bluuebunny/crossref_metadata_2025_split huggingface dataset:
#788 Mitigation of tubular apoptosis and cystogenesis in ADPKD: the impact of TRPM8 through restriction of mitochondrial function
Authors: Jao Tzu-Ming , Huang Jenq-Wen , Tsai Chia-Hui , Hu Liang-Shuan , Hsieh Chi-An 
Published: May 2024

Abstract

Background and Aims
Autosomal dominant polycystic kidney disease (ADPKD), characterized by numerous fluid-filled cysts and a progressive decline in renal function, is a prevalent hereditary kidney disorder. Approximately 70% of individuals affected by ADPKD may develop end-stage renal disease, typically manifesting around the median age of 58 years. Despite its prevalence, effective clinical treatments for ADPKD remain elusive.
Transient receptor potential melastatin member 8 (TRPM8), serving as a sensor for cold temperatures and activated by the cooling agent menthol, orchestrates cellular Ca2+ signaling by facilitating Ca2+ entry into the cytosol. However, the role of TRPM8 in ADPKD remains undefined.

Method
The WT 9-12, an epithelial cell line isolated from the proximal tubule of a patient with ADPKD, was utilized for in vitro experiments. Eight-week-old wild-type (WT), Pkd1 knockdown (pkd1kd), and Trpm8, Pkd1 double mutant (T-/-P) mice were used for experiments. Renal Trpm8 was activated by administration of a 0.5% menthol diet for 7 months in mice. The cyst index was measured by H&E stain and calculated using Image J. Apoptosis was evaluated by TUNEL assay (In Situ Cell Death Detection Kit, TMR red). Protein and mRNA expression of mice kidneys was detected by Western blotting and qRT-PCR, respectively. Blood urea nitrogen (BUN) was measured by HITACHI 7600 analyzer.

Results
The activation of TRPM8 by menthol treatment resulted in an elevation of intracellular Ca2+ levels, subsequently impeding proliferation in WT9-12 cells. Consistently, Trpm8 activation suppressed kidney weight, kidney weight-to-body weight ratio, BUN, fibrosis, and cystogenesis in Pkd1kd mice, while no such effects were observed in WT and T-/-P mice. This suggests a protective role of Trpm8 in ADPKD. Mechanistically, Trpm8 activation mitigated tubular apoptosis in the kidneys of Pkd1kd mice, as evidenced by reduced TUNEL-positive cells and downregulated Bax and cleaved caspase-3, with no such effects observed in WT and T-/-P mice. Intriguingly, the proliferation-associated signaling pathway, ERK, was also suppressed by Trpm8. Proteomic analysis of mice kidneys revealed that Trpm8 regulates mitochondrial dysfunction, EIF2 and Sirtuin signaling pathways. The result was verified in WT9-12 cells showing reduced mitochondrial respiration, particularly impacting oxidative phosphorylation by TRPM8.

Conclusion
Trpm8 inhibits tubular apoptosis and cyst formation through the restriction of mitochondrial function, subsequently retarding ADPKD development in mice. These findings illuminate a novel and promising strategy for intervening in ADPKD.
#2498 PKD2 recurrent haplotype in ADPKD patients
Authors: Corradi Valentina , Caprara Carlotta , Rigato Matteo , Mancini Barbara , Marzano Nenzi , Giuliani Anna , Perbellini Omar , Gastaldon Fiorella , Ronco Claudio , Zanella Monica 
Published: May 2024

Abstract

Background and Aims
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic renal ciliopathy characterized by progressive renal cyst expansion and extrarenal manifestations following loss-of-function mutations. ADPKD is primarily caused by PKD1 (72-75%) and PKD2 (15-18%), with a high level of allelic heterogeneity: it is rare to identify the same germ-line mutation in different families since mutations are “private”. In recent years the identification of several new genes has underlined the genetic heterogeneity of ADPKD.
The Aim of this study is to describe a cohort of PKD2 gene-linked families with the same germ-line mutation.

