bluuebunny/crossref_metadata_2025 huggingface dataset:
The gMOSS: the galaxy survey and galaxy populations of the large homogeneous field
Authors: Grokhovskaya A , Dodonov S N , Movsessian T A , Kotov S S
Published: May 2022

We present the gMOSS (Galaxies of Medium-band One-meter Schmidt telescope Survey) catalogue of ∼19 000 galaxies in 20 filters (4 broad-band SDSS and 16 medium-band filters). We observed 2.386 deg2 on the central part of the HS47.5-22 field with the 1-m Schmidt telescope of the Byurakan Astrophysical Observatory. The gMOSS is a complete flux-limited sample of galaxies with a threshold magnitude of r SDSS ≤ 22.5 AB. From photometric measurements with 16 medium-band filters and u SDSS, we get spectral energy distributions for each object in the field, which are used for further analysis. Galaxy classification and photometric redshift estimation based on spectral template matching with zebra software. The obtained redshift accuracy is σNMAD < 0.0043. Using the SED-fitting cigale code, we obtained the main properties of the stellar population of galaxies, such as rest-frame (u − r)res colour, stellar mass, extinction, and mass-weighted age with a precision of 0.16 ± 0.07 mag, 0.14 ± 0.04 dex, 0.27 ± 0.1 mag, and 0.08 ± 0.04 dex, respectively. Using a dust-corrected colour–mass diagram, we divided the full sample into populations of red and blue galaxies and considered the dependencies between stellar mass and age. Throughout cosmic time, red sequence galaxies remain older and more massive than blue cloud galaxies. The star formation history of a complete subsample of galaxies selected in the redshift range 0.05 ≤ z ≤ 0.015 with <$\mathrm{log} M \mathrm{\gt }_\mathrm{[M_\odot ]}$>8.3 shows an increase in the SFRD up to z ∼ 3, under the results obtained in earlier studies.
Mass loss of massive helium star supernova progenitors shortly before explosion constrained by supernova radio properties
Authors: Moriya Takashi J , Yoon Sung-Chul
Published: May 2022

Mass loss of massive helium stars is not well understood even though it plays an essential role in determining their remnant neutron-star or black hole masses as well as ejecta mass of Type Ibc supernovae. Radio emission from Type Ibc supernovae is strongly affected by circumstellar matter properties formed by mass loss of their massive helium star progenitors. In this study, we estimate the rise time and peak luminosity distributions of Type Ibc supernovae in radio based on a few massive helium star mass-loss prescriptions and compare them with the observed distribution to constrain the uncertain massive helium star mass-loss rates. We find that massive helium stars in the luminosity range expected for ordinary Type Ibc supernova progenitors (4.6 ≲ log L/L⊙ ≲ 5.2) should generally have large mass-loss rates (≳ 10−6 M⊙ yr−1) in order to account for the observed rise time and peak luminosity distribution. Therefore, mass-loss prescriptions that predict significantly low mass-loss rates for helium stars in this luminosity range is inconsistent with the supernova radio observations. It is also possible that massive helium stars shortly before their explosion generally undergo mass-loss enhancement in a different way from the standard radiation-driven wind mechanism.
OmicsNet 2.0: a web-based platform for multi-omics integration and network visual analytics
Authors: Zhou Guangyan , Pang Zhiqiang , Lu Yao , Ewald Jessica , Xia Jianguo
Published: May 2022

Researchers are increasingly seeking to interpret molecular data within a multi-omics context to gain a more comprehensive picture of their study system. OmicsNet (www.omicsnet.ca) is a web-based tool developed to allow users to easily build, visualize, and analyze multi-omics networks to study rich relationships among lists of ‘omics features of interest. Three major improvements have been introduced in OmicsNet 2.0, which include: (i) enhanced network visual analytics with eleven 2D graph layout options and a novel 3D module layout; (ii) support for three new ‘omics types: single nucleotide polymorphism (SNP) list from genetic variation studies; taxon list from microbiome profiling studies, as well as liquid chromatography–mass spectrometry (LC–MS) peaks from untargeted metabolomics; and (iii) measures to improve research reproducibility by coupling R command history with the release of the companion OmicsNetR package, and generation of persistent links to share interactive network views. We performed a case study using the multi-omics data obtained from a recent large-scale investigation on inflammatory bowel disease (IBD) and demonstrated that OmicsNet was able to quickly create meaningful multi-omics context to facilitate hypothesis generation and mechanistic insights.
WebCSEA: web-based cell-type-specific enrichment analysis of genes
Authors: Dai Yulin , Hu Ruifeng , Liu Andi , Cho Kyung Serk , Manuel Astrid Marilyn , Li Xiaoyang , Dong Xianjun , Jia Peilin , Zhao Zhongming
Published: May 2022

Human complex traits and common diseases show tissue- and cell-type- specificity. Recently, single-cell RNA sequencing (scRNA-seq) technology has successfully depicted cellular heterogeneity in human tissue, providing an unprecedented opportunity to understand the context-specific expression of complex trait-associated genes in human tissue-cell types (TCs). Here, we present the first web-based application to quickly assess the cell-type-specificity of genes, named Web-based Cell-type Specific Enrichment Analysis of Genes (WebCSEA, available at https://bioinfo.uth.edu/webcsea/). Specifically, we curated a total of 111 scRNA-seq panels of human tissues and 1,355 TCs from 61 different general tissues across 11 human organ systems. We adapted our previous decoding tissue-specificity (deTS) algorithm to measure the enrichment for each tissue-cell type (TC). To overcome the potential bias from the number of signature genes between different TCs, we further developed a permutation-based method that accurately estimates the TC-specificity of a given inquiry gene list. WebCSEA also provides an interactive heatmap that displays the cell-type specificity across 1355 human TCs, and other interactive and static visualizations of cell-type specificity by human organ system, developmental stage, and top-ranked tissues and cell types. In short, WebCSEA is a one-click application that provides a comprehensive exploration of the TC-specificity of genes among human major TC map.
MO001: Hydroelectrolytic Disorders During and Beyond the Month of Ramadan
Authors: Dammak Najla , Riguen Mouna , Fendri Baya , Agrebi Ikram , Toumi Salma , Chaker Hanene , Yaich Soumaya , Khawla Kammoun , Ben Hmida Mohamed
Published: May 2022

