacted by the gestation age, birthweight, and the age during the first four weeks after birth. Therefore, serum Cys-C may be a better marker neonatal AKI than serum creatinine. We aimed to assess the performance of serum Cys-C as an alternative biomarker for detecting neonatal AKI.

Method
This is a large multicenter cohort study including 52,333 hospitalized neonates. First, we assess the impacts of gestational age, birthweight, and days after birth on the level of Cys-C, and estimated the upper normal limit (UNL) and the reference change value RCV of serum Cys-C in neonates. Then, we proposed a Cys-C based criteria (CyNA) for detecting neonatal AKI based on both Cys-C level and the change in Cys-C using UNL and RCV as the cutoffs, respectively. Finally, we assessed the performance of CyNA in detecting neonatal AKI and the association of CyNA-detected AKI with the risk of in-hospital death, and compared the performance with that using the KDIGO creatinine criteria.

Results
Cys-C level in neonates did not vary with gestational age and birthweight, and remained relatively stable during the neonatal period (Figure 1). The UNL of Cys-C was 2.2 mg/L and the RCV (for Cys-C ratio) was 1.25. CyNA criteria defines AKI by a serum Cys-C of ≥2.2 mg/L (UNL) or an increase in Cys-C of ≥25% (RCV) during the neonatal period. Among 52,333 neonates 6,336 (12.1%) AKI cases were detected by CyNA criteria, of whom 96 (1.5%) died. In comparison, 202 (0.44%) death events occurred in 45,997 neonates who did not have AKI. After adjusting all comorbidities, CYNA-detected AKI was associated with a significantly increased risk of in-hospital mortality (adjusted HR 2.91, 95% confidence interval, 2.24 to 3.78). Among 45,839 neonates that had measurement of both Cys-C and SCr, 4,513 (9.8%) had AKI detected by CyNA only, 373 (0.8%) by KDIGO only, and 381 (0.8%) by both criteria (Table 1). After adjusting admission to ICU and comorbidities, AKI detected by CyNA only (C+/K-) was associated with a significantly increased risk of in-hospital mortality compared with those without AKI by both criteria (C-/K-), with an adjusted hazard ratio of 2.86 (95% CI, 2.02 to 4.04). In comparison, the HR for those detected by KDIGO only (C-/K+) was lower at 2.15 (95% CI, 0.96 to 4.81). Neonates with AKI detected by both criteria (C+/K+) had the highest risk of in-hospital mortality (HR 4.86, 95% confidence interval, 2.84 to 8.29).

Conclusion
Serum Cys-C is a robust and sensitive biomarker for detecting neonatal AKI. CyNA is 5.5 times more sensitive than the modified KDIGO in detecting neonates who are at an elevated risk of in-hospital mortality.
#5363 LONG-TERM CLINICAL OUTCOMES OF PATIENTS WITH LUPUS NEPHRITIS TREATED WITH AN INTENSIFIED B-CELL DEPLETION PROTOCOL WITHOUT MAINTENANCE THERAPY
Authors: Ceruti Cecilia , Amore Giorgio , Caruso Nunziante , Guarino Annalisa , Longo Roberta , Fenoglio Roberta , Sciascia Savino , Roccatello Dario 
Published: June 2023

Abstract

Background and Aims
The aim of this prospective study is to investigate the long term safety and efficacy of intesified B-cell depletion therapy (IBCDT) in patients with active lupus nephritis (LN), in comparison to a conventional immunosuppresant therapy, followed by a 3 year maintenence micophenolate mofetil (MMF) regimen.

Method
Thirty patients were administered an IBCDT (4 weekly rituximab [RTX] 375 mg/m2 and 2 more doses after 1 and 2 months; 2 infusions of 10 mg/kg cyclophosphamide [CYC], 3 methylprednisolone pulses), followed by oral prednisone (tapered to 5 mg/d by the third month). No immunosuppressive maintenance therapy was given. Thirty patients matched for LN class and age were selected as controls: 20 received 3 methylprednisolone pulses days followed by oral prednisone and mycophenolate mofetil (MMF) 2 to 3 g/d, whereas 10 were given the Euro Lupus CYC. MMF (1-2 g/daily) or azathioprine (AZA, 1-2 mg/kg/day) were given for &gt; 3 years as a maintenance therapy.