Method
Patients (pts) with ADPKD referral to the Genetic Kidney Diseases clinic of the UOC of Nephrology of ULSS8 Berica (San Bortolo Hospital in Vicenza) were enrolled and followed prospectively. Diagnosis of ADPKD was made upon the revised Ravine's criteria. Complete clinical details were recorded, including family history and pedigree. We performed NGS with Sophia Genetic “Nephropathies Solution” Panel or Sanger sequencing to identify disease-causing mutations in the cohort. Furthermore, microsatellite analysis was performed in PKD2 gene pts with same germ-line nonsense mutation c.2533C&gt;T (p.Arg845Ter), to identify disease haplotype.

Results
We identified a cohort of 30 ADPKD pts belonging to 13 families with same PKD2 germ-line nonsense mutation c.2533C&gt;T (p.Arg845Ter). Regarding pedigree analysis, 8 families had their origin from the same geographical area and the remaining 5 were from an area 100 km away. In 4 families, we found a common individual. Concerning the microsatellite analysis, all 30 pts shared the same haplotype Chromosome 4 CEN – VG2 (TG)20, VG3 (TA + GA)32, VG4 (CA)13, D4S2929 (AC)26, D4S1563 (TG)20 – TEL indicating that those families may originate from a common ancestor.

Conclusion
We found the same PKD2 germline mutation in 30 ADPKD pts belonging to 13 families that share the same haplotype. Since, ADPKD mutations are “private” and Vicenza province counts almost 860000 inhabitants, our findings provide an evidence that a founder effect exists, maybe due to a founder effect in our region.
#2556 Therapeutic monitoring in patients with APRT deficiency using UPLC-MS/MS-based plasma assay
Authors: Thorsteinsdottir Unnur Arna , Runolfsdottir Hrafnhildur , Eiriksson Finnur , Edvardsson Vidar Örn , Pálsson Runólfur , Thorsteinsdottir Margret 
Published: May 2024

Abstract

Background and Aims
Adenine phosphoribosyltransferase (APRT) deficiency is a rare disorder of purine metabolism, characterized by urinary excretion of the poorly soluble 2,8-dihydroxyadenine (DHA), leading to nephrolithiasis and chronic kidney disease (CKD). Treatment with xanthine oxidoreductase (XOR) inhibitor, allopurinol or febuxostat, reduces DHA excretion and slows or halts CKD progression. The aim of the study was to optimize and validate an ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS)-based assay for simultaneous quantification of DHA, adenine, allopurinol, oxypurinol and febuxostat in human plasma, for monitoring of pharmacotherapy in patients with APRT deficiency.

Method
The UPLC-MS/MS-based assay was optimized employing the chemometric approach design of experiments, using the software Modde Pro 13 (Sartorius, Umeå, Sweden). The assay was validated and used for absolute quantification of DHA, adenine, allopurinol, oxypurinol and febuxostat in plasma samples from both untreated and treated APRTd patients and healthy controls.

Results
Accuracy and precision were within ±15% for all analytes, and the analytes were stable in plasma for 12 months at −80°C. The median (range) concentration of DHA in plasma samples from six APRT deficiency patients was 204.0 (187.2–315.8) ng/mL when they were untreated and 69.2 (below the limit of quantification [BLQ]–131.6) ng/mL when treated with allopurinol (400 mg/day), and BLQ when febuxostat (80 mg/day) was the therapeutic agent. The median (range) plasma adenine concentration was 238.1 (218–502) ng/mL in the untreated patients, and 561.1 (418–2104) and 856.0 (726–1711) ng/mL in those on treatment with allopurinol and febuxostat, respectively. DHA was not detected in plasma samples from healthy controls. The median (range) plasma concentration of allopurinol, oxypurinol and febuxostat in patients receiving XOR inhibitor therapy was 1657 (BLQ-3266) ng/mL, 8102 (4778–34906) ng/mL and 109 (BLQ-1657) ng/mL, respectively.