BACKGROUND AND AIMS

Fasting during Ramadan is religiously obligatory for Muslims, who account for 1.8 billion of the world's population (24%). The lifestyle habits of Muslims significantly change during Ramadan. The objective of this study is to determine the incidence of hospital admissions for electrolyte disturbances comparatively during Ramadan and the month before and to review the risk factors in a Tunisian population specimen.

METHOD

We carried out a retrospective study on the hospitalizations for hydroelectrolytic troubles in the nephrology department during Ramadan, i.e. April 2021 (group 1) and one a month earlier, i.e. March 2021 (group 2).

RESULTS

We have collected 14 patients for group 1 and 9 patients for group 2. The incidence of hospitalizations due to electrolytic disorders amounted to 46.6% for group 1 versus 20.9% for group 2. During Ramadan, the most frequently occurring ionic disorders were hyperkalemia in 71.4% (n = 10), hyponatremia in 21.4% of cases (n = 3) and hypernatremia in 7.1% of cases (n = 1). As compared with group 2, the ionic abnormalities encountered outside the month of youth were hyperkalemia in 66.6% of cases (n = 6), hyponatremia associated with hyperkalemia in 22.2% of cases (n = 2) and hypokalemia in 11.1% of cases (n = 1).

All cases of hyponatremia were of depletion in group 1, hyperkalemia was due to dietary error with chronic renal failure, and hypernatremia was secondary to hydrosodic wasting.

By reviewing the factors predisposing to develop hydrolytic disorders, we find a higher frequency in group 1 of hypertensive patients (78.5%), chronic kidney failure (35.7%), heart failure and diabetes (28% each) compared with group 2, six patients had hypertension (66.6%), three chronic kidney failure patients (33.3%), one diabetic patient (1.1%) and no patient had heart failure.

CONCLUSION

At the end of this study, we note that despite the occurrence of the month of Ramadan in spring and the tempered weather, the incidence of ion disorders remains high in a population at risk. Therefore, a strategy of nutritional and behavioral education during the Ramadan month is recommended, with the necessity of a close biological follow-up. This educational therapy must be individualized and specific for each individual patient, and adaptations of the medication are most required to avoid the development of ion disorders.
MO010: Parameters Associated with Progression, Prognosis and Tolvaptan Indication in Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Authors: Gkika Vasiliki , Louka Michaela , Fokas Stavros , Tigka Eirini , Drakopoulos Angelos , Markou Niki , Doumani Georgia , Kostopoulou Myrto , Tsagkatakis Mihail , Tsirpanlis George
Published: May 2022

BACKGROUND AND AIMS

The identification of possible risk factors for the progression of autosomal dominant polycystic kidney disease (ADPKD) is an emerging field, especially after the introduction of tolvaptan as the first disease-specific treatment. The present study aims to explore the associations between epidemiological, clinical and imaging data in a large cohort of ADPKD patients.

METHOD

This study was from a single outpatient clinic, following patients with ADPKD. Patients were included in the study if they had recently undergone a magnetic resonance imaging for the measurement of total kidney volume (TKV). For all patients, the Mayo Clinic Imagining Category (MCIC) and the prediction of end-stage renal disease (ESRD) (future estimated-glomerular filtration rate [e-GFR] <10 mL/min) based on the Mayo Clinic formula were calculated. Patients eligible for tolvaptan treatment (MCIC 1C, 1D, 1E, age <55 years old and e-GFR ≥25 mL/min) were identified. Characteristics including individual medical history, clinical and laboratory data were examined for possible associations with renal and imaging parameters using multinomial logistic regression and linear regression models.

RESULTS

A total of 250 patients were included. Based on measurements of height-adjusted TKV (ht-TKV) and age, 8.4% of the patients were classified as 1A, 19.6% as 1B, 34% as 1C, 24.8% as 1D and 13.2% as 1E, MCIC. In multivariable analysis, patient's age (P < 0.001), male sex (P < 0.001), parent's age at ESRD (adjusted for patient age) (P < 0.001) and hypertension (P = 0.009) were associated with log (ht-TKV). Parent's age at ESRD differed significantly between the MCICs of the offspring (mean±SD), 65.63 (12.13) in 1A, 61.9 (11.3) in 1B, 55.6 (9.6) in 1C, 51.64 (9.2) in 1D and 49.7 (8.3) in 1E, (P < 0.001). Similarly, there were significant differences in the presence and age of hypertension onset (P =0.0005 and P = 0.0004, respectively). In 157 patients (74 females and 83 males) who were eligible for tolvaptan treatment, the age at ADPKD diagnosis, the age at hypertension onset and the parent's age at ESRD were significantly lower (P < 0.001 for all) when compared to noneligible patients. Finally, factors associated with the prediction score of ESRD were hypertension, uric acid and the age at ESRD of the affected parent (P = 0.038, 0.014 and 0.010, respectively).

