bluuebunny/crossref_metadata_2025_split huggingface dataset:
#242 Incidence of postoperative acute kidney injury is twice as high in men than women following radical colorectal surgery—key findings from PROSACC
Authors: Franzén Stephanie Therése , Enlund Mats , Frithiof Robert 
Published: May 2024

Abstract

Background and Aims
Acute kidney injury (AKI) affects approximately 8% of the general surgical population. Additionally, AKI increases the risk for morbidity and mortality by 8- and 3-fold respectively. It was earlier believed that women had a greater risk for postoperative AKI. However, recent literature indicates that the incidence of AKI is actually higher in hospitalized men than women (2.2 odds ratio). Hence the male sex is currently discussed to be a risk factor for AKI. We therefore hypothesized that the incidence of postoperative AKI will be higher amongst men than women after radical colorectal surgery.

Method
We conducted a post hoc analysis (PROSACC: Propofol or Sevoflurane Anesthesia in Colon Cancer, NCT05585866) on the database from the CAN-study (Cancer and Anesthesia: Survival After Radical Surgery, NCT01975064). The CAN-study included cancer patients undergoing radical surgery at several sites in China, Croatia, Poland, and Sweden. Patients included in PROSACC were those undergoing colorectal surgery at any predefined site. Primary outcome was incidence of AKI by changes in plasma creatinine, secondary outcome was AKI in association to gender (women/men). The KDIGO criteria was used for classifying AKI on postoperative days 1-3 and 4-10. Database management and statistical analysis was performed by Uppsala Research Centre. Men vs women AKI outcome at day 1-3 and 4-10 was statistically compared with the Pearson's chi-square test.

Results
A total of 3254 patients (n = 1900 men; n = 1354 women) were included in the analysis with their preoperative plasma creatinine. Demographics showed that of the women, 39% had hypertension, 12% had diabetes and 2% had pre-existing kidney disease. In comparison, amongst the men, 24% had hypertension, 9% had diabetes and 1% pre-existing kidney disease. Postoperative plasma creatinine values were obtainable from the database in 2741 patients (n = 1578 men; n = 1163 women) on postoperative day 1-3. One hundred and ninety patients (7%) of this group had developed AKI. Separated by gender, 6% of the women (n = 72) and 8% of the men (n = 118) had established AKI according to KDIGO (p = 0.190). Plasma creatinine values were obtainable in 986 patients (n = 582 men; n = 404 women) on postoperative day 4-10 whereas 87 patients (9%) in this group had developed AKI. Separated by gender, 6% of the women (n = 23) but 11% of the men (n = 64) had established AKI at this timepoint (p = 0.004).

Conclusion
With this post hoc analysis of a global, multicentre, randomized controlled trial we conclude that the incidence of postoperative AKI is twice as high in men compared with women after 4-10 postoperative days following radical colorectal surgery. Since the women had higher rate of pronounced preoperative risk factors yet still had lower incidence of AKI, this study aligns with the conclusion that the male sex is a risk factor for postoperative AKI.
#157 UNI-494 Phase I tolerability and pharmacokinetics: trial in progress
Authors: Reddy Guru , Mourya Sanjay , Hasal Steve , Gupta Shalabh 
Published: May 2024

Abstract

Background and Aims
Acute kidney injury (AKI) is a clinical syndrome defined by the sudden loss of kidney function, resulting in an inability to maintain electrolyte, acid-base and water balance. Currently, there are no effective treatments for AKI approved by the US Food and Drug Administration or the European Medicines Agency (EMA); management of the condition is primarily supportive. The most common cause of AKI was thought to be ischemia. However, more recently the focus has shifted from clinical causes to the underlying cellular processes inherent in these situations, in particular the dysfunction of mitochondria in AKI. UNI-494 is a novel nicotinamide ester derivative and selective mitochondrial ATP-sensitive potassium channel activator that improves mitochondrial function and may be beneficial for several disease states, including AKI. This study aims to evaluate the safety, tolerability, and pharmacokinetics of UNI-494.

Method
This is a single-center, double-blind, placebo-controlled, randomized single ascending dose (SAD) (Part 1) and multiple ascending dose (MAD) (Part 2) study in healthy male subjects and female subjects of non-childbearing potential. Part 1 will enroll up to approximately 40 subjects in 5 cohorts of 8 subjects each (randomized to a ratio of 6 active and 2 placebo per cohort). There will be an interim decision meeting after each cohort/period, to review the safety, tolerability, and PK data up to 48 h post-dose in order to decide the dose level for the subsequent cohort. Part 2 will enroll approximately 20 subjects in 2 cohorts of 10 subjects each, randomized to a ratio of 8 active treatment to 2 placebo who will be dosed for 5 days. The dose level for the Part 2 Cohort 1 will be selected based on the safety, tolerability and PK data from Part 1.

