bluuebunny/crossref_metadata_2025 huggingface dataset:
#4037 DEVELOPMENT OF AN EXPERT MODEL FOR THE DIAGNOSIS OF INHERITED KIDNEY DISEASES
Authors: de Arizón Leonor Fayos , Ramírez Elizabeth Romelia Viera , Leon Rafael , Teran Melissa Pilco , Furlano Monica , Vallverdu Montserrat , Guirado Lluis , Perera Alexandre , Torra Roser
Published: June 2023

Background and Aims

Inherited kidney diseases (IKDs) account for 10-20% of cases of Chronic Kidney Disease (CKD). Mutations in over 400 genes are known as drivers of more than 150 monogenic kidney disorders. Clinical diagnosis is often challenging as these disorders are characterized by numerous clinical features often shared by many diseases as well as very variable expression. Over the years, rare-disease databases such as OMIM and Orphanet have complied information to facilitate diagnosis of rare diseases. Based on these, The Human Phenotype Ontology (HPO) developed a standardized directory for phenotypes with phenotype-disease associations. New phenotype-driven gene-priorization tools such as Phenomizer have been developed in the recent years using these resources, however structural inaccuracies prevent a proper uptake of these tools. To date, no specific renal tool has been developed. The aim of the study was to develop an expert model for the diagnosis of IKDs based on phenotype semantic similarity distances such over Human Phenotype Annotations.

Method

Using MONDO ontology which encompasses HPO phenotypes, OMIM and Orphanet, HPO annotations corresponding to 196 IKDs were exported an analyzed. Based on literature, original HPO annotations for each IKD were manually curated (inaccurate terms were eliminated, new known HPOs were added and new annotations were generated in case they were missing). Frequencies were added to each annotation. Specific kidney data such as CKD stage, age at need of kidney replacement therapy and degree of proteinuria were included. Age of onset, prevalence, and specific gender sub analysis in case of diseases with X-linked inheritance was also integrated. All curated phenotype-disease associations were reviewed by European experts. Using MONDO annotations for each IKD as synthetic patients a statistical model with a friendly user web-based interface was developed in Java.

Results

Analysis of current ontologies by experts in the filed revealed that HPO terms associated to IKDs were inaccurate and non-specific. A new phenotype-driven tool fed with new curated terms and specific kidney data was found to be superior to current tools. Future contributions to ontologies such as HPO, MONDO and open data-sources with curated terms and updated classifications concerning IKDs will help to improving the diagnosis and characterization of IKDs.

Conclusion

Current phenotype-based gene prioritization tools and rare disease databases have contributed significantly to improving the clinical diagnosis of rare diseases. However, these tools are nonspecific and imprecise when focusing on a specific field such as IKDs. Curation of current annotations by experts in the field will greatly improve the accuracy of these tools and facilitate clinical diagnosis of IKDs.
#4046 ADVANCED CHRONIC KIDNEY DISEASE, PREOPERATIVE ISOMETRIC EXERCISE AND VASCULAR ACCESS: LET´S CLEAR THE DOUBTS
Authors: González Irati Tapia , Simó Vicent Esteve , Pallares Sara Ibañez , Guzmán Fátima Moreno , Oleas Diana , Julia Jorge Mario Alfonzo , Gallego Verónica Duarte , Potau Mónica Pou , Solé Anna Saurina , Serna Manel Ramírez de Arellano
Published: June 2023

Background and Aims

Arteriovenous fistula (AVF) is the best vascular access for hemodialysis. However, the role of preoperative isometric exercises in patients with advanced cronic kidney disease (CKD) who are candidates for AVF is unclear and not well reported in the literature. The main objetive of this study was to evaluate the effect of preoperative isometric exercise on vascular territory in advanced CKD prior to AVF creation.

Method

An 8 months prospective single-center study. We performed an isometric preoperative exercise program for 4 weeks on the non dominant arm (exercise arm) and was compared with the dominant arm (control arm) performing usual activity in our advanced CKD patients. Demographic data, upper limb muscle strength (ULMS), Doppler ultrasound (DUS) measurements (foream and distal cefalic vein (FCV, DCV) diameter, basilic vein (BV) diameter and depth, peak systolic velocities (PSVs) and diameters in the radial artery (RA) and braquial artery (BA), as well as percentage of patients candidates to AVF in both arm (exercise and control arm) according to Spanish Clinical Guidelines of Vascular Access (VA) and possible medical complications were analyzed.

Results

27 patients. 67,7%men. Mean age 70,3±10,4years. Main cardiovascular risk factors: HBP (93,5%) and DM (64,5%). Exercise arm was left side in 87,1%. A significant increase was observed in ULMS only in exercise arm at the end of study (23,8±8,7Kg vs 27, 6±9,5Kg, p = 0,001). Related to DUS measurements, there were not diffences between groups on vein caliber. However, a significant increase was observed in RA PSV (57,7±15,3 vs 62,6±17,4cm/seg, p = 0,044), BA diameter (4,6±0,6 vs 4,9±0,9mm, p = 0,029) and percentage of patients who could be candidates to AVF (70,4 vs 92,6%, p = 0,034) in exercise arm at the end of the study. We did not observe any related complications (pain, hypotension or muscle injury).

