bluuebunny/crossref_metadata_2025_split huggingface dataset:
#2810 Exploring non-renal vasculature: therapeutic implications of proton pump inhibitor and anthelmintic treatment in PCK rat model
Authors: Heigwer Jana , Clanget Tilmann , Bierhoff Kim , Mayer Tobias , Kraft Patricia , Liu Baoer , Korkmaz-Icöz Sevil , Tabatabaeifar Mansoureh , Schaefer Franz 
Published: May 2024

Abstract

Background and Aims
Cystic kidney diseases represent ciliopathies that can cause vascular damage through renal hypertension. Additionally, there is growing experimental evidence of endothelial cell abnormalities associated with ciliary protein deficiencies. PCK rats, a strain derived from Sprague-Dawley (SD) rats that develops both polycystic kidney disease (PKD) and liver disease, serve as a model for recessive PKD. The PCK rat model also presents abnormalities in non-renal vascular function. Another study from our group suggests a potential therapeutic benefit of repurposed therapy with a proton pump inhibitor (PPi) and an anthelmintic agent in attenuating the progression of PKD in a PCK rat model. Here, we investigated whether these drugs can also improve endothelial function.

Method
The compounds were administered to 3-week-old male and female PCK rats (n = 5-6) for a total of 10 weeks. Untreated PCK rats and age-matched SD rats (n = 5-6) served as controls. After perfusion fixation, the aorta was harvested and its thoracic rings were used to evaluate the contraction/relaxation responses ex vivo by organ bath experiments. Additional rings were preserved for histological and molecular biological analyses.

Results
Male PCK rats exhibited impaired endothelial function compared to healthy controls. Endothelium-dependent relaxation to acetylcholine was improved by 10% after treatment with PPi, while the anthelmintic administration had no protective effect. PKD also impaired endothelial function in female PCK rats compared to healthy SD controls. There was an improvement in endothelium-dependent relaxation to acetylcholine after treatment with PPi by 5.5%, while administration of the anthelmintic agent further impaired endothelial function.

Conclusion
13-week-old PCK rats show endothelial dysfunction in non-renal vasculature. Treatment with a proton pump inhibitor improved endothelial function in male PCK rats to the level of healthy SD controls. By contrast, in a parallel study, the anthelmintic had a positive effect on renal function but a detrimental impact on endothelial function. These intricate relationships underscore the need for further exploration to understand the underlying mechanisms and broader implications of our findings, illustrating the challenges and potential avenues for the development of effective treatments for PKD.
#2068 Factors affecting disease progression in individuals with heterozygous COL4A3/COL4A4 pathogenic variants
Authors: Teran Melissa Pilco , Furlano Monica , Pybus Marc , Jiménez Víctor Martínez , Gomá-Garcés Elena , Carrillo Isabel Galan , Leon Rafael , Romeo Maria Jose Soler , de Arizón Leonor Fayos , Perera Alexandre , Ars Elisabet , Torra Roser 
Published: May 2024

Abstract

Background and Aims
Individuals with heterozygous pathogenic variants in COL4A3/COL4A4 or also known as autosomal dominant Alport syndrome (ADAS) are increasingly diagnosed and show a wide spectrum of disease. Factors contributing to these different outcomes are not well understood. Here we study a cohort of patients with pathogenic (P) or likely pathogenic (LP) variants in COL4A3/COL4A4 with slow and rapid progression to evaluate risk factors associated with the condition.

Method
A retrospective observational multicenter study was performed in a cohort of individuals with heterozygous P and LP in COL4A3/COL4A4. Criteria were established to classify patients into rapid (RP) and slow progression (SP) (Fig. 1). In this study, we compared both cohorts and identified risk factors of rapid progression using T-score for numeric variables or Chi square for categoric variables. For the numerical variables that were correlated with RP, a cut-off point was established fitting the data with a regression curve. Further analyses are ongoing.