CONCLUSION

As a heritability estimator, the age at which an affected parent had reached ESRD was significantly associated with a worse phenotype, prognosis and tolvaptan indication. Hypertension was associated with poor prognosis and an aggravated phenotype, whereas age at diagnosis of the disease and hypertension onset were associated with tolvaptan indication in ADPKD.
MO011: The Use of a 4-Point Scoring Scale in 18F-FDG-PET/CT Imaging Helps for Diagnosis of Renal and Hepatic CYST Infections in Patients with Autosomal Dominant Polycystic Kidney Disease: A Validation Cohort
Authors: Demuynck Selina , Lovinfosse Pierre , Seidel Laurence , Mekahli Djalila , Jouret François , Bammens Bert , Goffin Karolien
Published: May 2022

BACKGROUND AND AIMS

Autosomal dominant polycystic kidney disease (ADPKD) is prone to multiple complications, including cyst infection (CyI). 18F-FDG PET/CT imaging proved useful in the diagnosis of renal and hepatic CyI. A 4-point scale comparing the uptake of 18F-FDG in the suspected infected cyst versus the hepatic physiological background has been proposed. We performed an independent validation of this semi-quantitative score system.

METHOD

All ADPDK patients hospitalized between January 2007 and March 2019 who underwent an 18F-FDG PET/CT for suspected CyI were retrospectively identified using computer-based databases. Medical files were systematically reviewed. CyI was conventionally defined by: fever (>38°C), abdominal pain, increased plasma CRP levels (≥70 mg/dL), absence of any other cause of inflammation and favorable outcomes after ≥21 days of antibiotics. The 18F-FDG uptake around the suspected CyI was evaluated using the 4-point scale. Stats were performed using SAS version 9.4.

RESULTS

Our cohort included 51 18F-FDG PET/CT in 51 patients, including 11 cases of CyI according to the above-detailed definition. The agreement between the 4-point scale and the gold-standard criteria of CyI was significant, with an odds ratio of 6.03 for CyI in case of a score ≥3 (P, 0.014). The corresponding sensitivity and specificity of PET/CT using the 4-point scale were 63.3% and 77.5%, respectively.

CONCLUSION

Our independent validation cohort confirms that the use of a semi-quantitative 4-point scoring system helps in the diagnosis of CyI by 18F-FDG PET/CT imaging in patients with ADPKD.
MO015: The Interaction of Gender and Genotype in the Development of Polycystic Liver Disease in ADPKD
Authors: Cong Eugene Chen Wen , Ong Albert , Gittus Matthew
Published: May 2022

BACKGROUND AND AIMS

Liver cysts are the most common extra-renal manifestation in autosomal dominant polycystic kidney disease (ADPKD) and polycystic liver disease (PLD) may result in significant morbidity in a proportion of patients. The major objective of this study was to investigate the relationship between the incidence of liver cysts and PLD with age, gender and genotype in a longitudinal ADPKD patient cohort (n = 625) followed up between 2010 and 2021.

METHOD

A retrospective analysis of PLD was performed on all patients with available abdominal US (US, n = 565) or abdominal MRI/CT (n = 321) imaging. Liver cyst counts were obtained from routine clinical reports (US) or quantified by a single-blinded observer (MR/CT). Patients were divided into subgroups of different severity based on cyst numbers detected on US (QIAN 0–4) or MRI/CT (CHEN 0–3): QIAN 0 (0), 1 (<10), 2 (10–20), 3/4 (>20); CHEN 0 (0), 1 (<20), 2 (21–40), 3 (>40). Patients who were genotyped (n = 390) were classified into those with PKD1 (T, truncating or NT, non-truncating), PKD2, other genes (non-PKD1 or PKD2) or NMD (no mutation detected). The potential influence of genotype and gender on the incidence of liver cysts and the time to the development of PLD (defined as QIAN 3/4 or CHEN 3) was investigated by survival analysis (Kaplan–Meier plots). Hazard ratios (HR) were calculated and statistical significance was determined via Log-rank (Mantel-Cox) or Chi-square tests.

RESULTS

Liver cysts were detected in 61% of patients by US and 72% by MRI/CT, increasing with age. Kaplan–Meier plots showed a significant effect of gender for the presence of liver cysts (M: F HR of 0.74 US, 0.69 MR/CT). Genotype had a major effect on the prevalence of liver cysts (US, n = 344) with a median age of 46, 53, 59, 75 and 77 years for PKD1-T, PKD1-NT, PKD2, other genes or NMD, respectively. A similar trend was noted for patients with MR/CT imaging. The percentage of patients with PLD (QIAN 3/4 or CHEN 3) ranged between 26% (US) and 36% (MR/CT) with a median age for developing PLD of 51 (US; min-max range 23–80 years) and 50 years (MR/CT; min-max range 27–81 years), respectively. The incidence of PLD was more strongly influenced by gender (M: F HR 0.53 US, 0.56 MR/CT) and was highly enriched in patients with PKD1 or PKD2 mutations.

CONCLUSION

Female patients with a PKD1-T genotype appear to be at the highest risk of developing PLD. Genotypes other than PKD1 or PKD2 are unlikely to develop PLD. Further work is needed to improve risk stratification and treatments for PLD by identifying additional pathogenic factors.
MO029: Urinary biomarkers in the progression of autosomal dominant polycystic kidney disease
Authors: Carolina Santos Ana , Novais Carla , Matos Andreia , Bicho Manuel , Almeida Edgar
Published: May 2022

BACKGROUND AND AIMS

Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disease characterized by the formation and growth of renal cysts, affecting the decrease of renal function, which may lead to end-stage renal disease (ESRD). Due to the enormous intrafamilial phenotypic variability of ADPKD and since serum creatinine and glomerular filtration rate (GFR) have a limited ability to assess the disease and predict its progression at earlier stages, there is a need to find new biomarkers to predict disease progression. The α-glutathione s-transferase (GST-α) and haptoglobin (Hp) are produced mainly by the proximal convoluted tubule, and these enzymes are released into the urinary lumen in direct response to tubular damage.