Results
At 12 months, complete renal remission was observed in 93% of patients on IBCDT, in 62.7% on MMF, and in 75% on CYC (P = 0.03); the dose of oral prednisone was lower in the IBCDT group (mean ± SD 2.9 ± 5.0 mg/dl) than MMF (10.5 ± 8.0 mg/d, P &lt; 0.01) or CYC group (7.5 ± 9.0 mg/d, P &lt; 0.01). Mean follow-up after treatment was 44.5 months (interquartile range [IQR] 36-120 months), 48.6 months (IQR 36-120 months), and 45.3 (IQR 36-120 months) for IBCDT, MMF, and CYC, respectively. At their last follow-up visit, we observed no significant differences in proteinuria and serum creatinine, nor in the frequency of new flares among the 3 groups.

Conclusion
In biopsy-proven LN, the IBCDT without further immunosuppressive maintenance therapy was shown to be as effective as conventional regimen of MMF or CYC followed by &gt;3-year maintenance either MMF or AZA regimen. Moreover, the use of IBCDT was associated with a marked reduction of glucocorticoid cumulative dose.
#5365 T2DM MODIFIES THE RELATIONSHIP BETWEEN CAC AND ADVERSE KIDNEY OUTCOME IN PATIENTS WITH CKD
Authors: Yun Hae-Ryong , Han Seung Hyeok 
Published: June 2023

Abstract

Background and Aims
Kidney function decline faster in patients with type 2 diabetes mellitus (T2DM) than in those without. We previously showed that coronary artery calcification (CAC) is a strong risk of adverse kidney outcome. Here, we examined whether T2DM could modify the relationship between CAC and the progression of chronic kidney disease (CKD).

Method
2067 participants from the KoreaN Cohort Study for Outcome in Patients With CKD were enrolled. The main exposures were T2DM and CAC. The primary outcome was CKD progression defined as a composite of a 50% decline in estimated glomerular filtration rate or kidney failure with replacement therapy. Multivariable cause-specific hazard function was employed to determine the association between the main exposures and the primary outcome.

Results
During 8633 person-years of follow-up, the primary outcome occurred in 565 (27.3%) participants. In the multivariable cause-specific hazard model, both T2DM and CAC Agatston score (CACS) &gt;0 were associated with a 1.80- and a 1.41-fold increased risk of CKD progression compared with counterparts. There was a significant interaction between T2DM and CAC for the primary outcome. In patients without T2DM, CACS &gt;0 was not associated with the primary outcome compared with CACS of 0. However, in patients with T2DM, CACS &gt;0 was associated with a significantly higher risk of CKD progression (adjusted hazard ratio, 2.12; 95% confidence interval, 1.64-2.75). In addition, a 1-SD increase in CACS was associated with 1.11-fold higher risk of CKD progression. Notably, this association was also significant in patients with T2DM who had CACS of 0. The slope of eGFR decline was steeper in patients with T2DM and the magnitude of decline was greater when CACS &gt;0.

Conclusion
CAC were more strongly associated with risk of CKD progression in patients with T2DM than in those without. Thus, clinical implication of CAC may differ depending on the presence of T2DM.
#5383 THE PREDICTIVE VALUE OF URINARY CONGOPHILIA AS A BIOMARKER IN PREGNANT AND NON-PREGNANT WOMEN WITH LUPUS NEPHRITIS
Authors: Younis Dalia , Shemies Rasha Samir , El-Kannishy Ghada , Mosbah Alaa , Zakaria Mahmoud , Awadalla Amira , Elnagar Sherouk 
Published: June 2023

Abstract

Background and Aims
Endoplasmic reticulum (ER) stress with protein misfolding has been introduced as a key pathogenetic mechanism in patients with lupus nephritis (LN). Pregnancy is thought to exaggerate ER stress in conjunction with autophagy inhibition. This probably explains disease flares during pregnancy; however, this is not fully addressed. The detection of the abnormally misfolded proteins is made using the Congo red stain, which is referred to as congophilia. This study aimed to assess the predictive value of urinary congophilia as a marker of protein misfolding in pregnant and non-pregnant women with lupus nephritis.