Conclusion

Preoperative isometric exercises would increase the percentage of performing a native AVF in those advanced CKD patients candidates for HD. Similarly, our results suggest that preoperative isometric exercise could be a useful tool to improve the vascular territory, mainly arterial, in our patients. However, more studies are required to confirm our results.
#4052 IMMUNOSUPPRESSIVE TREATMENT RESULTS IN PATIENTS WITH PRIMARY IGA NEPHROPATHY IN TURKIYE: A NATIONWIDE STUDY
Authors: Oruc Aysegul , Sumnu Abdullah , Turkmen Aydin , Basturk Taner , Cebeci Egemen , Turgutalp Kenan , Çetinkaya Hakkı , Kibar Muge Uzerk , Seyahi Nurhan , Tatar Erhan , Ergül Metin , Derİcİ Ülver , Ayli Deniz , Pınar Musa , Bakar Betul , Kazancioglu Rumeyza , Yildiz Abdulmecit , Dirim Ahmet Burak , Yilmaz Zulfikar , Turkmen Kultigin , Tunca Onur , Koc Mehmet , Kutlay Sim , Micozkadioglu Hasan , Azak Alper , Boztepe Burcu , Üstündağ Sedat , Ozturk Seda Safak , Unsal Abdülkadir , Karadağ Serhat , Sahin Gulizar Manga , Yenigun Ezgi Coskun , Eren Necmi , Gullulu Mustafa
Published: June 2023

Background and Aims

IgA nephropathy (IgAN) is the most common cause of primary glomerulonephritis in Turkey, as well as all over the world. Along with the frequent occurrence, deleterious renal outcome odds make treatment approaches important. Additionally, for high-risk individuals immunosuppressive treatment (IST) is recommended. However, studies to date revealed conflicting results regarding IST. Therefore, we aimed to investigate IST results among IgAN patients which is the leading primary glomerulonephritis in Turkiye.

Method

The data of 1656 IgAN patients in the Primary Glomerular Diseases Study of the Turkish Society of Nephrology Glomerular Diseases Study Group (TSN-GOLD) were analyzed. A total of 506 primary IgAN patients (63.4% male, mean age 38.9±12.5 years) were included and divided into two groups according to treatment protocols as isolated corticosteroid (69.6%) and combined IST (30.4%) groups. The median follow-up duration was 24 (3-218) months.

Results

Remission (66.6% partial remission, 33.4% complete remission) was achieved in 70.6% of patients. Systolic and diastolic blood pressures, urea, creatinine, and proteinuria levels were lower, and eGFR levels were higher in responsive patients (Table 1). There was no difference between the treatment groups in terms of remission rates (p = 0.147) and remission types’ rates (p = 0.279). Remission rates were different between treatment subgroups. However, there was no difference between the treatment subgroups according to the remission types (p = 0.132) (Table 2). Complete remission was lower in the S1 and T1 categories (p = 0.003 and 0.039, respectively). The serious infection was higher in the combined IST group (17.1% vs 2.9%). The outcome data of 229 individuals was evaluated, 40 of 229 (17.5%) developed ESRD and 8 were dead. In the multivariate analysis, eGFR (OR 1.007, 95%CI 1.001-1.013, p = 0.020), proteinuria (OR 1.000, p = 0.009), MEST-C S1 (OR 1.912, 95%CI 1.216-3.005, p = 0.005), MEST-C T2 (OR 0.226, 95%CI 0.102-0.501, p = < 0.001) were found to be significant regarding remission.

Conclusion

IST provides remission in high-risk IgAN patients but was associated with serious adverse events. The fact that the remission rates were similar between the treatment groups and that the complete remission rate was low in chronic changes supports the necessity of determining the treatment choice according to patient characteristics.
#4087 THE EFFECTS OF SOCIOECONOMIC STATUS ON MAJOR ADVERSE CARDIOVASCULAR EVENTS: A NATIONWIDE POPULATION-BASED COHORT STUDY
Authors: Bae Eun Hui , Lim Sang Yoeb , Kim Su In , Cho Da Hae , MA Seong Kwon , Kim Soo Wan
Published: June 2023

Background and Aims

Although multiple factors influence the risk of major adverse cardiovascular events (MACE), the effects of socioeconomic status on MACE in the presence and absence of renal dysfunction (RD) have not been comprehensively explored in South Korea.

Method

We examined the effects of socioeconomic status on MACE in individuals with and without RD. The data of 44,473 Koreans from 2008 to 2017 were obtained from the health care big data platform. Their socioeconomic status was assessed using a socioeconomic score (SES) based on their marital status, education, household income, and occupation. The incidence of myocardial infarction (MI), stroke, and death was compared according to five SES levels (0–4). Multiple linear regression analysis was used to evaluate the hazard ratios and 95% confidence intervals (CIs) for outcomes based on the participants’ SES.

Results

MI risk was only affected by education level. The participants’ income, education, and SES affected their stroke risk, whereas death was associated with all four socioeconomic factors. The incidence of stroke and death increased as SES worsened (from 0 to 4). SES was positively related to the risk of stroke and death in participants without RD. SES did not affect MI, stroke, or death in the participants with RD.

Conclusion

A low socioeconomic status is associated with the risk of stroke and death, especially in individuals without RD.
#4107 THE ROLE OF CYTOKINE ADSORBER IN REDUCTION INTERLEUKIN-6 LEVELS: A MATCHED CASE-CONTROL SINGLE CENTER ANALYSIS
Authors: Jerman Alexander , Gubensek Jakob , Berden Jernej , Peršič Vanja
Published: June 2023

Background and Aims

Extracorporeal cytokine adsorption is used with the aim to reduce pathogenic levels of cytokines in critically ill patients. Although technically and theoretically plausible, little convincing data exist to support wide use of cytokine adsorber in clinical practice. We aimed to retrospectively compare the time course of interleukin-6 (IL-6) in patients treated with or without the adsorber (CytoSorb®).

Method

In this retrospective, case-control study all patients treated between Jan 2017 and Dec 2021 in a medical ICU were screened and included, if at least two IL-6 measurements were available. Patients were divided to adsorber group and standard of care group based on the treatment received. Unmatched and matched groups were compared regarding IL-6, lactate, CRP, procalcitonin, and vasopressor demand at predefined time points. Mortality rates were also compared.