Results
A total of 374 patients were studied, the progression of the disease was classified in 135 individuals: 82 with RP (60.7%) and 53 SP (39.3%). The remaining patients couldn't be classified due to age or missing data during follow-up.
The mean age at diagnosis of classified patients was 46.61 years (SD 17.46), with 65% being women.
Genetic variant distribution was COL4A3 38%, COL4A4 58%, and digenic 4%.
At diagnosis, 72% of patients had albuminuria or proteinuria (mean age of diagnosis: 50 years). Among these, 52.7% had ACR or PCR greater than 300 or 500 mg/gCr, with mean ACR at 445.92 mg/gCr (SD 587.54, max 2240 mg/g) and mean PCR at 968.38 (SD 1422, max 10633).
94% individuals had hematuria (mean age at diagnosis: 36.27 years).
Forty-nine patients (36%) had CKD G-5, with a mean age of diagnosis of 53.08 years (SD 12.42). The mean eGFR was 67.56 (SD 30.56 ml/min). Results of kidney biopsy were available for 51 patients. 73 individuals had hypertension (HTN) with a mean age at diagnosis of 46.30 years (SD 13.81).
A total of 82 patients responded to personal habits questionnaire.
With all the variables studied, a total of 4 main variables were associated with RP.

Conclusion
The main variables associated with a worse outcome in individuals with heterozygous pathogenic variants in COL4A3/COL4A4 is the presence of albuminuria/proteinuria, HTN, age at diagnosis of HTN and age at diagnosis of the disease. Smoking has also been associated with a worse outcome when an exposure time over 11.8 years.
More studies are still needed to understand the reasons for the huge phenotypic variability of this condition.
#2662 Octreotide-LAR in ADPKD patients with very low kidney function: a monocentric real-life experience
Authors: Pisani Antonio , De Marco Oriana , Riccio Eleonora , Capuano Ivana , Amicone Maria 
Published: May 2024

Abstract

Background and Aims
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease, characterized by development of fluid-filled renal cysts leading to progressive expansion of kidney volume, with decline in kidney function up to end-stage renal disease (ESRD). Octreotide long-acting release (OCT-LAR) is a synthetic somatostatin analogue, which has been shown to reduce kidney and cysts growth and to slow the progression of kidney function decline in ADPKD patients. Although the evidence of the literature supporting the protective effect of the OCT-LAR against progression of the disease in ADPKD patients with both early and later-stages, to date no data are available in ADPKD patients treated with this somatostatin analogue in a real-world clinical setting. In August 2018 OCT-LAR was approved only in Italy for the treatment of ADPKD adult patients with eGFR ranging from 30 to 15 mL/min/1.73 m2 at elevated risk of progression towards ESRD. The present study is aimed to report for the first time the effects on renal function of OCT-LAR in ADPKD patients with severe renal insufficiency (stage 4 CKD) receiving this somatostatin analogue for therapeutic indication in a real-world clinical setting.

Method
We conducted a retrospective, ADPKD-population-based cohort study using healthcare data from the medical records of patients with ADPKD referred to the Department of Nephrology of University “Federico II” of Naples from November 2018 to April 2023 aimed to analyse within-patient clinical outcomes, including eGFR decline, before and after treatment with OCT-LAR. We include adult ADPKD patients (≥18 years) with GFR (eGFR) between 30 and 15 mL/min/1.73 m2, stably treated from at least 1 years with the regular dose of OCTR-LAR.
The primary endpoint was the assessment of eGFR decline from 1 year before the start of the treatment (T-1) to baseline (T0), and after 1 year of therapy with OCT-LAR (T1) in the overall population and in two subgroups of patients with eGFR ≥ or &lt; 25 ml/min/1.73 m2.

Results
31 ADPKD patients were analysed (18 with eGFR ≥ 25 and 13 with eGFR &lt; 25). Compared to pre-treatment period, eGFR decline significantly slowed during therapy with OCT-LAR in both eGFR groups (Table 1), while no difference was found between eGFR groups. After the first year of observation, 7 patients required dialysis (all with eGFR &lt;25).

Conclusion
This is the first study reporting the effects of OCT-LAR on eGFR of ADPKD patients with advanced chronic kidney disease (CKD) in a real-world clinical setting. Our results suggest that, compared the last year of follow-up pre-treatment, OCT-LAR slows eGFR decline after 1 year.
#2639 Unraveling complement activation profiles on endothelial cells in healthy donors using an ex vivo model
Authors: Duval Anna , Meuleman Marie-Sophie , Grunenwald Anne , Vieira-Martins Paula , Apithy Marie-Joelle , Benotmane Ilies , Martzloff Jonas , Lemonnier Lisa , Chauvet Sophie , Roumenina Lubka , Caillard Sophie , Bacchi Veronique Fremeaux 
Published: May 2024

Abstract

Background and Aims
Complement is involved in numerous kidney diseases. However, functional approaches to properly examine individual's susceptibility to complement dysregulation are limited.