Results
We intend to present results elucidating safety, tolerability, and pharmacokinetics of UNI-494 in healthy subjects.

Conclusion
The safety, tolerability, and pharmacokinetics of UNI-494 in healthy subjects will be evaluated in this study.
#3067 Comparison of the removal of bile acids between hemoperfusion and new extracorporeal albumin detoxification device (Albunique) in critical care
Authors: Stange Jan , Koball Sebastian , Hinz Michael 
Published: May 2024

Abstract

Background and Aims
In subjects with multiorgan failure and in need for CRRT, new onset of jaundice is associated with a significant mortality. Recent research suggests that elevated serum bile acids contribute to severe immune dysfunction, hepatocellular apoptosis, vasodilation, tubular necrosis and thereby are important drivers of multi-organ failure in new onset of liver dysfunction. Extracorporeal Albumin Detoxification and Dialysis (ECAD) and Hemoperfusion have been used to sustain or recover organ function. Recently, Cytosorb, a hemoperfusion device developed for the removal of proinflammatory molecules in cytokine storm showed a reduction of bilirubin and bile acids in vitro. The aim of this study was to compare the reduction of small albumin bound bile acids with the current standard (ECAD), which was developed not to affect the plasma proteome but effectively remove toxins.

Method
After obtaining consent, plasma samples were obtained from the extracorporeal circuit of subjects on CRRT due to acute on chronic liver failure (ACLF) and bile acids above 50 µmol/l before and after a day of treatment from the venous and arterial ports and the total removed bile acids were calculated by Area under the curve calculation. The measurements were done during Cytosorb treatments versus during ECAD using a new Albunique Device based on a new recycling technology.

Results
Despite a high initial reduction rate the capacity of Cytosorb decreased and the total amount of extracorporeal removal was 1720+1189 µmol whereas Albunique removed 7111+2556 µmol, more than 4 times as much and was not saturated after 24 hours.

Conclusion
Although Cytosorb may prove a role in ACLF with hyperinflammation in the future, hemoperfusion appears to loose efficacy for toxic, albumin bound small molecules and therapies based on diffusion appear to be more cost effective and less additional effects with an unclear impact on the course of ACLF.
#2940 Expression and modulation of SGLT2 in human podocytes. Not all in tubule
Authors: Riera Marta , Barrios-Barrera Clara , Galdon Eric , Martyn Claudia , de Bruin Florance , Mosquera Eva Marquez , Crespo Marta 
Published: May 2024

Abstract

Background and Aims
Inhibitors of the sodium-glucose cotransporter type 2 (iSGLT2) modify important non-glycemic pathways that lead to the protection of target organs. Its renoprotective pleiotropic effects in CKD, associated or not with diabetes, justifies further studies to elucidate the mechanisms of action (MoA) of these drugs. Although the co-transporter SGLT2 is mostly expressed in the proximal tubule, its location and function in other cells, that can be potential therapeutic targets for inhibitor drugs, has not been well studied. We explored the presence of SGLT2 in human podocyte cells and whether it is modified in different situations of cellular stress.

Method
Differentiated immortalized human podocytes were cultured under different experimental conditions for 24 or 48 h: Normoxia (Control); Normoxia + High concentration of glucose (HG); Hypoxia(1%)+2 h Reoxygenation(H) and the combination H + HG. Cells were also incubated with 0.1 uM Dihydrotestosterone (DHT). SGLT2 gene expression was determined by quantitative PCR and SGLT2 protein was detected by Western Blot (WB) and immunofluorescence (IF).

Results
Sglt2 gene expression was detected in human podocytes in culture, with an increase of expression after 24 h of exposure to HG. Protein expression by WB showed a trend to increase after 48h of exposure to HG and hypoxia, which was significant with co-incubation with DHT. HG plus DHT also increased the protein expression of SGLT2 under normoxic conditions. The IF measured by intensity of area did not show an increase in the protein expression of the transporter under HG incubation. However, protein expression increased under all hypoxic conditions: Control 50.05 ± 3, Hypoxia 140 ± 16.3 (p &lt; 0.05 vs control) and HG + Hypoxia 253 ± 21.29 (p &lt; 0.001 vs control).