This study aims to evaluate the urine concentration of α-GST and Hp biomarkers at different stages of ADPKD progression and correlate the levels of urinary biomarkers α-GST and Hp with traditional markers of renal dysfunction.

METHOD

Twenty-five patients with ADPKD, mean age of 41.57 ± 14.43 years, mostly female (56.0%), diagnosed according to the Ravine criteria and with a follow-up of at least 60 months. Demographic, hemodynamic, urinary creatinine (UCr) and serum creatinine (SCr) data were collected in baseline (T0) and at the end of the follow-up period (T1). GFR was determined using the CKD-EPI formula, grouping patients into early stages (CKD1 and CKD2) and advanced stages (CKD3 to CKD5). Biomarkers were determined by the ELISA method and indexed to UCr in T1. In addition, α-GST was determinate in a control sample composed of 17 individuals without diagnosed kidney disease.

Statistical analysis was performed by SPSS version 26 with a significant value of P < 0.05.

RESULTS

Comparing the means of SCr and GFR between T0 and T1 were observed a decrease of renal function during the follow-up period (P = 0.013 and P = .017, respectively). About 14.4% of patients were in an advanced stage of kidney disease in T1, compared with 4.8% in T0.

ADPKD patients had increased values of α-GST in relation to the control group (P < 0.001), but no difference in the SCr was found. We also found a trend for higher levels of HP in advanced stages of CKD (P = 0.071). In ADPKD patients, direct correlations were observed between the variation of SCr during the follow-up with α-GST and Hp (r = 0.606, P = 0.048 and r = 0.738, P = 0.037, respectively). A trend to correlation was found between the levels of Hp and the Scr in T1 (r = P = 0.058).

CONCLUSION

The levels of α-GST and Hp are associated with renal damage and may be helpful in the early identification of the decline in renal function in ADPKD patients.
MO034: Novel MUC1 variant identified by massively parallel sequencing explains interstitial kidney disease in a large Dutch family
Authors: de Haan Amber , Eijgelsheim Mark , Rump Patrick , Van der Zwaag Bert , Zivna Martina , Kmoch Stanislav , Bleyer Anthony , Kidd Kendrah , Van Eerde Albertien M , Knoers Nine , De Borst Martin
Published: May 2022

BACKGROUND AND AIMS

Chronic kidney disease (CKD) can be caused by a wide variety of systemic and renal disorders. In approximately 20% of patients, the cause of CKD remains unknown. Previous studies have shown that massively parallel sequencing (MPS) can be a valuable diagnostic tool in patients with unexplained CKD. Here, we describe a large family with kidney failure of unknown origin, in which we aimed to identify the primary renal disease diagnosis with MPS in a routine healthcare setting.

METHOD

We conducted MPS in a large family in the Netherlands including six generations with documented kidney failure at young age. Affected individuals had a bland sediment and kidney biopsy revealed interstitial fibrosis in several family members. Whole exome sequencing followed by variant filtering and analysis based on the CKD-Y (CKD-young) gene panel (v18.1, 141 genes) was performed by the Genome Diagnostics Section of the University Medical Center Utrecht.

RESULTS

MPS revealed a novel frameshift variant [c.326_350dup, p.(Ser119Profs*119), NM_001 204 286.1] in MUC1, which co-segregated with the renal phenotype in the family. This variant is positioned before the first variable number of tandem repeat (VNTR) domain of MUC1 and leads to a + 1 base frameshift in the open reading frame of the MUC1 mRNA. The predicted C-terminal amino-acid sequence of the resulting mutant protein is the same as the previously reported pathogenic cytosine insertions in the VNTR. Variants in MUC1 are associated with autosomal dominant tubulointerstitial kidney disease (ADTKD), which matches the clinical phenotype in this family. Immunohistochemical analysis in the index patient showed MUC1fs deposition in kidney tissue, confirming the diagnosis of ADTKD-MUC1.

CONCLUSION

We report a novel frameshift mutation in MUC1 identified with MPS. This study highlights that MUC1 variants positioned before the first VNTR region can lead to ADTKD and that genetic testing in patients with suspected ADTKD-MUC1 should also include regions outside of the VNTR. Additionally, this study confirms the relevance of MPS as a tool to screen adult patients with early-onset kidney failure.
MO037: Burosumab in adult patients with X-linked hyphophosphatemic rickets: an Italian Experience
Authors: Edvige Foligno Nadia , Arcidiacono Teresa , Bologna Arianna , Brioni Elena , Del Mastro Teresa , Avino Monica , Vezzoli Giuseppe
Published: May 2022

BACKGROUND AND AIMS

X-linked hypophosphoremic rickets (XLH) is a rare disease caused by mutations in the PHEX gene leading to an increase in the serum levels of FGF23, which inhibits the tubular reabsorption of phosphates and the production of 1,25(OH)2D. These alterations cause hypophosphatemia, rickets, bone deformities, growth retardation and muscle activity impairment.

METHOD

Burosumab (B) is a monoclonal antibody against FGF23, used for the treatment of XLH. In Italy B can be employed in adults only as compassionate use. In 2020, we treated four adult XLH patients with B (1 mg/kg sc every 4 weeks) for 24 weeks. These patients, V.M. (M, 32 years), S.T. (F, 47), E.R. (M, 46) and S.M. (F, 20) had legs deformities, musculoskeletal pain and severe disability.