Results

We screened 3865 patients and included 52 patients in the adsorber group and 94 patients in the standard of care group. After matching, there were 21 patients in each group. Patients had similar age (53 (41, 68) vs. 61 (56, 67) years), ECMO was used in 24% (both groups) and renal replacement therapy in 100% of patients (both groups), baseline noradrenaline requirement (0.04 vs. 0.03 mg/kg/h), serum lactate (6.8 vs. 5.4 mmol/l), pH (7.27 vs. 7.21), CRP (182 vs 167 mg/l), and IL-6 (2441 vs. 2552 ng/l) were comparable between adsorber group and SOC group. There were no significant differences in the time course of IL-6, lactate, CRP, procalcitonin, and noradrenaline requirement between the groups. Two-day (33% vs. 28%) and ICU (57% vs. 62%) mortality and Kaplan-Meier survival curves (log-rank p = 0.9) were comparable.

Conclusion

In our matched case-control study, no difference in IL-6 or inflammatory parameters reduction, noradrenaline demand, or mortality was observed between patients, treated with adsorber (CytoSorb) or standard of care.
#4124 SEX AND CARDIOVASCULAR DISEASE IN STAGE G2-5 CKD PATIENTS
Authors: Mallamaci Francesca , Provenzano Pasquale Fabio , Parlongo Giovanna , Leonardis Daniela , Caridi Graziella , Marino Francesco , D'arrigo Graziella , Tripepi Giovanni Luigi , Zoccali Carmine
Published: June 2023

Background and Aims

Male sex is considered a major risk factor for cardiovascular (CV) disease in the general population, but the role of this factor in the high risk for CV disease in the pre-dialysis CKD population is still debated.

Methods

We tested the relationship between sex and fatal and non-fatal major CV events (myocardial infarction, heart failure, arrhythmia, angina, stroke, transient ischemic attack, peripheral vascular disease, major arterial or venous thrombotic episodes and sudden death) in a cohort including 759 stage 2-5 CKD consecutively recruited from 22 Nephrology units in southern Italy between October 2005 and September 2008. After the initial assessment, patients were followed up for a median time of 36 months (range 0.3–48 months).

Results

Four hundred fifty-five patients were males (60%). The proportion of smokers was about 4 times higher in males (71.4%) than in females (17.4%). Males and females differed in the prevalence of diabetes (38.5% versus 29.6%) and the frequency of background CV comorbidities (35.6% versus 19.7%, P<0.001). Waist circumference (100.9±12.4 versus 96±14.1 cm), eGFR (37.5±13.4 versus 33±12.7 ml/min/1.73 m2), 24-hour urinary protein excretion (median: 0.7 g/24h, IQR: 0.2-1.6 g/24h versus 0.5, IQR: 0.2-1.2 g/24 h), and haemoglobin (13.4±1.9 versus 12.0±1.4 g/dL) were higher in males than in females. Serum phosphate (3.6±0.75 versus 3.9±0.75 mg/dL), hs-CRP (median; 2.2 mg/dl, IQR: 1-4.7mg/dl versus 2.8 mg/dl, IQR: 1.2-6.4 mg/dl) and total cholesterol (178.3±42.1 versus 198.8±45.6 mg/dl) were lower in males than in females. During follow-up, 42 patients died, and 118 had fatal and non-fatal CV events. On univariate Cox regression analyses, male gender failed to be associated with all-cause mortality but was strongly related to the incidence rate of fatal and non-fatal major CV events [HR 1.75, 95% CI: 1.18-2.60, P=0.006]. Data adjustment for a series of major potential confounders did not materially affect the strength of this relationship [HR:1.78, 95% CI: 1.03-3.09]. Further analysis testing the effect of age on major CV outcomes by gender showed an effect modification by this risk factor on the same outcome (P=0.037) because the hazard ratio of male versus female CV events increased progressively with ageing (Figure 1).

Conclusion

The excess risk for CV mortality by the male gender in the general population holds in stage G2-5 CKD patients. Age is a modifier for the excess risk for CV events in CKD patients because the risk excess of the male gender increases linearly across a wide age spectrum in CKD patients.
#4150 INTERNATIONAL COMPARISON AND TIME TRENDS OF FIRST KIDNEY TRANSPLANT RECIPIENT CHARACTERISTICS ACROSS EUROPE: A STUDY FROM THE ERA REGISTRY
Authors: Boenink Rianne , Kramer Anneke , Stel Vianda , Jager Kitty J , Ortiz Alberto
Published: June 2023

Background and Aims

Large international differences exist in the kidney transplantation (KT) rate across Europe. Countries might transplant a different group of end-stage kidney disease (ESKD) patients, but up to now an overview of recipient characteristics in first kidney transplant recipients in the different European countries is lacking. Therefore, the aim of this study was to give an overview as well as time trends in age, sex and primary renal disease (PRD) distribution of first kidney transplant recipients in Europe.

Method

The European Renal Association (ERA) Registry database was used to obtain data on adult patients receiving their first KT between 2010 and 2019 from 12 European countries. The numbers and percentages of recipients in each age, sex and PRD group were calculated by country, donor type and year. The first KT rate was calculated by dividing the number of first KTs by the adult general population counts and multiplied by one million.

Results

In total, 99,543 patients received a first KT between 2010 and 2019 for all countries combined. The percentage of recipients aged 65 years and older varied greatly between countries, with Bosnia and Herzegovina having the lowest percentage (1%), and the Netherlands, Spain and Norway having the highest percentages (>25%). Similar results were found for deceased donor first KT, but for living donor first KT Spain was no longer among the countries with the highest percentage of recipients aged 65 years and older. The percentage of female recipients ranged between 33% in Austria and 38% in the Netherlands for total first KT, between 33% in Austria and 38% in Denmark for deceased donor first KT and between 30% in Austria and 39% in the United Kingdom for living donor first KT. When comparing the distribution of PRDs, Bosnia and Herzegovina had a relative high percentage of recipients with glomerulonephritis (35%), while Finland had a high percentage of recipients with diabetes mellitus (29%) and the Netherlands and Norway a high percentage of recipients with hypertension / renal vascular diseases (17% and 22% respectively). This distribution was similar for deceased and living donor first KT recipients. Over time, the most prominent change regarding the recipient characteristics was observed for the age of the recipient, with an increasing proportion of recipients aged 65 years and older from 18% in 2010 to 28% in 2019 for all countries combined, and with a similar trend observed in most countries.