Method
Urine samples from non-pregnant lupus nephritis patients (n = 45) and pregnant women with lupus nephritis (n = 12), as well as pregnant healthy controls (n = 38) were collected. Urinary congophilia was assessed by Congo Red Dot Blot assay. The disease activity was defined according to SLE Disease Activity Index (SLEDAI) criteria. Renal biopsy was done for 26 adults of non-pregnant lupus nephritis patients at time of urine sampling as it was clinically indicated and modified NIH activity index was assessed.

Results
The median and range values for SLEDAI score were 14(4-34) for non-pregnant LN patients, and 4(0-6) for pregnant women with LN (Table 1). Congo red retention (CRR) was significantly higher for non-pregnant LN patients (24.18%(0.75-126.29%)), in comparison with pregnant LN patients (0.67%(0.31-27.69%), P = 0.001), and healthy controls (0.33%(0.18-2.7%), P≤0.001). There was a significant positive correlation between CRR on one hand, and anti-ds-DNA (r = 0.791, P≤0.001), as well as SLEDAI score (r = 0.623, P≤0.001) on the other hand. However, no significant correlation has been found between CRR with renal histopathological activity index (r = 0.2, P = 0.425). CRR at a cut point ≥ 21.85% had 83% sensitivity, and 58% specificity to capture high LN activity status (NIH-AI &gt;10) versus lower LN activity status (Fig. 1).

Conclusion
Urinary congophilia may add a diagnostic value in patients with lupus nephritis and can be a reliable marker of disease activity. CRR is related to disease activity rather than pregnancy.
#5402 ASSOCIATION BETWEEN URINARY N-ACETYL-β-D-GLUCOSAMINIDASE AND BISPHENOL AND ITS SUBSTITUTE EXPOSURE IN TAIWANESE ADULTS
Authors: Huang Po-Chin , Lin Yu-Jung , Chang Wan-Ting , Chen Hsinchang , Chang Jung-Wei 
Published: June 2023

Abstract

Background and Aims
Urinary N-acetyl-β-D-glucosaminidase (NAG) is a sensitive and reliable indicator of renal damage, like proximal tubular cell injury. Bisphenol A (BPA), a known endocrine disruptor, or its substitute has been reported as a risk factor that caused kidney damage in experimental studies. We aimed to investigate the correlation between urinary NAG and Bisphenol and its Substitute Exposure in Taiwanese Adults.

Method
We collected urine samples including 271 adults (145 female and 126 men) from Taiwan Environmental Survey for Toxicants 2013, and analyzed for three urinary BPA, BPS and BPF by using ultraperformance liquid chromatography–tandem mass spectrometry. The bisphenol and their substitutes in the human urine samples were converted into daily intake (DI) values. We measured by the indicators of renal function, included urine creatinine (crea, mg/dL), microalbumin (mg/dL), NAG (IU/L), etc. We used logistic regression analysis to elucidate their correlations and adjustment for significant covariate.

Results
We found the median levels were 7.96 for BPA, 7.89 for BPF, and 1.96 (μg/L) for BPS, respectively, and yielded a median estimate daily intakes were 3.01 (BPA), 2.99 (BPF), and 0.76 (BPS) (ng/kg/day) in the Taiwanese adults. We found that the ratio of urinary NAG and creatinine (NAG/crea) was a significantly increased trend with exposure doses of BPA, BPF and BPS whereas no similar trend for ACR. After adjustment for age, sex, BMI and other covariate, we found that DI of BPA increased the risk of NAG/crea by 5.8 times (ORAdj: 5.8, p&lt;0.01, 2nd tertile) and 9.6 times (ORAdj: 9.6, p&lt;0.01, 3rd tertile).