RESULTS

In all patients, phosphorus levels were normalized by B 2 weeks after the B injection, but its levels decreased during the following 28 days; the effect of B on serum phosphate declined during the 24-week follow-up. Plasma values of 1,25(OH)2D and CTX (C-terminal telopeptide of type I collagen) increased after burosumab, but their increase was less marked after the first two injections. In contrast, PTH and bALP values did not change during B therapy.

Scores of BPI test, chair test and walking test confirmed an improvement in the fatigue resistance and physical performance. Other tests showed the improvement of self-reported well-being and quality of life in all patients. These effects were not observed in adult patients on conventional therapy with phosphate salts and active vitamin D.

CONCLUSION

Therefore, markers of physical conditions and life quality may be more indicative for the necessity of burosumab treatment than serum phosphate, which may not be a significant marker to initiate burosumab treatment in adult patients. Burosumab treatment of XLH patients is well-tolerated and leads to prolonged beneficial effects on general conditions of patients although the inconstant improvement of serum phosphate.
MO045: Kidney involvement in hereditary transthyretin amyloidosis: a cohort study of 103 patients
Authors: Solignac Justine , Delmont Emilien , Fortanier Etienne , Mancini Julien , Attarian Shahram , Daniel Laurent , Ion Ioana , Ricci Jean-Etienne , Robert Thomas , Habib Gilbert , Moranne Olivier , Jourde-Chiche Noemie
Published: May 2022

BACKGROUND AND AIMS

Hereditary transthyretin amyloidosis (ATTR) is a disabling and life-threatening disease that primarily affects the nervous system and heart. Its kidney involvement has been poorly studied and is not well known to nephrologists.

METHOD

We conducted a retrospective study describing kidney phenotype of all prevalent patients with ATTR mutations, with symptomatic amyloidosis or asymptomatic carriers, followed-up in two university hospitals from the South of France, between June 2011 and June 2021.

RESULTS

103 patients were included, among whom 79 were symptomatic and 24 asymptomatic carriers, and 54% carried a V30M mutation. After a mean follow-up of 7.9 ± 25.7 years, 30.4% of the symptomatic patients had developed chronic kidney disease (CKD) and 20.7% had a urinary protein/creatinine ratio ≥0.5 g/g. None of the asymptomatic carriers had CKD or proteinuria. Median CKD-free survival in the global cohort was 81.0 years, and the average age of CKD onset was 69.3 ± 13.0 years. In a multivariate analysis, late onset of ATTR symptoms (after 60 years), the V122I mutation and proteinuria were significantly associated with CKD. In a 38-year-old V30M female, who presented a kidney-predominant phenotype, treatment with Patisiran resulted in remission of the nephrotic syndrome.

CONCLUSION

CKD affects almost one-third of patients with symptomatic ATTR amyloidosis. The role of ATTR amyloidosis per se in the development of CKD in this population remains to be determined, but some patients may benefit from specific therapies.
MO048: Genome-wide studies reveal factors associated with circulating uromodulin and its relations with complex diseases
Authors: LI Yong , Cheng Yurong , Consolato Francesco , Schiano Guglielmo , Chong Michael , Pietzner Maik , Quynh Nguyen Ngoc , Scherer Nora , Biggs Mary , Kleber Marcus E , Haug Stefan , Göçmen Burulça , Pigeyre Marie , Sekula Peggy , Steinbrenner Inga , Schlosser Pascal , Joseph Christina , Brody Jennifer , Grams Morgan , Hayward Caroline , Schultheiß Ulla T , Kraemer Bernhard , Kronenberg Florian , Peters Annette , Seissler Jochen , Steubl Dominik , Then Cornelia , Wuttke Matthias , Maerz Winfried , Eckardt Kai-Uwe , Gieger Christian , Boerwinkle Eric , Psaty Bruce , Coresh Josef , Oefner Peter , Pare Guillaume , Langenberg Claudia , Scherberich Juergen E , Yu Bing , Akilesh Shreeram , Devuyst Olivier , Rampoldi Luca , Köttgen Anna
Published: May 2022

BACKGROUND AND AIMS

UMOD is a major risk gene for monogenic and complex forms of kidney disease. The encoded kidney-specific protein uromodulin is the most abundant protein in urine and related to chronic kidney disease, hypertension and pathogen defense. Through basolateral release from kidney epithelial cells, uromodulin also reaches the blood, where its function is largely unknown. To gain insights into potential systemic roles, we performed genome-wide screens of circulating uromodulin in seven cohorts using two complementary assays.

METHOD

Separate genome-wide association study meta-analyses for circulating uromodulin were conducted for the antibody-based assay (five cohorts, N = 13 985) and the aptamer-based SOMAscan assay (two cohorts, N = 18 070). Genome-wide significant loci were placed into their functional genomic context using RNA-seq, ATAC-seq and Hi-C data generated from primary human kidney tissue. An array of downstream genetic analyses was then performed for significant loci, including fine-mapping, colocalization analyses and gene-by-gene interaction analyses. The B4GALNT2 p.Cys466Arg allele was expressed in MDCK cells and studied by immunofluorescence and Western blotting analyses.

RESULTS

We detected and replicated 13 genome-wide significant loci (P <5e−8; 12 novel). At the UMOD locus, functional genomics data of primary human kidney tissue highlighted an upstream regulatory variant with differential accessibility and UMOD transcription in uromodulin-synthesizing kidney cells. Shared association patterns with complex traits, including chronic kidney disease and blood pressure, placed the PRKAG2 locus in the same context as UMOD. Experimental validation of another locus, B4GALNT2, showed that the detected p.Cys466Arg variant of the encoded N-acetylgalactosaminyltransferase has a loss-of-function effect leading to higher serum uromodulin levels. Lastly, our results point to enzymes writing glycan marks present on uromodulin and to their receptors in the circulation.