Conclusion

We observed large differences in the recipient characteristics at first KT between European countries and over time, especially for the recipient age and PRD. These new insights in the distribution of recipient characteristics in the first KT population could elucidate which ESKD patients receive a KT.
#4151 POLYCYSTINS ARE REQUIRED FOR RENAL TUBULOINTERSTITIAL FIBROSIS
Authors: Xing Yufeng , Wu Ming , Ye Chaoyang
Published: June 2023

Background and Aims

Renal fibrosis is the common pathway of various chronic kidney diseases progressing to end stage renal failure. Polycystin-1 (encoded by PKD1 gene) and polycystin-2 (encoded by PKD2 gene) form a transmembrane complex and function as a stress sensor, which is located in the primary cilia. Polycystins are involved in the disease condition of different organs. Mutation of PKD genes causes autosomal dominant polycystic kidney disease and deletion of polycystin attenuates heart injury induced cardiac fibrosis. The role of polycystins in renal tubulointerstitial fibrosis is currently unclear.

Method

Unilateral ureteral obstruction (UUO), unilateral ischemia-reperfusion injury (UIRI), aristolochic acid or folic acid induced mouse models of renal fibrosis were established for this study.

Results

Here we showed that polycystin-2 is up-regulated in these three mouse models of renal fibrosis and tightly correlated with the expression of collagen-I in a time dependent manner. Treatment with triptolide inhibited the expression of polycystin-2 and pro-fibrotic markers in UUO and UIRI models. Moreover, triptolide or PKD2 siRNA inhibited the expression of polycystin-2 and pro-fibrotic markers in vitro. Using Pkd2 conditional knockout mice, we showed that genetic deletion of Pkd2 reduced the expression of pro-fibrotic markers in UUO kidneys. Polycystin-1 was also up-regulated in renal fibrotic models and conditional deletion of Pkd1 reduced the expression of pro-fibrotic markers in UUO or folic acid induced fibrotic kidneys. Furthermore, the expression of the methyltransferase EZH2 is positively correlated with the expression of polycystins in fibrotic kidneys. Conditional knockout of EZH2 attenuated the anti-fibrotic responses induced by Pkd1 deletion in UUO kidneys.

Conclusion

In conclusion, polycystins are up-regulated in fibrotic kidneys and promote renal tubulointerstitial fibrosis through up-regulation of EZH2, suggesting that primary cilia are required for renal tubulointerstitial fibrosis.
#4158 URINE DERIVED STEM CELL AMELIORATES RENAL FIBROSIS VIA KLOTHO ACTIVATION
Authors: Choi Dae Eun , Lee Kang Wook , Na Ki Ryang , Ham Young Rok , Chang Yoon-Kyung , Lee Eu Jin , Park Heyrim , Jeong Jin Young , Shin Jin Ah
Published: June 2023

Background and Aims

After renal IRI, regeneration and recovery of the renal tubular cell occurs. However, if the renal repair process is maladaptive, it progresses to renal fibrosis. The role of stem cells in kidney regeneration or fibrosis has not been fully elucidated. we evaluated the urine drived stem cells (UDSC) for renal inflammation and fibrosis after renal ischemia reperfusion (IR).

Method

10 week old balb/c nude male mice were used. sham, sham with UDSC, IR, IR with UDSC. UDSC were infused 3 times via tail vain at 6, 7, 8th day after renal IR. Urine NGAL/creatinine (Cr) were checked. The kidneys tissue were harvested at day 14 day. In vitro, TGF-β treated HK2 cell were co-cultured with UDSC. Klotho siRNA silencing was performed in UDSC.

Results

Urinary NGAL/Cr were significantly increased in IR mice after 14 day IR, compared to sham mice. Urinary NGAL/Cr significantly decreased in UDSC treated IR mice, compared to IR mice. In H&E stain, renal tubulo-interstitial injury were significantly decreased in UDSC treated IR mice, compared to IR mice. In masson trichrom stain, renal fibrosis area were were significantly decreased in UDSC treated IR mice, compared to IR mice. The renal expression of TGF-β, α-SMA, and collagne IV were significantly decreased in UDSC treated IR mice, compared to IR mice. The renal expression of Klotho were increased in UDSC treated IR mice, compared to IR mice. in vitro, UDSCs were stem cells that expressed Klotho protein more strongly than other mesenchymal stem cells (MSCs). UDSCs also suppressed fibrosis by inhibiting transforming growth factor (TGF)-β in HK-2 human renal proximal tubule cells in an in vitro model. Klotho siRNA silencing reduced the TGF-β-inhibiting ability of UDSCs.

Conclusion

UDSC attenuate renal fibrosis after renal IR. Klotho-secretion of UDSC play a role in these anti- fibrotic effects.
#4171 DIALYSIS WITHOUT SOCKS: DETECTION OF ULCERS AND AMPUTATIONS IN HEMODIALYSIS
Authors: González-Mariño Rocío Zamora , Hernández Rosa Sánzhez , Jiménez Laura Rodríguez-Osorio , Gúrpide Beatríz Durá
Published: June 2023

Background and Aims

Dialysis patients are at high risk of ischemia and foot ulcers (14.4%) that frequently precede severe complications, including amputations (5.9%), hospitalizations, and mortality. Critical ischemia in this location accounts for 20% of the annual causes of death in hemodialysis, produces pain that is difficult to control and greatly reduces the quality of life. The aim of this work was to analyze the prevalence and factors associated with amputations in hemodialysis patients, and to assess the evolution after amputation.

Method

Carrying out a survey by email sent by the SEN (Spanish Society of Nephrology) and SOMANE (Madrid Society of Nephrology). Retrospective, cross-sectional, multicenter study. The survey sent to all hemodialysis units nationwide. Answered by 47 Centers. The exclusion criteria were oncological-traumatic amputations.

