bluuebunny/crossref_metadata_2025 huggingface dataset:
#2394 Inhibition of ACSS2-mediated H3K9 crotonylation alleviates kidney fibrosis via IL-1β-dependent macrophage activation and tubular cell senescence
Authors: LI Lingzhi , Xiang Ting , Fu Ping , MA Liang
Published: May 2024

Background and Aims

Histone lysine crotonylation (Kcr), a novel posttranslational modification, is widespread as acetylation (Kac); however, its roles are largely unknown in kidney fibrosis.

Method

Human renal tissue, fixed in formaldehyde, and embedded in paraffin, was selected from the files of the Service of Pathology of West China Hospital, Sichuan University.ACSS2 knockout mice and tubular specific knock out of ACSS2 mice in C57BL/6N background and wild-type littermates (WT) were used to induce the FAN and UUO model or as control groups (n = 6 each). In the parallel study, C57BL/6N mice were randomly divided into three groups: control, FAN/UUO and FAN/UUO+ACSS2 inhibitor (n = 6 each). At day 7, mice were sacrificed and the serum creatinine, BUN and urinary albumin/creatinine ratio (ACR) were tested. Renal histological injury was measured by HE and Masson's trichrome staining. SA-β-gal staining was used to check cellular senescence. Renal tissues of the mice were analyzed by western blot and qPCR assay for the expression of ACSS2, H3K9cr, fibrosis and cellular senescence related proteins and genes. RNA-sequencing and ChIP-sequencing combined with in vitro cell experiments were used to figure out the underlying mechanism.

Results

In this study, we reported that histone Kcr of tubular epithelial cells was abnormally elevated in fibrotic kidneys. By screening these crotonylated/acetylated factors, a crotonyl-CoA-producing enzyme ACSS2 (acyl-CoA synthetase short chain family member 2) was found to remarkably increase histone 3 lysine 9 crotonylation (H3K9cr) level without influencing H3K9ac in kidneys and tubular epithelial cells. The integrated analysis of ChIP-seq and RNA-seq of fibrotic kidneys revealed that the hub proinflammatory cytokine IL-1β, which is regulated by H3K9cr, play crucial roles in fibrogenesis. Furthermore, genetic and pharmacologic inhibition of ACSS2 both suppressed H3K9cr-mediated IL-1β expression, which thereby alleviated IL-1β-dependent macrophage activation and tubular cell senescence to delay renal fibrosis.

Conclusion

Collectively, our findings uncover that H3K9cr exerts a critical, previously unrecognized role in kidney fibrosis, where ACSS2 represents an attractive drug target to slow fibrotic kidney disease progression.
#2222 Suppression of miR-199a-3p ameliorates TGF-β-induced EMT in renal tubular cells
Authors: Garmaa Gantsetseg , Manzéger Anna , Kökény Gábor
Published: May 2024

Background and Aims

Various kidney conditions, such as acute kidney injury and fibrosis, cause dysregulation of miRNAs. TGF-β is one of the most potent inducer of epithelial-to-mesenchymal transition (EMT) and fibrosis. We recently reported increased miR-199 expression in TGF-β-induced kidney fibrosis mouse model (doi: 10.3390/ijms242115520). However, the exact role of miR-199 in fibrosis and EMT development is still unknown.

Method

Primary tubular cells were isolated from a 4-week-old C57BL6 mouse and kept in DMEM/F12 medium containing 2% serum, supplemented with insulin/transferrin/selenium. Cells were treated for 24 hours with 30 nM miR-199-3p miRNA inhibitor (anti-miR), with or without TGF-β (10 ng/ml). The expression of profibrotic genes, as well as miR-199a-3p, was assessed by qPCR. Western blot was used to evaluate the protein expression. Results are presented as mean fold expression relative to calibrator. Statistical significance was assessed using the Kruskal-Wallis test, and the level of significance was set to p < 0.05.