Method
We assessed ex vivo complement activation induced by sera from 38 healthy donors on resting microvascular endothelial cells (HMEC-1) with or without complement dysregulation by an anti-FH monoclonal antibody (OX-24 mAb). Following incubation, immunofluorescence was used to reveal and quantify membrane-bound C3c (evaluating C3b/iC3b) and C5b-9 with a computer-assisted method (H-score). Additionally, complement anaphylatoxins (C3a and C5a) were quantified in cell supernatants by ELISA. Further exploration of ex vivo complement activation profiles were conducted by next generation sequencing of a panel of alternative pathway genes in 32 donors.

Results
Increase in complement deposition on HMEC-1 surface was defined for a H-scoreC3c &gt; 50 and/or a H-scoreC5b-9 &gt; 30. Combined analysis of C3b/iC3b and C5b-9 deposition in 35 donors showed that one donor (2.8%) had an isolated increase in C3b/iC3b deposits, 3 (8.6%) had an isolated increase in C5b-9 deposits and one other (2.8%) had both increased C3b/iC3b and C5b-9 deposition. Genetic analysis of 32/38 donors revealed 3 heterozygous rare or low frequency missense variants in CFH (p.N1050Y and p.R1210C) and CFI (p.A76G) in 3/5 donors (60%) with increased complement deposition.

Conclusion
Our ex vivo model for measuring complement activation allowed the identification of distinct complement activation profiles among healthy donors, revealing genetic susceptibility in 3 donors. This new dynamic and functional model provides an exciting avenue for exploring the mechanisms governing complement dysregulation in various kidney diseases in research.
#2531 Autosomal dominant polycystic kidney disease with cerebrovascular complications in South Africa: clinical characteristics and prognosis
Authors: Kapche Cedric Xavier Mbobnda , Assounga Alain 
Published: May 2024

Abstract

Background and Aims
Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent inherited kidney disease worldwide. It is characterized by inexorable cyst formation in the kidney and extrarenal manifestations, such as liver cysts, colonic diverticula, valve prolapse, and cerebrovascular complications. The latter is associated with high morbidity and mortality and results from a higher prevalence of cerebral aneurysms (12–25%) compared to the general population. we aimed to evaluate the clinical and imaging characteristics and prognosis of patients with ADPKD with cerebrovascular complications.

Method
We reviewed the electronic medical records of patients seen at the nephrology department of the Inkosi Albert Luthuli Central Hospital from 2006 to 2023. We are reporting on 13 patients with ADPKD complicated by intracerebral haemorrhage (ICH), subarachnoid haemorrhage (SAH), non-traumatic subdural hematomas (NTSDH), and unruptured intracranial aneurysms (UIAs). We extracted demographic, clinical, and paraclinical data. We performed bivariate analysis to find associated factors.

Results
Of the 13 patients, 8 were women and 5 men with 6 of African ethnicity, 4 Asians, and 2 Caucasians. The median age at presentation was 52 (31, 72). Vascular risk factors included hypertension (mean SBP150.3 ± 17.25, mean DBP 84.5 ± 12.2), dyslipidaemia, and smoking. Most patients presented with various levels of altered consciousness. Imaging showed 4 NTSDH, 4 ICH, 3 SAH, and 2 unruptured aneurysms. The affected vessels were the left Middle Commutating Artery, the posterior perforating artery, and the anterior choroidal artery. Follow-up duration ranged from 1 to 15 years. The NTSDH reoccurred in 2 patients. Patients with unruptured aneurysms were managed conservatively while the others benefited from a surgery after which 2 died of surgical complications. These 2 patients who died were end-stage kidney disease(ESKD) and presented with a lower Glasgow Coma Scale. In Univariate analysis cerebrovascular haemorrhage was associated significantly with tobacco (P = 0.011), younger age at diagnosis of ADPKD (P = 0.010), and higher systolic BP (P = 0.021) but not ethnicity (P = 0.106).