Results

Conclusion
#4292 PATIENT-REPORTED MENTAL HEALTH PROBLEMS, SUICIDE IDEATION, AND CLINICAL OUTCOMES IN ADULTS WITH NON-DIALYSIS CKD: RESULTS OF THE KNOW-CKD STUDY
Authors: Lee Kyu-Beck , Yang Jihyun , Hyun Young Youl
Published: June 2023

Background and Aims

Mental health is important for health and well-being at every stage of life and disease. Mental health problems are common and bothersome in chronic kidney disease (CKD). Mental health problems of CKD are poorly understood and evaluated. To address the importance of mental health in CKD, we analyzed a prospective cohort database from prospective CKD cohort.

Method

We analyzed 1897 participants from the KNOW-CKD cohort. We evaluated 4 items as indicators of patient-reported mental health: sleep duration, perceived stress, depressive symptoms, and suicidal ideation. To facilitate interpretation of the mental health problems in CKD, we measure a scaled effect size (ES) for the Kidney Disease Quality of Life Short Form (KDQOL-SF) differences among the groups of mental health problems. We investigated the association between patient-reported mental health problems and clinical outcomes of incident end-stage kidney disease (ESKD) all-cause death in non-dialysis CKD.

Results

The mean age was 53 ± 12 years and 62% were male. The participants had mental health problems of inadequate sleep duration (17.4%), subject distress (27.3%), experience of depression (13.2%), and suicide ideation (16.8%), but had not well taken care (psychiatric counselling 1.9%, antidepressant therapy 2.8%). The 4 item indicators of mental health showed large effect size between-groups KDQOL mental component summary (ES = 1.67). In the fully adjusted Cox proportional model, poor mental health (≥2 mental health problems) was associated with high risk of ESKD [HR = 1.46; 95% CI (1.18∼1.08)] and death [HR = 1.55; 95% CI (1.04∼2.32)] compared to good mental health (no mental health problems). Among 4 item indicators of patient-reported mental health, suicide ideation was the most predictive indicator of clinical outcomes.

Conclusion

Mental health problem is common and undertreated in CKD. Poor mental health is associated with high risk of ESKD and death in non-dialysis CKD and the single question of suicide ideation is significantly associated with high risk of ESKD and death. It suggests that the evaluation and management of mental health problem is important to the clinical outcomes in CKD.
#4346 SERUM NONSKELETAL ALKALINE PHOSPHATASE AS A MARKER OF METABOLIC ENDOTOXINEMIA AND PREDICTOR OF ADVERSE OUTCOME IN PATIENTS WITH CKD
Authors: Smout Dieter , Joergensen Hanne , Meijers Björn , Dejongh Sander , Haarhaus Mathias , Cavalier Etienne , Van Craenenbroeck Amaryllis , Evenepoel Pieter
Published: June 2023

Background and Aims

Elevated alkaline phosphatase (ALP) levels are widely recognized as a marker of poor outcomes in chronic kidney disease (CKD). This association remains poorly understood, with arguments pointing to the skeletal and non-skeletal isozyme fractions as being decisive factors. The liver and intestinal isoenzymes of ALP are able to dephosphorylate and thus inactivate a number of substrates which have been implicated in the promotion of inflammation, including the bacterial endotoxin lipopolysaccharide (LPS). Present study aimed to test the hypothesis whether association of total ALP with all-cause mortality is mainly driven by non-skeletal ALP and its link with metabolic endotoxemia and inflammation.

Method

Laboratory parameters of mineral and bone disease, inflammation (C-reactive protein, CRP), and metabolic endotoxemia (Lipopolysaccharide binding protein, LBP) were assessed in 431 CKD patients enrolled in the Leuven Mild-to-Moderate CKD Study between Nov 2005 and Sept 2006. Non-skeletal ALP levels were estimated as residuals of the linear regression of log transformed total and bone-specific ALP. Spearman correlation, multivariate regression, and Cox proportional hazard analyses were performed to investigate the associations between skeletal and non-skeletal ALP, LBP, CRP and mortality. Data were censored at start of renal replacement therapy.

Results

Median age was 63 years, 54% were men, 19% had diabetes, 31% had established cardiovascular disease. At baseline, non-skeletal ALP was associated with inflammatory parameters (CRP: rho = 0.33, P<0.001) and with metabolic endotoxemia (LBP: rho = 0.32, P<0.001). Non-skeletal ALP was a significant predictor of elevated CRP (>3 mg/dL) in multivariate models (odds ratio (OR) per standard deviation (SD) increase 1.97; 95% CI 1.21-3.21; P = 0.006). This association was attenuated by further adjustment for LBP (OR 1.40; 95% CI 0.69-2.80; P = 0.3). During a median follow-up of 8.0 (interquartile range, 2.6-14.7) years 131 patients died. High non-skeletal ALP associated with increased risk of all-cause mortality, even after adjusting for demographics, Framingham risk factors and comorbidities (Hazard ratio (HR) per SD increase 1.28; 95% CI 1.05 – 1.56; P = 0.016). This association was attenuated by further adjustment for LBP (HR 1.22; 95% CI 1.00-1.50; P = 0.051). High bone-specific ALP was not associated with increased risk of all-cause mortality.

Conclusion

In patients with CKD not yet on dialysis, increased non-skeletal ALP (as opposed to skeletal ALP) is associated with inflammation and increased risk of all-cause mortality. These associations are at least partly driven by metabolic endotoxemia.
#4375 LANOSTEROL SYNTHASE RS2254524 POLYMORPHISM MODULATES SALT SENSITIVITY AND RENAL EXPRESSION IN A NOVEL MICE MODEL, LSSV643L/V643L
Authors: Citterio Lorena , Faienza Sipontina , Messaggio Elisabetta , Zagato Laura , Lanzani Chiara Livia , Simonini Marco , Manunta Paolo
Published: June 2023

Background and Aims

The blood pressure (BP) response to different salt intakes (salt sensitivity-SS), shows variability among individuals, with more frequency in hypertensives compared to the general population. Elevated levels of the Endogenous Ouabain (EO) have been associated with hypertension (HT) and SS. We characterized the missense variation rs2254524 (Val642Leu; C>A) of the Lanosterol Synthase gene (LSS) coding for an enzyme in steroid biosynthesis, since AA patients on a low-salt diet showed a greater reduction in BP compared to the LSS CC, with only CC having an increase in plasma EO. Moreover, AKI incidence following cardiovascular surgery was greater among those with the LSS rs2254524 AA genotype than in those with the CC genotype. We aim at dissecting the functional correlation between LSS polymorphism, EO, SS-HT, and renal function.