CONCLUSION

This study provides human genetic evidence of new pathway members of uromodulin and delivers novel insights into its determinants and systemic role in the circulation.
MO051: Single-Cell Transcriptomics of Lupus Nephritis with ANCA Positive
Authors: Meng Ting , Lin Wei , Ooi Joshua , Eggenhuizen Peter , Zhong Yong , Xiao Xiangcheng
Published: May 2022

BACKGROUND AND AIMS

Lupus nephritis (LN) is one of the most common complications of SLE that can lead to worsened kidney function or renal failure. Antineutrophil cytoplasmic antibodies (ANCA) are autoantibodies that are against antigens in the cytoplasm of neutrophils and monocytes and can lead to an autoimmune disease characterized by vascular necrotizing inflammation. The presence of ANCA in serum can also be found in SLE. Positive ANCA serology in patients with LN is associated with distinct histopathologic features on renal biopsy and seems to affect outcome of LN. Deeper understanding of the molecular pathogenesis in LN with ANCA positive is needed to identify novel targets improve the outcome of LN.

METHOD

Single-cell RNA sequencing (scRNA-seq) was applied to kidney biopsies from one LN patient with PR3-ANCA positive and a healthy adult kidney. We identified distinct cell clusters through unsupervised clustering analysis. Identification of the differentially expressed genes (DEGs) and enrichment analysis as well as the interaction between cells were also performed.

RESULTS

Unsupervised clustering analysis identified 15 distinct cell types including all of the renal intrinsic cells and major immune cells. The DEGs in kidney endothelial cells and intercalated cells were primarily enriched in genes involved in the regulation of inflammation and immune response including IL-17 signaling, TNF signaling, NOD-like receptor signaling and Th17 cell differentiation. Macrophages displayed increased expression of HLA-DRB5, which plays a central role in the immune system by presenting peptides derived from extracellular proteins. TYROBP, a gene plays a role in signal transduction and inflammation, was also high-expressed in macrophages from kidney of LN with PR3-ANCA positive. The receptor-ligand crosstalk analysis highlighted the interactions between endothelial cells and other cells in LN, which infers great importance in LN.

CONCLUSION

We provide a searchable resource of single-cell RNA sequencing to LN with PR3-ANCA positive to uncover intercellular interactions, elucidate key pathways underlying the pathogenesis and offer new insight into therapeutic targets of this unique type of LN.
MO052: New Trend in the Diagnosis of Kidney Disease in Cancer Patients: A Multicenter Study
Authors: Bolufer Mónica , Garcia Carro Clara , Blasco Miquel , Fernando Quintana Porras Luis , Shabaka Amir , Rabasco Cristina , Draibe Juliana , Merino Ribas Ana , Rosa Melero Martin Maria , Alonso Garcia Fabiola , Buxeda Anna , Batalha Paula , Teresa Visus Maria , José Soler Romeo Maria
Published: May 2022

BACKGROUND AND AIMS

The new advances in cancer treatments and the increasing prevalence of kidney disease in the population with cancer have extended the indication of kidney biopsies. The purpose of the study is to analyze clinical and histological characteristics of patients with active solid organ malignancy that underwent kidney biopsy.

METHOD

Multicenter collaborative retrospective registered study supported by two working groups GLOSEN/Onconephrology from the Spanish Society of Nephrology. Clinical, demographical and histological data were collected. Comparison of continuous variables between two groups was performed by Student’s T-test, and Cox survival analysis adjusted for clinical conditions was performed to identify risk factors associated with mortality.

RESULTS

A total of 148 patients with cancer who underwent a kidney biopsy from 12 hospitals were included. About 64.3% men and mean age 66.9 years old. The indications for biopsy were acute renal failure (67.1%), proteinuria (17.1%) and acute on top of chronic kidney disease (8.2%). The most frequent malignancies were lung (29.1%) and abdominal (25%), with 49.7% metastatic cancer. As oncospecific treatment, 28.3% received chemotherapy, 29.9% immunotherapy, 19.3% specific therapies and 2.1% conservative treatment (Figure 1)

At the time of kidney biopsy, median creatinine was 2.58 mg/dL [1.81–4.1(IQ 25–75)], median urine protein/creatinine, 700 mg/g [256–2463 (IQ 25–75)] and 53.1% presented hematuria. The renal biopsy diagnosis most frequent was acute interstitial nephritis (39.9%), followed by acute tubular necrosis (8.8%) and IgA nephropathy (7.4%). Acute interstitial nephritis was more frequent in the period from 2017 to 2021 as compared with the period from 2010 to 2016 (P = 0.001). About 67.1% received corticosteroids and 18.9% required kidney replacement therapy. Median follow-up was 15.2 months [5.7–31.4 (IQ 25–75)]. The only factor associated with mortality was the presence of the metastasis at the time of kidney biopsy (P = 0.006).

CONCLUSION

There is a new trend in kidney disease and patients with cancer in terms of diagnosis and treatment. At present, acute interstitial nephritis has consolidated as the most common kidney pathology in this population. Renal biopsy is valuable tool for diagnosis, treatment and prognosis of solid organ cancer patients with kidney damage.
MO055: Multi-Class Segmentation of Kidney Tissues using Convolutional Neuronal Networks (CNNS)
Authors: Schmitz Jessica , Christensen David , Müller Lena , Neugebohren Lina , Zachrau Tim , Philine Brandt Hannah , Größler Frederik , Johannes Tilman , Gwinner Wilfried , Hinrich Bräsen Jan
Published: May 2022

BACKGROUND AND AIMS

Routine pathological diagnostics in kidneys are mainly based on semi-quantitative eyeballing. In own former studies, we showed predictive value of precise immune cell quantification in allografts using digital semi-automated techniques. We now aim to achieve fully automated segmentation workflow with CNNs.