Conclusion
Our findings supported that the exposure of bisphenol and its substitute may increase the risk of renal tubular injury. Further large and longitudinal studies are warrant.
#5409 FACTORS ASSOCIATED WITH THE CIRCUIT LIFESPAN OF CONTINUOUS KIDNEY REPLACEMENT THERAPY (CKRT)
Authors: Hashimoto Yorikazu , Moromizato Takuhiro 
Published: June 2023

Abstract

Background and Aims
Approximately half of patients in intensive care unit (ICU) experienced acute kidney injury (AKI). ICU patients with severe AKI and hemodynamic instability sometimes require continuous kidney replacement therapy (CKRT). Termination of CKRT circuits leads to blood loss, attenuation of therapeutic effects of CKRT, and a heavy workload and resource burden for medical staff. Identification of the factors which can prolong the lifespan of CKRT circuits is clinically essential. We aimed to elucidate the factors affecting the lifespan of CKRT circuits in ICU patients.

Method
We evaluated the lifespans of 559 CKRT circuits used for 63 ICU patients at the Okinawa Prefectural Nanbu Medical Center and Children's Medical Center from April 1st, 2021 to March 31st, 2022. We enrolled all ICU patients who required CKRT. Our research team prospectively collected information on the patients' basal characteristics, CKRT prescription, activated clotting time (ACT) after the hemofilter, CKRT circuit lifespan, and causes of termination of circuits prospectively. Effects of ACT were examined by grouping patients into three with their ACT values: &lt;140, 140≦ and &lt;180, and ≧180 seconds. The primary outcome of this study was a termination of the CKRT circuit within 24 hours after the initiation of the CKRT circuit. The secondary outcome was the cause of terminating CKRT circuits. Primarily, we examined the impacts of factors associated with CKRT circuit lifespan using multivariable Cox-proportional hazards regression.

Results
Our cohort's median follow-up period of CKRT hemofilter was 18.5 hours. The total number of participants was 63, and 63.5% were male. In the multivariate Cox regression analysis, targeting ACT between 140 to 180 seconds was associated with a longer circuit lifespan (HR = 2.11(1.43-3.11), p&lt;0.0001) than the group of CKRT circuits with ACT&lt;140 seconds. Based on our results, targeting ACT between 140 to 180 seconds extended the median survival time of the circuit lifespan to 1.4 times longer than the group of circuits with ACT less than 140 (Fig. 1). There were no differences in the causes of hemofilter occlusion among the three ACT groups. Notably, COVID-19 was not significantly associated with a reduction in circuit lifespans (HR = 0.63(0.35-1.11), p = 0.110).

Conclusion
Appropriate monitoring of ACT during CKRT may help prolong circuit lifespan, and the optimal ACT range was 140 to 180 seconds. In contrast, COVID-19 was not a risk factor for an early occlusion of CKRT circuits.
#5417 EARLY MARKERS AND VASCULAR IMPAIRMENT IN THE PROGRESSION OF CHRONIC KIDNEY DISEASE (CKD)
Authors: Virgala Julia Martin , Martín-Carro Beatriz , Villabrille Sara Fernández , Bande Jose Joaquin , Fernandez-Mariño Belinda , López Teresa Naves , Faedo Mónica Llaneza , Andía Jorge Cannata , Diaz Manuel Naves , Carrillo-Lopez Natalia 
Published: June 2023

Abstract

Background and Aims
Soluble Klotho (sKlotho) is thought to decrease early in CKD, but its use as biomarker of the CKD progression is controversial. In addition, the use of newnon-invasive techniques to diagnose incipient vascular damage in CKD would be of clinical interest. The aims of this study were: to assess the utility of serum and urinary sKlotho as a useful biomarker of kidney impairment and; to analyse the value of carotid adventitial neovascularization and aortic stiffness in the course of CKD.