Method

We generated by CRISPR-Cas9 a knock-in mouse model carrying the Lss V643L (LssV643L/V643L), homologous to V642L to dissect the functional correlation between LSS polymorphism, EO and salt-sensitive hypertension, and kidney expression. Male mice were fed with a normal-salt diet (0.5% NaCl), high-salt diet (4% NaCl), or low-salt diet (<0.03% Na) and BP was measured every two days by the tail-cuff system.

Results

LssV643L/V643L mice were viable, healthy, and undistinguishable phenotypically from WT. At baseline, the Lss AA affected kidney weight that was significantly enlarged at 3 (p = 0.02) and 12 months of age, compared to WT (kidney p = 0.04; liver p = 0.003). The Lss V643L mutation did not affect EO and SBP at 3 and 12 months, per se, but affects SBP responsiveness to salt intake. Indeed, we observed an increased SBP upon a high-salt diet only in LssV643L/V643L mice 12 months old compared to the control diet (p = 0.01). Moreover, the 12-month-old LssV643L/V643L mice in high-salt diet showed cardiac hypertrophy and showed a higher incidence of heart fibrosis. At 12 months, in the adrenal gland of LssV643L/V643L mice, Lss mRNA level was reduced upon high-salt diet (p = 0.03), while RNA-seq analysis of renal differentially expressed genes revealed a different regulation of multiple Slc genes, both in control and high-salt diet, but also of Cbr2, and Arhgap26.

Conclusion

The new LssV643L/V643L mouse model resembles the SS-HT phenotype together with EO non-responsiveness observed in HT patients, thus providing a good model of SS-HT. Our results reveal a role of Lss gene in the regulation of BP upon salt stimulus, and its influence at renal level at 3 and 12 months of age.
#4425 EZH2 PROMOTES RENAL INTERSTITIAL FIBROSIS THROUGH DOWNREGULATION OF PHOSPHOENOLPYRUVATE CARBOXYKINASE 1 MEDIATED GLUCONEOGENESIS
Authors: Bai Yanfang , Wu Ming , Ye Chaoyang , Chen Dongping
Published: June 2023

Background and Aims

Renal fibrosis is the common pathological pathway of various chronic kidney diseases progressing to the end stage of renal failure. The methyltransferase enhancer of zeste homolog 2 (EZH2) has been identified as a therapeutic target to inhibit renal interstitial fibrosis. However, the mechanism underlying the role of EZH2 in renal fibrosis is not completely understood.

Method

Unilateral ureteral obstruction (UUO), unilateral ischemia-reperfusion injury (UIRI) mouse models were established. PCR, cleavage under targets and tagmentation (CUT&Tag) and Western blotting was performed to evaluate the expression of EZH2 and phosphoenolpyruvate carboxykinase 1 (PCK1).

Results

By using EZH2 inhibitor 3-DZNeP and Ezh2 conditional knockout mice, we confirmed the pro-fibrotic effect of EZH2 in unilateral ureteral obstruction (UUO). Through RNA sequence and cleavage under targets and tagmentation (CUT&Tag) sequence analysis, we found that the phosphoenolpyruvate carboxykinase 1 (PCK1), a critical enzyme in gluconeogenesis, is negatively regulated by EZH2 in fibrotic kidneys, which was further confirmed by quantitative PCR, CUT&Tag and Western blotting. We further showed that deletion or inhibition of EZH2 inhibited renal fibrosis and enhanced PCK1 expression and activity in unilateral ischemia-reperfusion injury (UIRI) and folic acid induced mouse nephropathy. Moreover, the dysregulated production of renal glucose and lactate in mouse UUO kidneys was restored after EZH2 inhibition by 3-DZNeP. Finally, inhibition of PCK1 by 3-mercaptopropionic acid (3-MPA) abrogated the anti-fibrotic effect of 3-DZNeP in UUO kidneys.

Conclusion

We conclude that EZH2 promotes renal interstitial fibrosis through inhibition of PCK1 mediated gluconeogenesis.
#4466 EXPLAINABILITY OF A DEEP LEARNING BASED CLASSIFICATION MODEL FOR ANCA-ASSOCIATED GLOMERULONEPHRITIS
Authors: Trejo Maria Wester , Sadeghi Maryam , Singh Shivam , Kronbichler Andreas , Hruskova Zdenka , Puéchal Xavier , Goebel Georg , Bajema Ingeborg
Published: June 2023

Background and Aims

The histopathological classification for ANCA-associated glomerulonephritis (ANCA-GN) is a well-established tool to reflect the variety of patterns and severity of lesions that can occur in renal biopsies of patients with ANCA-associated vasculitis. As with many fields, medicine saw a rapid emergence of Artificial Intelligence (AI) and Deep learning (DL) approaches. In the field of digital pathology AI can now serve as decision-support for pathologists, with the potential for gains in productivity and time-saving. It was demonstrated previously that AI can aid in identifying histopathological classes of renal diseases, e.g. of diabetic nephropathy. Although these models reach high prediction accuracies, their black box structure makes them very non-transparent. The disadvantage is that the networks’ decisions are not easily interpretable by humans and it is not clear what information in the input data underlies their decisions. This necessitates the use of Explainable AI (XAI), so that decisions made by AI models become accessible for validation by a human expert.