Conclusion
Our data suggest that podocyte may be one of the therapeutic targets on which the iSGLT2 is acting. The experimental conditions described did not show differences in the expression of the transporter before the single stimulus of glucose, but they did under hypoxia and the combination Hypoxia-high glucose. In addition, co-incubation with testosterone seems to enhance the expression. Studying the MoA of iSGLT2 will open better comprehension of the kidney pathophysiology, particularly in the podocytopathies, regardless of diabetes.
#1792 Phenotypic variability in PAX2-related nephropathies: a monocentric study
Authors: Ciccone Martina , Zacchia Miriam , Perna Alessandra 
Published: May 2024

Abstract

Background and Aims
Pax2 mutations are known to cause kidney disease; both syndromic conditions, as kidney coloboma syndrome, and kidney specific disorders, as FSGS, have been described. Due to the rarity of Pax2-related nephropathies, data on genotype-phenotype correlation are limited.

Method
This observational and mono-centric study describes three families (A, G, P) referring to our Nephrology center, carrying Pax2 mutations. A total of 12 subjects were investigated: 2 individuals in family A, 4 in family G and 6 in the family P. Genetic analysis was carried out by NGS; detected mutations were confirmed by Sanger sequencing.

Results
Family A
It includes 2 affected subjects, a 40 year-old woman and her mother (Fig. 1A). The mother had chorioretinic coloboma and was under hemodialytic therapy since the age of 50. The daughter had chorioretinic coloboma and bilateral renal hypodysplasia, proteinuria and a progressive decline of the eGFR since 34 years; renal biopsy excluded the presence of GN (Table 1).
Both have the heterozygote c.890delC variant (p.Thr297fs) in Pax2.
Family G
It includes 4 affected individuals belonging to 3 different generations (Fig. 1B). The disorder was discovered after the evidence of advanced renal failure in a pregnant 27 y-old lady. The study of her family revealed the presence of kidney disease in her sister (transplanted on young age) and her father; one of her children has the mutation (Table 1).
The PAX2 c.194T&gt;C(p.Val65Ala HET) mutation segregates with the phenotype in the family.
Family P
It includes 6 affected individuals of 3 different generations (Fig. 1C); the index-case presented with heavy proteinuria: kidney biopsy revealed a C3 nephropathy. His son was transplanted when 18 years old for bilateral renal hypoplasia. His mother died after some years of dialysis (Table 1).
PAX2 mutation on exon3: c.361G&gt;A(p.Glu121Lys HET).

Conclusion
This case series demonstrates the phenotypic variability of patients with Pax2 mutations and suggests the utility of new generation genetics (NGS) to get the diagnosis in atypical conditions. The implementation of international registers and basic studies will be indispensable to define the mechanisms involved in the development of the disease and to address the reasons of clinical variability.
#2675 Role of ANXA4 as a modifier in VHL-dependent ccRRC
Authors: Wess Maximilian , Feilen Tobias , Kössinger Anna , Rogg Manuel , Gräwe Katja , Sammarco Alena , Schilling Oliver , Schell Christoph 
Published: May 2024

Abstract

Background and Aims
The von Hippel-Lindau (VHL) syndrome is a rare genetic disease caused by inactivating mutations of the VHL tumor suppressor gene. VHL syndrome patients frequently develop clear cell renal cell carcinomas (ccRCCs). pVHL acts as the substrate recognition subunit of an E3 ligase involved in the ubiquitinylation of HIFs. Consequently, aberrant HIF-signalling results in a pseudo-hypoxic state characterized by pronounced vascularization in respective tumours. Previous studies have indicated VHL-dependent alterations of the extracellular matrix (ECM). However, to date comprehensive description and understanding of VHL-dependent matrisome signatures is missing.

Method
Proteomics were used to reveal VHL-dependent protein expression in ccRCC cell lines (A498, 786-O) and CRISPR/Cas9-modified human proximal tubular epithelial cells (hRPTECs) as well as syndromic and sporadic ccRCC patient cohorts. For candidate proteins analysis of proteomic and histological datasets was performed. Further functional analysis was conducted using overexpression, CRISPR/Cas9-mediated knockout (KO) and shRNA-mediated knockdown (KD) approaches (assessment of proliferation, migration, invasion, ECM, cellular membrane-integrity, protein localisation studies and transcriptomics).