Method
Forty-three CKD patients were classified according to their estimated glomerular filtration rate (eGFR) into 4 groups (CKD-2/3a, CKD-3b, CKD-4 and CKD-5) and 38 sex and age matched controls were studied. Carotid and femoral adventitial neovascularization was assessed by ultrasensitive ultrasonography without contrast (Superb microvascular image, SMI). Aortic pulse wave velocity (PWV) was measured to determine stiffness.

Results
No differences in age and body mass index between control group and the four CKD stages were observed. The eGFR showed a significant and progressive decrease (Table 1). Serum PTH, FGF23 and proteinuria were significantly higher and serum calcitriol lower in CKD stages 3b to 5 (Table 1). No changes were observed in serum Ca and serum P increased only in CKD-5 (Table 1). Serum sKlotho displayed a progressive decrease from CKD-2/3a to CKD-5, before other CKD parameters, such as FGF23 and PTH changed. A significant correlation between serum sKlotho and serum creatinine was observed (r = -0.394, p = 0.0003). Urinary sKlotho increased in CKD-2/3a stage and remained similar up to CKD-5 (Table 1). The carotid artery of CKD patients stages 4 and 5 showed a higher number of adventitial vasa vasorum (CKD-4 = 2.09±2.26, p = 0.002; CKD-5 = 1.56±1.67, control = 0.90±2.37, p = 0.019) and a greater area of adventitial neovascularization (CKD-4 = 3.52±3.49, p = 0.0008; CKD-5 = 4.51±7.75, control = 0.84±2.18, p = 0.009) compared to controls. No differences in femoral neovascularization were found. PWV was significantly higher only in CKD-5 (CKD-5 = 12.91, control = 10.81, p = 0.045). A significant correlation was observed between PWV and the area of adventitial neovascularization (r = 0.360, p = 0.001) and the number of adventitial vasa vasorum in the carotid artery (r = 0.246, p = 0.028).

Conclusion
Serum sKlotho decreased before FGF23 levels begun to rise, indicating the sKlotho decrease as the earliest marker of CKD-MBD, although it remains with no changes throughout the CKD progression. Carotid adventitial neovascularization by SMI and PWV increased in advanced CKD stages, suggesting that they have a limited clinical utility as early markers of vascular damage in CKD.
#5458 HISTOLOGICAL STUDY OF KIDNEY INJURY ASSOCIATED WITH IMMUNE CHECKPOINT INHIBITORS COMBINED WITH CHEMOTHERAPY IN A MURINE MODEL
Authors: Tascón Javier , Casanova Alfredo G , Vicente-Vicente Laura , Pescador Moisés , Martín Ana Isabel Morales , Prieto Marta 
Published: June 2023

Abstract

Background and Aims
The most current lines of cancer treatment aim to increase efficacy and decrease adverse effects. In this sense, one of the main therapeutic strategies is immunotherapy. Immune checkpoint inhibitors (ICIs) constitute the most relevant immunotherapeutic pharmacological group in the clinical setting. Despite their greater safety than conventional therapies, these agents still cause adverse events. Renal effects, although rare, have been shown to worsen the prognosis of patients. In addition, immune and chemotherapy combination have been approved nowadays. Although they have improved efficacy, they have increased risk of suffering nephrotoxic side effects. Our hypothesis is that kidney damage caused by ICIs could be subclinical, and therefore, not evidenced by the classic clinical biomarkers (plasma creatinine and urea). The aim of this work was the histological evaluation of renal damage associated with anti-CTLA-4 in combination with cisplatin.