METHOD

Standard routine stains (immuno/histochemistry, immunofluorescence) were digitized (20×) with Metafer, a commercial scanning/imaging platform. Diagnostically relevant anatomical compartments (cortex, medulla, glomeruli, tubuli [proximal/distal/collecting duct], glomerular/peritubular capillaries and nuclei) were manually annotated by use of immunomarkers to generate large data sets on human renal biopsies and nephrectomies. Data were used to train multi-class semantic segmentation CNNs with broad data augmentation to achieve a robustness against staining variances.

RESULTS

Using Jones-HE stains for multi-class segmentation, a cortex-medulla-extrarenal CNN revealed pixel based hit rates above 97.9%, detection of glomeruli had a pixel based hit rate above 99%, a multi-class CNN for tubules, tubular membranes and peritubular capillaries resulted in a hit rate of 91.5%, and nuclear-based cell detection shows pixel based hit rates above 98%. Identification of cell location in interstitium, tubuli, glomeruli, peritubular and glomerular capillaries reached very high hit rates: Glomerular endothelial cells actually result in 83% true positives, 13% false negatives and 4% false positives. Additionally, a tubulus classifier (proximal tubulus, distal tubulus, collecting duct and atrophic tubulus) with an accuracy >90% was developed.

CONCLUSION

Automated structure segmentation by CNNs can complement and specify classical nephropathological diagnostics, especially for spatial risk marker evaluation in early transplant biopsies.
MO056: Alteration of Glycocalyx on Endothelium of Peritubular Capillaries in CKD
Authors: Ermert Katja , Mara Klinkhammer Barbara , Miriam Buhl Eva , Floege Jürgen , Boor Peter
Published: May 2022

BACKGROUND AND AIMS

The glycocalyx is a carbohydrate-rich gel-like mesh, which covers the luminal surface of cells, including the endothelium. The glycocalyx is involved in many regulatory functions of the endothelium, including vascular permeability. In chronic kidney disease (CKD), peritubular capillaries undergo anatomical, structural and functional alterations such as rarefaction, increased tortuosity and increased permeability. Here, we hypothesized that the glycocalyx of peritubular capillaries might be affected in CKD and investigated morphological and ultrastructural pathological alterations of the glycocalyx in different murine CKD models and human kidney tissue.

METHOD

We stained the glycocalyx of peritubular capillaries in kidney tissue of murine and human CKD specimen using different fluorescently labeled plant-derived lectins. Next, we established the Lanthanum Dysprosium Glycosamino Glycan adhesion (LaDy GAGa) staining technique to visualize the ultrastructure of the glycocalyx using transmission electron microscopy and to perform quantitative analyses. Finally, we analyzed the expression and regulation of glycocalyx components in primary murine endothelial cells.

RESULTS

Fluorescence stainings using different lectins with high affinity to components of the renal glycocalyx revealed a reduced binding to the endothelium in CKD. We found a similar change in a human kidney tissue. The LaDy GAGa staining technique visualized the ultrastructure of the glycocalyx and enabled quantitive analyses. We found a significant reduction of the glycocalyx thickness and density in two different models of renal fibrosis and CKD, i.e. unilateral ureteral obstruction and ischemia–reperfusion injury. Additionally, mRNA expression of proteins involved in glycocalyx biology, synthesis and turnover, i.e. syndecan 1 and glypican 1, which are main components of the glycocalyx, and exostosin 2, involved in the synthesis of the glycocalyx, were significantly upregulated in endothelial cells isolated from murine CKD models.

CONCLUSION

Visualization of glycocalyx using specific ultrastructural analyses allows qualitative and quantitative analyses, revealing significant pathological alterations in the glycocalyx of peritubular capillaries in CKD.
MO068: Paraoxonase 2 Protects the Kidney Tissue from Aldosterone-Promoted Oxidative Stress in Milan Normotensive Rats Strain
Authors: Suzumoto Yoko , Manco Giuseppe , Capasso Giovambattista , Trepiccione Francesco
Published: May 2022

BACKGROUND AND AIMS

Kidney plays a pivotal role on the maintenance of blood pressure by the regulation of sodium reabsorption. Aldosterone sensitive distal nephron finely tunes salt reabsorption through several transporters, including the epithelial sodium channel (ENaC). Alteration in ENaC function leads to clinical relevant conditions associated with high or low blood pressure when gain or loss of function mutations occur, respectively.

Recently, accumulating evidence suggests the putative role of renal Paraoxonase 2 (PON2) as regulator of ENaC function. PON2 is a membrane-associated enzyme showing hydrolytic activity against 3-oxo-C12 homoserine lactone, a signaling molecule produced by bacteria and mainly Pseudomonas aeruginosa. PON2 also exhibits antioxidant property. In the distal nephron, PON2 is expressed in principal cells, and in vitro it physically interacts with ENaC subunits and inhibits ENaC channel activity in Xenopus oocytes likely by modulating channel assembly in the endoplasmic reticulum. However, the role of PON2 in the kidney is still not known.

In the present study, we investigate whether PON2 is regulated by changes in aldosterone state and its role in aldosterone-induced oxidative stress in the kidneys.