Conclusion
The UPLC-MS/MS-based assay provides accurate and precise quantification of DHA, adenine, allopurinol, oxypurinol and febuxostat in human plasma. Measurement of plasma DHA is being implemented as a diagnostic test for APRT deficiency and the full assay for monitoring of XOR inhibitor treatment in patients with the disorder.
#2406 Echocardiographic characteristics of autosomal dominant polycystic kidney disease
Authors: Koska-Ścigała Agata , Jankowska Magdalena , Jankowska Hanna , Dudziak Maria , Hellmann Marcin , Dębska-Ślizień Alicja 
Published: May 2024

Abstract

Background and Aims
Cardiovascular complications in patients with autosomal dominant polycystic kidney disease (ADPKD) are one of the most frequently investigated extrarenal manifestations. The results are many times contradictory. This is caused by a limited size of studied populations and high inter- and intrafamilial heterogeneity of ADPKD. Expanding knowledge of populations of patients from different regions and cohorts is crucial for improving the understanding and treatment of cardiovascular morbidity and mortality. This study aims to explore the prevalence of cardiovascular abnormalities in echocardiography and to analyze their relationships with clinical characteristics across different stages of CKD progression in patients with ADPKD.

Method
Sixty-eight patients were included in the study. All patients underwent transthoracic echocardiography with the use of GE Vingmed Ultrasound (GE Norway Health Tech, Oslo, Norway). Information about demography, prior medical history and taking antihypertension drugs was recorded. The results of creatinine, lipids and haemoglobin were collected. To diagnose the rapid progression of CKD, creatinine was sampled twice, in a one-year interval.

Results
Using different indicators of left ventricular hypertrophy (LVH), we found it in above 40% of ADPKD patients. A single associate of left ventricular mass was eGFR decline after one year of observation. Other highly prevalent findings were asymptomatic left ventricular diastolic dysfunction (ALVDD) (39%), left atrium (LA) enlargement (39%) and mild valvular regurgitations (80%). Ejection fraction, aortic root dimension, tricuspid annular plane systolic excursion (TAPSE) and prevalence of mitral valve prolapse were not importantly increased. Apart from age, the strong determinant of ALVDD diagnosis was the treatment with beta-blockers. Cardiac indices were not different across the eGFR stages.

Conclusion
LVH, LA enlargement, ALVDD and valvular regurgitations are characteristics of cardiac phenotype in ADPKD. Cardiac indices were not different across different stages of CKD pointing towards the diagnosis of ADPKD being main drive of their occurrence.
#1607 Prevalence and risk factors of aortic root dilatation in children with X-linked Alport syndrome
Authors: Aksenova Marina , Tutelman Konstantin , Anykalchuk Lilia 
Published: May 2024

Abstract

Background and Aims
Aortic dilatation in X-linked Alport syndrome (XLAS) is considered a specific manifestation. On the other hand, all patients with CKD have been shown to have an increased risk of aortopathies. The aim was to define prevalence and risk factors for aortic dilatation in children with XLAS.

Method
Retrospective cross-section single center study included XLAS’ children (n = 98,64 M) and patients with CACUT (comparison group, n = 26,12 M). The aorta was measured at level of the sinus of Valsalva (SoV), aortic dilatation was determined by z-score &gt;2 for BSA. Body mass index (BMI, kg/m2), z-scores of mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP), mean blood pressure (MBP), proteinuria (Pr, mg/m2/day), eGFR (ml/min/1.73 m2), z-scores of left ventricular mass index (LVMI), left ventricular end diastolic diameter (LVEDD), relative wall thickness of the left ventricle (RWT, N &lt; 0,42) data were obtained.