Results
Filtering of proteomic datasets (ccRCC tumors and cell lines) for matrisomal proteins highlighted an enrichment of the ANXA-protein family. Interestingly, functional genetic titration of ANXA4 employing knockdown, overexpression or complete ablation using CRISPR/Cas9 genome editing did not translate into major changes of cellular proliferation or migration in renal cancer or tubular cells. Detailed localization studies revealed that ANXA4 is detectable in distinct cellular compartments, namely the cell membrane and nucleus/nuclear lamina. Various cellular stressors (including cellular densities) initiated shuttling of ANXA4 between these different compartments. Remarkably, similar distribution patterns were detectable in situ in tumours tissue of ccRCC patients. Further transcriptomic analysis of ANXA4 knockout cells demonstrated a major impact on ECM- and cell-adhesion-associated gene sets, reflected by impaired invasive migratory capacity in conditions of reduced ANXA4-expression.

Conclusion
Loss of VHL distinctly alters the ECM composition in ccRCC. We have identified the ECM-associated ANXA4 as a prominently upregulated protein, although canonical hallmarks of cancer were not directly influenced. Based on RNA-sequencing studies and subcellular localization patterns we assume that ANXA4 (co-)regulates matrisome-related transcriptomic signatures in response to various external stressors. These observations highlight the intricate regulation of ECM-associated signalling pathways in the context of VHL-dependent renal cell carcinoma.
#1616 Pregnancy and fetal outcome in women with Alport syndrome
Authors: Aksenova Marina , Konkova Natalya , Lepaeva Tatjana , Nikishina Tatjana , Piruzeeva Oxana , Zaikova Natalya , Dlin Vladimir 
Published: May 2024

Abstract

Background and Aims
Pregnancy in patients with CKD is associated with maternal and fetal risks. The data about pregnancy outcome in Alport syndrome (AS) is limited. The aim was to evaluate the fetal and maternal pregnancy outcome in women with AS.

Method
One center retrospective study included 88 women with AS (86 with COL4A5, 2 with COL4A4 variants). Data at conception (age, arterial hypertension (HP), proteinuria (Pr), GFR), course of pregnancy (HP, Pr, GFR, pre-eclampsia (PE)), delivery (preterm (PD): &lt; 37 weeks; early preterm (EPD): &lt; 34 weeks), fetus characteristics (intrauterine fetal growth restriction (IUGR): L &lt; 2 z-score for gestational age; small for gestational age (SGA): m &lt; 2 z-score (SGA)) were obtained from medical charts and a cross-sectional survey.

Results
Information of 88 women, 133 term pregnancies (2 in 25 pts, 3 in 2 pts) were analyzed. Only 16 (q = 0,18) from 85 (q = 0,96) women with hematuria had diagnosis of AS before pregnancy; one of them had HP, 13 pts had Pr. HP, Pr, decreased GFR were revealed in 11 (q = 0,13), 27 (q = 0,2) and 9 (q = 0,06) pregnant, respectively. PE occurred in 8 cases (q = 0,06); PD was seen in 24 (q = 0,18) and EPD in 1 (q = 0,01) cases; cesarean section was performed in 8 cases (q = 0,07). IUGR and SGA were recorded in 8 (q = 0,06) and 11 (q = 0,08) neonates, respectively; 6 babies (q = 0,05) required a neonatal intensive care unit stay. Pr was the risk factor for PE (CI 14,86 ± 0,85, p &lt; 0,001), PD (CI 6,267 ± 0,49; p &lt; 0,001), IUGR (CI 14,86 ± 0,85, p &lt; 0,001), SGA (CI 8,93 ± 0,67, p &lt; 0,001).

Conclusion
The risk of pre-eclampsia and slowing of fetal growth in women with AS and normal kidney function appears comparable to that in the general population. But AS should be considered as a potential risk factor for preterm delivery. Proteinuria is associated with unfavorable pregnancy and fetal outcome in AS.
#191 An unusual cause of hypocalcemia in a young patient
Authors: Bae Eun Hui , Lim Sang Yup , Choi Hong Sang , MA Seong Kwon , Kim Soo Wan 
Published: May 2024

Abstract

Background and Aims
A 33-year-old man visited the Nephrology Department outpatient clinic with abnormal laboratory findings: his serum calcium level was 5.9 mg/dL in a recent health examination. He denied any underlying disease and was on no medications. He complained of a tingling sensation in his hands and of eyelid twitching. On physical examination, he showed Chvostek's sign. His laboratory findings including serum calcium level are shown in Table 1. He did not have any morphological abnormalities, such as a round face, brachydactyly, or dental anomalies.

Method
Since he showed hypocalcemia, normal 25-hydroxyvitamin D, and elevated parathyroid hormone (PTH) levels, the presence of PTH resistance was presumed. Under strong suspicion of pseudohypoparathyroidism (PHP) in this patient, DNA sequence analysis and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) of GNAS and STX16, genetic regions that are often affected by mutations or imprinting changes in PHP, was performed. No pathogenic mutations in GNAS and STX16 were detected by sequencing.