Method

Renal biopsy slides of 80 patients with ANCA-GN from 3 European centers, who underwent a diagnostic renal biopsy between 1991 and 2011, were included. On the scanned slides glomeruli were labelled as ‘normal’, ‘sclerotic’, ‘crescentic’ or ‘abnormal - other’. We developed a DL-based computational pipeline, which detects and classifies the glomeruli. We investigated the explainability of our model, using XAI techniques to shed light on the decision-making criteria of our trained DL classifier using saliency maps. These maps were analyzed by pathologists to compare the decision-making criteria of humans and the DL model.

Results

Our DL model shows a prediction accuracy of 93% for classifying glomeruli. The saliency maps from our trained DL models help us to better understand the decision-making criteria of the DL black box.

Conclusion

AI and DL play an increasingly important role in (nephro)pathology. To ultimately enable safe implementation of these models in clinical practice, validation of their decisions is needed. To achieve this, we used XAI techniques, which showed great potential for illuminating the decision-making criteria of the DL black box.
#4473 PREVALENCE OF POST-COVID-19 CONDITION IN PATIENTS WITH CHRONIC KIDNEY DISEASE, ON DIALYSIS AND LIVING WITH A KIDNEY TRANSPLANT
Authors: Bouwmans Pim , Malahe Reshwan , Messchendorp Lianne , Vart Priya , Sanders Jan-Stephan , Gansevoort Ronald , De Vries Aiko , Abrahams Alferso C , Bemelman Frederike , Vervoort Hanneke , Hilbrands Luuk , Dam Marc Ten , Dorpel van den René , Reinders Marlies , Hemmelder Marc
Published: June 2023

Background and Aims

The prevalence of post-COVID-19 condition (PCC) is estimated to be 13% in healthy individuals. We analyzed the prevalence and disease burden of PCC in patients with chronic kidney disease (CKD) G4/5, dialysis patients and kidney transplant recipients (KTR).

Method

Patients participated in the RECOVAC study, in which SARS-CoV-2 antibodies were measured in CKD G4/5, dialysis patients and KTR after the second and third COVID-19 vaccination in the Netherlands. A questionnaire was sent to 4868 participants one year after initial vaccination asking for the presence of long-lasting symptoms after diagnosis in COVID-19 positive patients, or since the start of the pandemic in COVID-19 negative patients. PCC was defined according to the WHO clinical case definition. Blood samples at one month after the second and third vaccination were analysed with anti-RBD IgG ELISA. COVID-19 diagnosis was assessed by questionnaire or positive anti-nucleocapsid IgG antibodies. Logistic regression analysis was used to compare the presence of one or more long-lasting symptoms between COVID-19 positive and negative patients. In COVID-19 positive patients, we likewise identified predictors of PCC by backward selection and estimated the association between log-transformed antibody levels and PCC.

Results

2747 patients were included, of which 222 patients with CKD G4/5, 390 dialysis patients and 2135 KTR. PCC was present in 25%, 16%, and 21% of CKD G4/5 patients, dialysis patients and KTR with high or very high symptom burden in 57%, 61% and 71%, respectively. In COVID-19 negative patients, long-lasting symptoms were present in 15%, 13% and 18%, respectively. COVID-19 positive patients (n = 1004) were at higher odds of having one or more long-lasting symptoms compared with COVID-19 negative patients (n = 1743) (OR: 1.33 [1.09–1.61], p = .005). Predictors of PCC were chronic lung disease (adjusted OR 2.04 [1.18#x2013;3.50], p = .01) and hospital/ICU admission (adjusted OR 5.03 [3.22-7.86], p < .001). Log anti-RBD IgG antibody level was negatively associated with PCC (adjusted OR: 0.79 [0.66#x2013;0.94], p = .008).

Conclusion

Patients with CKD G4/5, dialysis patients and KTR are at risk for PCC with a high symptom burden, especially if antibody levels after COVID-19 vaccination are low.
#4478 HIF-1α REGULATED LNCRNA-ATP6V0E2-AS1 MEDIATES HYPOXIA-INDUCED MITOPHAGY IN RENAL TUBULAR CELLS
Authors: LI Chi-Yuan
Published: June 2023

Background and Aims

Mitophagy activation is crucial for hypoxia signaling in acute kidney injury (AKI). Selective removal of damaged mitochondria is mediated through a concerted function of coding and non-coding RNA expressions. Insights on HIF-1α signaling in lncRNA-regulated mitophagy mechanism are not known. The study aims to investigate the role of hypoxia-inducible factor 1α (HIF-1α) regulated long non-coding RNA (lncRNA) ATP6V0E2-AS1 in acute kidney injury (AKI) by examining its effect on mitophagy.

Method

Mitophagy proteins (PINK1, p-PARKIN, LC3) were determined through western blot analysis. Immunofluorescence studies of PINK1 mitochondrial translocation and LC3/TOMM20 localization were determined using confocal analysis. HIF-1α interaction with lncRNA-ATP6V0E2-AS1 through promoter binding activity was evaluated through chromatin immunoprecipitation analysis. RNA interaction between lncRNA-ATP6V0E2-AS1 and PINK1 was analyzed by dual-luciferase reporter assay.

Results

Hypoxia upregulated PINK1, p-PARKIN, LC3 expressions, and mitophagosome in HK-2 cells. Overexpression and knockdown studies of hypoxia-regulated lncRNA-ATP6V0E2-AS1 significantly regulated PINK1/p-PARKIN expressions, subsequent PINK1 mitochondrial co-localization, and mitophagosome formation. shHIF-1α knockdown in HK-2 cells reveals that HIF-1α mediates PINK1/p-PARKIN mitophagy regulation under hypoxic conditions. In detail, HIF-1α binds to the promoter of lncRNA-ATP6V0E2-AS1 and down-regulates its expression under hypoxia. Deficiency of both HIF-1α and lncRNA-ATP6V0E2-AS1 reverted shHIF-1α mediated suppression of PINK1 expression and mitophagosome formation. Further, ATP6V0E2-AS1 post-transcriptionally regulates PINK1 expression by RNA-RNA interaction.