Results
There were no difference in age (11,12 ± 3,75 vs 10,87 ± 2,34 yrs; p = 0,78), gender (males 0,55 vs 0,46; p = 0,45), BMI (18,7 ± 3,7 vs 19,1 ± 4,7; p = 0,78), eGFR (103,1 ± 16,9 vs 90,5 ± 11,4; p = 0,50), prevalence of hypertension (0,11 vs 0,19; p = 0,21) between the groups. The prevalence of SoV dilatation did not differ between XLAS and CACUT (0,06 vs 0,08; p&gt;0,18). SoV dilatation was associated with male gender (β1 = 0,31, p = 0,02; β2 = 0,34, p = 0,02), LVMI (β1 = 0,26, p = 0,02; β2 = 0,24, p = 0,02) in both groups, with BMI (β1 = -0,27, p = 0,03), LVEDD (β1 = 0,21, p = 0,04) in children with XLAS. No statistically significant effect of SBP, DBP, MBP, Pr, eGFR on SoV dilatation has been demonstrated.

Conclusion
The prevalence of SoV dilatation in children with XLAS was higher than in general population, but comparable to children with CACUT. The male gender, low BMI, LVMI and LVEDD were associated with SoV dilatation in XLAS. We did not show the relationship between blood pressure load, proteinuria, eGFR and SoV dilatation in XLAS.
#1236 Translation reprogramming in autosomal dominant polycystic kidney disease
Authors: Leemans Charlotte , El Hachem Najla , Mekahli Djalila , Decuypere Jean-Paul , Rapino Francesca , Jouret François , Close Pierre 
Published: May 2024

Abstract

Background and Aims
Global regulation of mRNA translation has emerged as a central mechanism driving cellular adaptation to innate or acquired metabolic challenges. tRNA modifications are emerging as key drivers in the reprogramming of mRNA translation. Metabolic dysregulation is a central feature in the pathophysiology of PKD1-associated autosomal dominant polycystic kidney disease (ADPKD). Here, we aim at investigating the putative role of mRNA translation regulation in the development of cysts in ADPKD.

Method
The classical murine Inner Medullary Collecting Duct (IMCD) cells knocked out for Pkd1 by CRISPR-Cas9 were used. We combined proteomics and transcriptomics analyses of wild-type versus Pkd1-KO IMCD cells. A series of bioinformatic tools was used to identify pathways and processes dysregulated at the level of mRNA translation. Moreover, global mRNA translation rates were assessed in Pkd1-KO cells by measuring translating ribosomes and nascent protein synthesis by flow cytometry labelling methods. Finally, systematic analyses of tRNA regulation (sequencing and modification) were performed in Pkd1-KO cells.

Results
The proposed combination of analyses highlighted pathways differentially regulated in Pkd1-KO cells. We focused on pathways and proteins significantly upregulated in Pkd1-KO as compared to controls cells. On top of expected up-regulated pathways, we also uncovered a series of specific cellular and molecular pathways that are specifically and significantly upregulated in Pkd1-KO cells, including intracellular vesicular metabolism and ciliary transport. Interestingly, the pathway “tRNA modification” was significantly enriched in Pkd1-KO cells. Given the role of tRNA modifications in translation reprogramming during cell adaptation, we further validated that several enzymes known to regulate tRNA modification were differentially expressed in Pkd1-KO cells. In order to investigate the changes in tRNA modifications taking place in Pkd1-KO cells, we performed an unbiased analysis of tRNA modifications (LC-MS). This uncovered reproducible differences in the abundance of specific tRNA modifications between control and Pkd1-KO IMCD cells.