Conclusion
Patients of African ethnicity were more likely to present with NTSDH and it reoccurred. Overall surgical management led to full recovery except for patients with ESKD and those with lower GCS.
#654 Double-blind randomised controlled trial of nitrate-replete beetroot juice on blood pressure in autosomal dominant polycystic kidney disease
Authors: Rangan Gopi , Sagar Priyanka , Elhindi James , Chau Katrina , Harris David C H , Lee Vincent W , Sud Kamal , Wong Nikki 
Published: May 2024

Abstract

Background and Aims
Hypertension in autosomal dominant polycystic kidney disease is in part mediated by reduced polycystin-regulated nitric oxide synthase activity. In this study, the hypothesis that beetroot juice (BRJ, a rich natural dietary source of nitrate) reduces blood pressure in hypertensive autosomal dominant polycystic kidney disease (ADPKD) patients was evaluated.

Method
Stable hypertensive patients (n = 60) with ADPKD (eGFR &gt; 30 mL/min/1.73 m2) were randomised (1:1) to either nitrate-replete BRJ (400 mg nitrate/day) or nitrate-deplete BRJ for 4 weeks. Patients and investigators were blinded to the allocation. The primary endpoints were changes in systolic and diastolic clinic blood pressure between baseline and at 4 weeks. The secondary endpoints were serum nitrate/nitrite levels, daily home blood pressure and albuminuria.

Results
Serum nitrate/nitrite increased 3.6-fold in the nitrate-replete compared to the nitrate-deplete group (p &lt; 0.01). Both groups had similar baseline characteristics. After 4 weeks, clinic systolic and diastolic blood pressure significantly declined in both nitrate-replete and nitrate-deplete BRJ groups compared to baseline (systolic blood pressure: −5.36 vs. −7.65 mmHg; diastolic blood pressure: −3.55 vs. −2.73 mmHg; P &lt; 0.05). Other secondary endpoints, treatment adherence, discontinuations and adverse effects were similar in both groups.

Conclusion
Increasing serum nitrate with BRJ did not lower blood pressure in hypertensive patients with ADPKD. The blood pressure reduction in both groups could be due to non-nitrate phytonutrients in BRJ and/or placebo-associated effects. These data further emphasise the importance of healthy eating and regular monitoring of blood pressure in patients with ADPKD.
#3010 Characteristics of a Brazilian cohort with primary hyperoxaluria type 1 (PH1), an admixed population with different ethnic origins
Authors: Vaisbich Maria , Naghettini Alessandra , Melo Ana Paula , Molin Christine Zomer Dal , Sylvestre Lucimary C , Requiao Lucio M , Da Rocha Pedro Túlio , Sobral Roberta M L , Michelon Tatiana , Cerqueira Tiago L , Vitorino Vanessa , Heilberg Ita Pfeferman 
Published: May 2024

Abstract

Background and Aims
Primary Hyperoxaluria type 1 (PH1) is caused by biallelic variants in the AGXT gene, leading to alanine:glyoxylate aminotransferase deficiency, hepatic overproduction of oxalate, hyperoxaluria, nephrolithiasis (NL), and/or nephrocalcinosis (NC), often progressing to chronic kidney disease (CKD) with variable phenotypes. Brazilian population is unique due to its diverse ancestry and high admixture rate, which makes this population an interesting group to expand clinical and genetic profile of PH1.

Method
A descriptive study of genetic confirmed PH1 patients from various regions of Brazil, involving demographic, clinical-laboratory, and genetic data.

Results
Twenty-one patients (17 families) were identified; 4 detected by family screening (2 with active disease). Parental consanguinity detected in 4 families (23.5%). Nineteen symptomatic patients (12 males) included. At PH1 diagnosis, 3 patients were on CKD stage 1, 1 on CKD 3 and 15 were on CKD 5. We observed notable clinical heterogeneity, and 3 groups are described according to the age at onset. Table 1 shows data for each group and symptomatic cases. All patients have received pyridoxine since PH1 diagnosis.

Conclusion
In this Brazilian cohort we observed a high percentage of patients diagnosed on CKD 5, detected by recurrence in the renal graft after isolated renal transplantation, and patients achieving CKD 5 after obstructive kidney stones episode. Several factors, including the broad phenotypic spectrum, the lack of awareness among physicians about the disease and the scarcity of diagnostic tools, may explain this delay in diagnosis. Therefore, there is a need to improve information to the Brazilian medical community. The genetic findings are similar to European and North America genetic descriptions and 2 novel variants were identified expanding the AGXT variants profile. However, it is noteworthy, the high percentage of compound heterozygous variants compared with other cohorts worldwide, which may be characteristic of an admixed population.
#1211 IGFBP-5/TGF-β1-mediated cell crosstalk between endothelia and tubular epithelia promotes renal fibrosis
Authors: Wu D I , Wang Shuqiang , Hong Quan 
Published: May 2024

Abstract

Background and Aims
Renal fibrosis is a common pathophysiological characteristic of chronic kidney disease (CKD) for which there is no effective treatment. The mechanism of renal fibrosis is complicated and remains unclear. Our previous study revealed that Insulin-like growth factor binding protein 5 (IGFBP-5) induces glycolytic activation in ECs and ultimately aggravates renal inflammation in diabetic kidney disease (DKD). This study aims to discover the relationship between IGFBP-5 and renal fibrosis.