Conclusion

Altogether, our study shows novel findings on the HIF-1α mediated lncRNA-ATP6V0E2-AS1 in hypoxia-induced mitophagy regulation in the renal tubular cells. Thus, downregulated ATP6V0E2-AS1 expression with subsequent mitophagy activation is critical for hypoxia-induced mitophagy regulation through HIF-1α/ATP6V0E2-AS1/PINK1 axis.
#4500 IMPLEMENTATION OF A NEW GENERATION DIGITAL STETHOSCOPE FOR ARTERIOVENOUS FISTULA MONITORING IN HEMODIALYSIS PATIENTS
Authors: Carullo Nazareno , Presta Pierangela , Musolino Michela , Fabiano Giuseppe , Bianco Maria Giovanna , Oliva Giuseppe , Armeni Annarita , Chiarella Salvatore , Andreucci Michele , Fiorillo Antonio , Bolignano Davide , Pullano Salvatore , Coppolino Giuseppe
Published: June 2023

Background and Aims

The management of complications of arteriovenous fistula (AVF) for hemodialysis, principally stenosis, remains a major challenge for clinicians with a substantial impact on health resources. Stenosis not infrequently preludes to thrombotic events with the loss of AVF functionality. A frequent monitoring with physical examination is at the basis for an appropriate clinical care. It includes a regular inspection, palpation and auscultation of the arm. A normally functioning AVF, when listened by a stethoscope, has a continuous systolic-diastolic low-frequency murmur while with stenosis the frequency of the murmur increases and the duration of diastolic component decreases, disappearing in severe stenosis. These evidences are strictly subjective and dependent from operator skill and experience. New generation digital stethoscopes are able to record sound and subsequently dedicated software allows to extract quantitative variables (amplitude and frequency) that characterize the sound in an absolutely objective and repeatable way. The aim of our study was to analyze with an appropriate software listenable sound from AVFs taken by a commercial digital stethoscope and to investigate the potentiality to develop an objective new monitoring system to detect stenosis.

Method

Between September 2022 and January 2023, we screened forty-eight patients from two hemodialysis centers in Catanzaro (Italy). Patients were screened from two blinded experienced examiners for recognized criteria for stenosis by doppler ultrasound (DUS). We recorded the sound coming from the AVFs using a 3M™ Littmann® CORE Digital Stethoscope 8570 (Figure 1-A), in standardized sites: on the anastomosis chamber, at a distance of 5 and 10 cm from it, on the site of stenosis and immediately after. The sound waves were transformed into quantitative variables (amplitude and frequency) using a sound analysis software.

Results

Based on doppler evaluation, 14/48 patients (29%) were classified as stenotic of which three were hemodynamically significant. The sounds detected in the stenosis sites had a significant higher average frequency compared to non-stenotic sites (Figure 1-B). Characteristics of sound waves were significant different for stenotic and non-stenotic patients in term of average power, mean amplitude and mean frequency. Analysis of waves permitted us to determine peculiar shape for stenosis and another for normal AVF (Figure 1-C,D).

Conclusions

The analysis of sound waves by a digital stethoscope permitted us to distinguish between stenotic and no stenotic AVFs. The standardization of this technique and the introducing of data in a deep learning algorithm could allow an objective and fast method for a frequent monitoring of AVF.
#4580 ELEVATED LEVELS OF UREMIC SOLUTES IN THE CEREBROSPINAL FLUID OF HEMODIALYSIS PATIENTS
Authors: Wang Xin , Haq Zahin , Dias Gabriela Ferreira , Debure Ludovic , Wang Lin-Chun , Tao Xia , Thijssen Stephan , Wisniewski Thomas , Kotanko Peter , Grobe Nadja
Published: June 2023

Background and Aims

Uremic solutes are considered as contributing factors to impaired cognitive function in end stage kidney disease (ESKD) [1]. However, the distribution and accumulation of uremic solutes in the central nervous system (CNS) of ESKD patients are not well understood. We measured four uremic solutes in the cerebrospinal fluid (CSF) and plasma of two ESKD patients and investigated the role of routine hemodialysis (HD) in clearing these solutes from their CNS.

Method

We accessed CSF in HD patients with a ventriculo-peritoneal shunt. A review of about 160,000 electronic health records revealed 30 eligible patients, two of whom consented to participate in this IRB-approved one-week study (Western IRB #20172182). On dialysis days, CSF and plasma were collected 2 hours pre- and 2 hours post-HD. Non-dialysis day samples were collected 20 hours post-HD. Samples from healthy subjects were purchased from BioIVT (Westbury, NY). Urea was measured using Horiba C400 Chemical Analyzer. Indoxyl sulfate (IS), p-cresol sulfate (pCS) and trimethylamine N-oxide (TMAO) were analyzed using Agilent Ultivo triple quadrupole mass spectrometer. The dialytic reduction ratio (RR; in %) was calculated as 100 × (pre-HD level – post-HD level) / pre-HD-level.

Results

In both CSF and plasma, levels of all four uremic solutes were elevated in HD patients compared to healthy subjects (Table 1). The ratio of CSF-to-plasma levels was <100% for all solutes. Ratios for HD patients are altered compared to those reported in healthy subjects (Table 1). Longitudinal plasma and CSF solute levels are shown in Figure 1. Plasma RRs for IS, pCS, TMAO and urea were 32%, 23%, 77%, and 67%, respectively. The respective CSF RRs were 29%, 20%, 3%, and 25%.

Conclusion

To the best of our knowledge, this is the first report on CSF levels of IS, pCS, and TMAO in HD patients. Our results indicate that uremic solute levels are elevated in the CSF from HD patients compared to healthy subjects. Moreover, HD only moderately reduces uremic solute levels in CSF. Whether increased CNS levels of uremic solutes are related to cognitive impairment warrants further investigation.