Conclusion
Our data uncovered different patterns of tRNA modifications between Pkd1-KO versus wild-type IMCD cells. This suggests that a specific tRNA-modification-dependent reprogramming of mRNA translation may occur in ADPKD. These data will be further validated using patient derived ADPKD cyst models.
#2633 Navigating complexity: a case report of chronic kidney disease with renal stone unravelling a rare metabolic disorder
Authors: Green Darren , Eltahan Alshymaa , Lewis David , Rana Seema 
Published: May 2024

Abstract

Clinical Presentation
A 48-year-old female of Asian heritage was referred for renal assessment after experiencing recurrent acute kidney injury (AKI) with incomplete recovery between episodes. This was initially attributed to dehydration and interstitial nephritis stemming from long-standing vomiting, a manifestation of gastroscopy-proven erosive gastritis, compounded by the use of high-dose proton pump inhibitors (PPI). Her relevant medical history is of right nephrectomy in 1996 due to recurrent urinary tract infections (UTIs), and previous left renal calculus in 2019 with no visible stones on further CT imaging. Despite living with a single kidney, her baseline eGFR had been normal prior to referral. While unaware of her mother's medical history, her father was recently diagnosed with kidney disease (no clear history) and her sister Wilson's disease.
A kidney biopsy was undertaken given the incomplete eGFR recovery between episodes. The biopsy revealed adequate tissue including 24 glomeruli, no significant glomerular pathology was seen. There is 65% tubulointerstitial atrophy and fibrosis, and yellow to red-brown-tinged crystals within tubular lumina and epithelial cells, prompting a histiocytic reaction. These crystals were birefringent under polarized light and did not stain with Perl's and Von Kossa stain (Fig. 1a-d). Immunofluorescence was negative for all immunoglobulins and complement fractions. No immune complex/substructure deposits were seen in the glomeruli on electron microscopy.
Blood tests assessing APRT activity indicated values within the carrier range (Table 1). The patient and her family have been referred for a comprehensive genetic testing for APRT genetic mutations.
Treatment with Allopurinol 300 mg daily resulted in a sustained eGFR improvement from 19 to 33 ml/min/1.73m2 at 6 months after initiation (Fig. 1).

Discussion
Adenine phosphoribosyl transferase (APRT) deficiency, also known as Dihydroxyadenineuria, is a rare autosomal recessive inherited condition leading to kidney stones. If left untreated, up to 25% progress to end-stage kidney disease (ESKD). Although inherited, half of patient present in adulthood and may do so with laboratory findings of CKD rather than specifically with stones [1].
This case highlights the significance of precise diagnosis in calculi-related kidney diseases. Early intervention can alter the trajectory of specific conditions, averting progression to ESKD. This case is unusual in being a carrier of an autosomal recessive condition presenting with full manifestations of the disease.

Patient Consent
The patient has given verbal, documented consent for case publication.

Acknowledgment
We thank all renal and pathology staff members at Salford Care Organisation who contributed to the diagnosis and management of our case.
#2258 Hypochloremia and inflammation in a cohort of patients undergoing cardiac catheterization: a disturbing association
Authors: Monzon Tania , Amado Ernesto Francisco Valga , Santana Ana Yurena Sánchez , Aladro Sara , Galvan Mario , Perez Patricia 
Published: May 2024

Abstract

Background and Aims
Serum chloride is an emerging marker of mortality in patients with hypertension, heart failure, sepsis, and chronic kidney disease. The causes of this finding are still unknown, although it is suggested that both haemodynamic and inflammatory factors may play a role. On the other hand, Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been found to be associated with increased inflammation in various cohorts.

Method
Retrospective cohort study. We analysed data from 558 patients who underwent cardiac catheterization at our hospital between June and October 2022. Baseline, pre- and post-procedural analytical data, as well as concomitant treatment were obtained (Table 1).

Results
The mean age was 65.89 years. Women accounted for 31.2%. 40.9% had diabetes, 71.9% had hypertension, and 21.9% had ischaemic heart disease. Pre-procedural serum creatinine (Crs) was 1.08 mg/dl (±0.44). Patients with pre-procedural hypochloremia (defined as serum chloride levels less than 98 mEq/L) had higher NLR (5.89 vs 3.6) (p = 0.002) and PLR (139.44 vs 132.08) (p = 0.009). This relationship was maintained in the post procedure analysis. (Table 1 and Fig. 1).