Method
HK-2 and HUVEC cells were included in this study. UUO and ANN model were obstructed by Wild-type, IGFBP-5−/− and IGFBP-5flox/flox, cre mice. IGFBP-5, TGF-β and fibrosis makers were detected to explore the mechanism of IGFBP-5 in fibrosis.

Results
We found that the serum IGFBP-5 levels were significantly increased in CKD, that IGFBP-5 was dominantly localized in vascular endothelial cells (ECs) of kidney tissue, and that IGFBP-5 deficiency relieved renal fibrosis in CKD model mice. In vitro experiments indicated that IGFBP-5 exacerbated the fibrosis phenotypic alteration of tubular epithelial cells (TECs) by the TGF-β1/p-Smad3 signaling pathway. In turn, TGF-β1 could facilitate the synthesis of IGFBP-5 in ECs. The crosstalk between TECs and ECs mediated by IGFBP-5 and TGF-β1 was confirmed in a coculture system and endothelial-specific IGFBP-5-deficient mice.

Conclusion
Renal fibrosis is exacerbated by TEC-EC cellular crosstalk through the feedback loop consisting of IGFBP-5 and TGF-β1. These findings suggest that IGFBP-5 may be a new pathogenic factor in renal fibrosis and a potential new therapeutic target in CKD.
#1169 Class-specific gene expression profiling of glomerulus of lupus nephritis by spatial transcriptomics
Authors: Joo Kwon Wook , Park Sehoon 
Published: May 2024

Abstract

Background and Aims
Lupus nephritis exhibit various clinical features and subclassifications. Subclassification-specific alteration of transcriptomic profile of lupus nephritis needs additional study which may provide new insights regarding the subclass-specific pathophysiologic mechanism.

Method
Spatial transcriptomic profiling was conducted using GeoMx Digital Spatial Profiler on formalin-fixed paraffin-embedded kidney biopsy specimens obtained from control (n = 7), LN class I to V (n = 24). We also profiled native kidney primary glomerulonephritis (e.g. anti-PLA2R-associated MN) as additional disease control group. Subclass-specific transcriptomic alteration of glomerulus was compared between the subclasses and primary glomerulonephritis cases. Gene Ontology (GO) terms for DEGs were annotated using the ToppGene suite.

Results
We first focused on the glomerular transcriptomic alteration in class IV lupus nephritis, which was the most active form with high degree of proteinuria. We found 104 upregulated DEGs and 166 downregulated DEGs which were specifically different in the class IV lupus nephritis cases but not in other subclasses of the disease. The upregulated GO terms included interleukin 10 receptor activity, T cell activation, leukocyte activation, and vesicle membrane. On the other hand, the downregulated DEGs were mostly annotated with GO terms of double-stranded DNA binding domain. In our analysis regarding class V lupus nephritis, total of 128 DEGs were downregulated in class V LN compared to MN. These genes were also downregulated in class V LN when compared to control samples, while no significant expression differences were observed in other LN classes compared to controls. Eleven of 128 downregulated DEGs were annotated with biological process GO terms related to Golgi vesicle transport. Regarding cellular component GO terms, Golgi apparatus (30/128 DEGs), endoplasmic reticulum (ER) membrane (19/128 DEGs), and ER-Golgi intermediate compartment (6/128 DEGs) were among the annotated GO terms associated with the DEGs. DEGs in annotation included GOLGA3, TMED7, BET1L, and RAB10.

Conclusion
We profiled the class-specific transcriptomic changes in glomerulus of lupus nephritis. Class IV LN was associated upregulation of interleukin 10-mediated inflammatory pathway and downregulation of double stranded-DNA binding domain. The ER-Golgi network and related molecular pathway may be involved in the distinct pathogenesis and clinical features of class V LN. The findings provide novel view of the class-specific pathophysiologic mechanism of lupus nephritis.