METHOD

We addressed these issues utilizing both in vivo and in vitro approaches, such as

RESULTS

We first demonstrated that in Milan normotensive rats strain, PON2 is upregulated by low-salt state according with α-ENaC activation. This regulation is aldosterone sensitive since pretreatment with mineralocorticoid receptor antagonist spironolactone prevented the stimulatory effects of sodium restricted diet. Furthermore, low-sodium diet inducing PON2 upregulation was associated with reduced ROS levels, more specifically superoxide levels, but treatment with spironolactone prevented this beneficial effect, by increasing ROS level in kidney cortex.

Since antihypertensive drugs spironolactone and canrenone contain a lactone residue in their molecular structure, we tested whether they could directly interact with PON2. We demonstrated in vitro that spironolactone and canrenone were able to inhibit PON2 lactonase activity and so to directly interfere with PON2 function. Finally, Milan hypertensive rats, carrying a mutation of α-adducin as determinant of their hypertensive phenotype, presented with higher level of ROS while PON2 was upregulated.

CONCLUSION

These results demonstrate PON2 as a novel target of steroid hormone aldosterone. PON2 may serve as a potential ROS scavenger mechanism protecting the kidneys from aldosterone-promoted oxidative stress.
MO078: Dietary Supplementation with Cysteine During Pregnancy Rescues Maternal Chronic Kidney Disease-Induced Hypertension in Male Rat Offspring: The Impact of Hydrogen Sulphide and Microbiota-Derived Tryptophan Metabolites
Authors: Tain You-Lin , Hsu Chien-Ning
Published: May 2022

BACKGROUND AND AIMS

Maternal chronic kidney disease (CKD) is linked to offspring hypertension. Gut microbiome and its tryptophan metabolites, nitric oxide (NO) and renin–angiotensin system (RAS) are closely related to the development of hypertension. Hydrogen sulphide (H2S) has shown antihypertensive effect. Our objective was to test whether L- or D-cysteine supplementation in pregnancy can prevent hypertension programmed by maternal CKD in adult offspring and explored the protective mechanisms.

METHOD

CKD was induced in pregnant Sprague-Dawley rats by a 0.5% adenine diet for 3 weeks. L- or D-cysteine was supplemented at 8 mmol/kg body weight/day during pregnancy. Male offspring were sacrificed at the age of 12 weeks (n = 8/group).

RESULTS

Maternal CKD-induced hypertension was similarly prevented by L- or D-cysteine supplementation. The protective effects of L- and D-cysteine are related to reducing oxidative stress, rebalancing the RAS and reshaping the gut microbiome. L-cysteine therapy protected adult offspring against hypertension and was associated with enhanced H2S production, restoration of NO bioavailability, enhancement of beneficial genera Oscillibacter and Butyricicoccus, depletion of indole-producing genera Alistipes and Akkermansia and reduction of indole metabolites. D-cysteine treatment increased tryptophan metabolites in the kynurenine pathway, decreased those in the serotonin pathway and enriched the genera Bacteroides and Odoribacter abundance.

CONCLUSION

In summary, these results suggest that L- and D-cysteine protect against maternal CKD-induced offspring hypertension, likely by enhancing H2S production, modulating gut microbiota and its derived metabolites and restorating NO and RAS.
MO097: Idiopathic Hypercalciuria: Calciuria and Citraturia Evolution. A 20-year Longitudinal Study
Authors: Maria Barrera Herrera Aidana , Pérez Suárez Germán , Isabel Luis Yanez Maria , Lopez Martel Debora , Monge Zamorano Margarita , García Cantón César , Manuel Garcia-Nieto Victor
Published: May 2022

BACKGROUND AND AIMS

Reduction and normalization of calciuria in children with idiopathic hypercalciuria (IH) was published by Aladjem et al. (1996). The association between IH and hypocitraturia was described in two Brazilian studies; however, further studies are needed to determinate the caracteristics of its relation.

We studied calcium and citrate urinary excretion in children diagnosed with IH and followed up until adulthood.

METHOD: A total of 34 patients (12 M and 22 F) were studied. IH diagnosis was performed at the age of 7.9 ± 3 years (range: 1–14). Hypercalciuria was defined as urinary calcium excretion of >4 mg/kg/day in two successive samples. Calciuria and citraturia were collected in the first urine sample of the day at the same time as bone densitometry was performed.

Three determinations were made: the first (D1) at age 10.5 ± 2.7 years (range: 6.5–16.8), the second (D2) at age 14.5 ± 2.7 years (range: 9.9–19.5) and the third (D3) at age 28.2 ± 2.8 years (range: 24.1–35.9).

RESULTS: Calcium/creatinine ratio (P = 0.005) and citrate/creatinine ratio (P < 0.001) reduction during follow up was observed. In addition, we observed an increase in the calcium/citrate ratio (P = 0.008). Patients with a calcium/creatinine ratio higher than 0.20 mg/mg decreased from 100% at diagnosis to 52.9% (18/34) on D1 and to 26.5% (9/34) on D2 and 23.5% (8/34) in adulthood (D3). Lithogenetic risk decreased from diagnosis (15/28; 53.6%) to D1 (13/32; 40.6%) and D2 (8/28; 28.6%) but increased in adulthood (21/30; 70%).

CONCLUSION

It is difficult to explain why some IH patients present a decrease in both calcium and citrate excretion in adolescence and early adulthood, which has an impact on lithogenic risk. The interpretation of these results is complex. Bone is the largest reservoir of alkaline salts in the body. Our hypothesis is that late hypocitraturia observed in patients with IH would be an indirect sign of high functional osteoblastic activity. Increased proximal tubular citrate reabsorption would denote an increased bicarbonate production, which is necessary as osteoblastic activity increases, thus requiring increased inputs of alkali, calcium (normalized calciuria) and phosphate. Another option could be the development of incomplete distal renal tubular acidosis.