Conclusion
In our sample, the presence of hypochloremia (serum chloride levels below 98 mEq/L) was associated with higher NLR and PLR levels both pre and post cardiac catheterization.
#2809 Peroxiredoxins, the potential predictor of eGFR decline in patients with IgA nephropathy
Authors: Krata Natalia , Tanska Julia , Moszczuk Barbara , Knioła Emilia , Monticolo Marta , Foroncewicz Bartosz , Mucha Krzysztof 
Published: May 2024

Abstract

Background and Aims
Multiple factors may contribute to development and progression of glomerulopathies (GN), one of them is oxidative stress (OS). 2-cysteine-peroxiredoxins (PRDXs) possess the ability to reduce excessive levels of OS mediators and are crucial for cellular OS regulation. In our pilot study, we found that PRDXs 1-5 are differentially changed in patients with IgA nephropathy (IgAN), lupus nephritis (LN) and membranous nephropathy (MN). Thus, the aim of the current study was to evaluate if PRDXs 1-5 may be a prognostic marker for these 3 types of GN.

Method
We followed-up (5-year observation) 80 previously recruited patients with: IgAN (n = 36); MN (n = 23) and LN (n = 21). Patients were classified, based on the eGFR change (decline vs. stable and/or increase) and baseline PRDXs 1-5 levels (Table 1). The Mann Whitney-U, Kruskal-Wallis Test and Pearsons’ correlation were used for statistical analysis, the p-values &lt;0.05 were considered significant.

Results
Baseline measurements indicated that the mean serum PRDXs 1-5 concentrations differ between the GN types. During the follow-up, we observed the significant association of eGFR decline with low baseline PRDX-2 level (p = 0.049) in patients with IgAN (Fig. 1).

Conclusion
We suggest the possible link between peroxiredoxins and deterioration of kidney function, particularly in IgAN patients.
#752 Ponatinib exacerbates renal damage in MRL/lpr lupus model mice through the lipid metabolism pathway
Authors: Li Xuemei , Wang Gangan 
Published: May 2024

Abstract

Background and Aims
The role of tyrosine kinase inhibitors (TKIs) in lupus nephritis is controversial. Ponatinib is a third-generation tyrosine kinase inhibitor that targets multiple receptors. This study aims to explore the effect of ponatinib in lupus nephritis, with the hope of providing insights for the clinical application of ponatinib.

Method
At 8 weeks of age, mice were randomly divided into four groups. One group received no treatment, while the other three groups were respectively administered Ponatinib, prednisolone acetate, and a combination of Ponatinib and prednisolone acetate. The treatment was concluded when the mice reached 16 weeks of age. ELISA was employed to measure the levels of anti-dsDNA IgG, ANA, and C3 in mouse serum. DEGs and DELs were identified using the DESeq2 package in R. Pathway and gene ontology enrichment analyses were performed using the MetaCore database.

Results
Compared to the negative control, those mice receiving ponatinib showed a significant increase in the urinary protein/creatinine ratio (P &lt; 0.01), along with notable elevations in blood creatinine and blood urea nitrogen. Pathological examination of kidney tissue suggested predominant acute lesions, including transparent thrombi, cellulose-like necrosis, cellular/fibrous crescents, and interstitial inflammation. Interestingly, serum testing in MRL/lpr mice revealed no significant differences in lupus activity-related indicators, including autoantibodies ANA, double-stranded DNA, and complement C3, between the negative control group and the ponatinib group. Furthermore, it was discovered that the kidney damage caused by ponatinib in MRL/lpr mice could be reversed by prednisone. RNA-Seq of kidney tissue from MRL/lpr mice showed a total of 44 differentially expressed genes when comparing the negative control with mice receiving ponatinib, including 23 upregulated and 21 downregulated genes. Pathway analysis revealed that the top four pathways were all related to lipid metabolism.

Conclusion
Ponatinib significantly exacerbated kidney damage in MRL/lpr mice and did not induce changes in lupus activity.