Results
Results of MS-MLPA of the GNAS locus demonstrated abnormal methylation patterns in the patient after HhaI restriction enzyme treatment. The methylation ratio showed a gain of methylation in the NESP55 region and loss of methylation in the AS, XL, and A/B differentially methylated regions (DMRs) in the patient as compared to a healthy control (Fig. 1). The patient was diagnosed with PHP type 1B (PHP1B) due to the methylation abnormalities in multiple DMRs. His parents both showed normal serum calcium levels; thus, no further genetic testing was conducted. He is on outpatient follow-up with adequate calcium replacement and no specific symptoms.

Conclusion
PHP is a rare disorder of unknown prevalence. It is characterized by hypocalcemia, hyperphosphatemia, and increased PTH levels. PHP1B is a subtype of PHP characterized by isolated renal PTH resistance, usually without physical abnormalities such as Albright hereditary osteodystrophy or other endocrine abnormalities. PHP1B can be sporadic or familial. The genetic characteristics of most sporadic PHP1B remains unclear, but GNAS imprinting abnormalities and hypomethylation at the A/B DMRs have been reported. Symptoms of PHP1B usually begin in childhood due to low calcium levels and may include numbness, seizures, tetany, cataracts, and dental problems. However, as in our case, specific symptoms may not occur until adulthood. Therefore, when evaluating the cause of hypocalcemia, it is necessary to differentiate PHP1B, even in adults, and particularly in cases with hyperphosphatemia and high PTH levels.
#1891 Evaluating the safety and effectiveness of Tolvaptan for management of adult Korean ADPKD patients (ESSENTIAL study): final report
Authors: Kim Yong Chul , Park Hayne Cho , Kim Hyunsuk , Kim Yaerim , Kim Yong-Soo , Jung Yeonsoon , Yoo Tae-Hyun , Na Ki Young , Kim Yeong Hoon , Kim Sung Gyun , Ahn Curie , Oh Yun Kyu 
Published: May 2024

Abstract

Background and Aims
Tolvaptan, a selective vasopressin V2 receptor antagonist, was first approved by Korean FDA in 2015 as a treatment option in autosomal dominant polycystic kidney disease (ADPKD). In order to prescribe Tolvaptan safely and effectively, we designed the phase 4 clinical trial among Korean ADPKD patients with chronic kidney disease (CKD) stage 1-3.

Method
Korean patients aged 19 to 50 with rapidly progressing ADPKD were enrolled in the study. The dose titration was performed every one week for a total of 4 weeks. The patient was prescribed Tolvaptan with the maximum tolerable dose up to 120 mg per day. A total duration of Tolvaptan prescription was 24 months. The primary outcome was the incidence of treatment emergent adverse events (TEAE) including drug-induced liver injury (DILI). The secondary outcomes were the annual mean percent change of total kidney volume (TKV) and the annual mean change of estimated glomerular filtration rate (eGFR).

Results
A total of 117 patients were included in the analysis. Mean age was 38.7 ± 8.4 years old and male were predominant (58.1%). The average TKV was 2066 ± 1094 mL and mean eGFR was 79.7 ± 27.7 mL/min/1.73 m2. Mean duration of Tolvaptan exposure was 1.7 ± 0.6 years and the average daily dose of Tolvaptan was 94.4 ± 24.1 mg/day. A total of 489 treatment-emergent adverse events (TEAE) occurred in 106 (90.6%) patients during study duration. The drug-induced liver injury and aquaresis-related adverse events were two most common adverse events. A total of 17 DILI cases (14.5%) occurred during the study period and mostly within 18-month period. However, liver enzymes were normalized after drug discontinuation The patients with previous history of liver disease as well as those who were prescribed higher dose of Tolvaptan demonstrated higher frequency of DILI. Mean growth rate of TKV after Tolvaptan treatment was 4.5 ± 0.5% and mean eGFR decline rate was -3.0 ± 0.39 mL/min/1.73 m2/year. Comparing with the predicted value from calculation, Tolvaptan attenuated both TKV growth and eGFR decline rate.

Conclusion
This study is the first post-marketing survey assessing the safety and efficacy of Tolvaptan in Korean ADPKD patients. The incidence of DILI was higher than the previous studies and especially in those with liver disease and higher Tolvaptan prescription dose. While Tolvaptan can effectively reduce TKV and attenuate eGFR decline, the clinicians should be aware of higher frequency of DILI among Korean population.