Method
An experimental model was designed in C57BL/6 mice treated with the combined therapy of cisplatin (10 mg/kg, single dose) and anti-CTLA-4 (10 or 15 mg/kg/day, for 6 days) administrated by intraperitoneal injection. In addition, groups treated with drug monotherapies and a control group were included. On the day of sacrifice (day 6) the kidneys were collected and histological sections were made and stained with hematoxylin-eosin. Histological quantification of kidney damage was performed blindly following a tissue damage quantification protocol. For this, 10 photos were taken per kidney (600X), 5 of the external cortex and 5 of the corticomedullary region. Each photo was segmented into 6 areas and a score was assigned to each area as follows. 0: no damage, 1: damage up to 1/3 of the area, 2: damage between 1/3 and 2/3 of the area, and 3: damage over 2/3 of the area. Subsequently, the mean scores of the kidneys from the same experimental group were calculated, as well as the standard error of the mean. Data was analyzed with the statistical software SPSS®.

Results
Our results showed tubular renal damage associated with cisplatin treatment. It was more pronounced in the external cortical area. However, no structural alterations associated with ICI treatment were found. Co-treatment with both drugs potenciated renal structural damage from cisplatin.

Conclusion
This potentiation was more evident in the corticomedullary region, so it seems that the drugs combination causes a deeper lesion in the kidney than cisplatin monotherapy. Our study suggests that the combined therapy of anti-CTLA-4 and cisplatin could induce generalized tubular lesions.
#5461 KIDNEY TUBULE POLYPLOIDIZATION DURING PHYSIOLOGIC AGEING IN MICE
Authors: Lazzeri Elena , Antonelli Giulia , Conte Carolina , Angelotti Maria Lucia , Mazzinghi Benedetta , Carangiolo Giulia , De Chiara Letizia , Romagnani Paola 
Published: June 2023

Abstract

Background and Aims
The aged population is constantly increasing, and kidney-aging is a risk factor for both acute kidney injury (AKI) and chronic kidney disease (CKD). Accordingly, CKD is a major global health problem with an increasing prevalence in older population. Therefore, there is an urgent need to understand the age-related mechanisms underpinning CKD development during ageing. Recent findings contributed to clarify the cellular and molecular mechanisms underlying CKD development and progression, posing tubular cells (TC) at the center of this process. In this regard, we have demonstrated that polyploidization of TC promotes fibrosis, CKD development and its progression in the long run. Here, we aimed to investigate TC polyploidization during physiologic ageing in mice.

Method
To investigate TC polyploidization during ageing, we took advantage of inducible Pax8/FUCCI2aR mice. In these mice, FUCCI2aR reporter is expressed by all TC after doxycycline hyclate induction. Mice were sacrificed and analyzed at 2, 5, 11 and 20 months of age. By combining DNA content with detection of FUCCI2aR fluorescent proteins, FACS analysis shows diploid (2C), tetraploid (4C) and octaploid or greater (≥8C) TC. Single cell RNA-sequencing (scRNA-seq) analysis was performed on mouse kidneys at 2 and 20 months of age to dissect the transcriptomic profile of polyploid TC and interrogate putative altered signaling pathways. Renal function parameters were assessed at 2, 5, 11 and 20 months before sacrifice. Kidneys were analyzed for senescence and interstitial fibrosis at 2, 5, 11 and 20 months of age.

Results
Genetic and single-cell transcriptomic approaches in mice were used to investigate TC polyploidization during ageing. Pax8/FUCCI2aR mice showed a progressive increase of polyploid TC during ageing starting from 5 months of age. ScRNA-seq analysis on kidneys of mice at 2 and 20 months of age revealed that polyploid TC were characterized by polyploidy regulators, p21 expression, accumulation of DNA damage and by acquiring senescent/fibrotic markers, demonstrating that polyploid TC rather than diploid TC accumulate DNA damage and acquire a senescent/pro-fibrotic state during physiologic ageing in vivo. In accordance with the increase of polyploid TC, mice developed interstitial fibrosis, showed a marked senescent phenotype and an age-related decline of renal function starting from 5 months of age. Collectively, these results suggest TC polyploidization is a potential trigger for CKD development and progression during physiologic kidney ageing in mice.

Conclusion
This study demonstrates the increase of TC polyploidization, which is associated with a progressive fibrosis, senescence and CKD development during physiologic kidney ageing in mice.