Results

The miR-199a-3p expression in the anti-miR transfected control and TGF-β groups decreased by 93.5% and 85.5%, respectively, as compared to non-transfected groups (p < 0.05). Morphologically, cells transfected with miR-199a-3p and TGF-β1 showed no difference from cells exposed to only TGF-β1 but appeared more elongated compared to the control groups. However, the suppression of miR-199a-3p alleviated TGF-β1-induced fibrotic cell responses as shown by downregulated fibronectin mRNA (Fn1) and protein expression by 30.2% (p < 0.05) and by 4.3%, respectively. This was accompanied by reduced Acta2 (α-SMA) and Tgfb1 mRNA expressions by 30.2% and 17.5%, respectively (p < 0.05).

Conclusion

Our findings suggest that in murine renal tubular epithelial cells, miR-199a-3p suppresses TGF-β1-induced EMT by inhibiting FN1, Acta2, and Tgfb1 both at mRNA and protein levels. Further studies are needed to elucidate the underlying molecular interactions.
#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

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

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

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 < 25 ml/min/1.73 m2.

Results

31 ADPKD patients were analysed (18 with eGFR ≥ 25 and 13 with eGFR < 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 <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

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 > 50 and/or a H-scoreC5b-9 > 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

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

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 > 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 < 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 < 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

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

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

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.
#1777 Proteomic profiling of laser capture microdissection kidneys from diabetic nephropathy patients
Authors: Yang Ziqian , Liu Fanna , Tang Donge
Published: May 2024

Background and Aims

Diabetes nephropathy (DN) remains the primary cause of end-stage renal disease (ESRD), warranting equal attention and separate analysis of glomerular, tubular, and interstitial lesions in its diagnosis and intervention. This study aims to identify the specific proteomics characteristics of DN, and assess changes in the biological processes associated with DN.

Method

5 patients with DN and 5 healthy kidney transplant donor control individuals were selected for analysis. The proteomic characteristics of glomeruli, renal tubules, and renal interstitial tissue obtained through laser capture microscopy (LCM) were studied using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS).

Results

The expression of multiple heat shock proteins, tubulin, and heterogeneous ribonucleoprotein particle in glomeruli and tubules was significantly reduced. Differentially expressed proteins (DEPs) in the glomerulus showed significant enrichment in pathways related to cell junctions and cell movement, including the regulation of actin cytoskeleton and tight junction. DEPs in renal tubules were significantly enriched in glucose metabolism-related pathways, such as glucose metabolism, glycolysis/gluconeogenesis, and the citric acid cycle. Moreover, the glycolysis/gluconeogenesis pathway was a co-enrichment pathway in both DN glomeruli and tubules. Notably, ACTB emerged as the most crucial protein in the PPI analysis of DEPs in both glomeruli and renal tubules.

Conclusion

By using LCM and the proteomics analysis, we provide insights into the distinctive characteristics of each sub-region of renal tissue, shedding light on the impact of glycolysis metabolic disorder in DN and the potential role of the glomerular cytoskeleton and cell junction.
#400 A new notable compression source of left renal vein entrapment: the Right Renal Artery
Authors: Du Xuanyi , Sun Zhanfeng , Wang Haitao
Published: May 2024

Background and Aims

Clinically, left renal vein (LRV) entrapment is almost equivalent to the nutcracker phenomenon (NCP). However, there is still much uncertainty and debate about the prevalence of NCP and its diagnostic criteria. As a particular type of LRV entrapment, the LRV compression by the right renal artery (RRA) was primarily reported as case reports. The study was designed to investigate the RRA-sourced LRV compression in two selected patient cohorts.

Method

The cross-sectional study consecutively selected 38 hospitalized kidney patients diagnosed with membranous nephropathy (Renal group) and 305 peripheral vascular inpatients or outpatients (Non-renal group) in the Second Affiliated Hospital of Harbin Medical University in China from November 2018 to March 2023. The patients with computed tomography (CT) of renal veins or abdominal aorta were included in both groups if axial CT imaging could visualize the renal vessels and was with regular and adequate layer thinness to perform multiplanar reconstruction analysis. Any potential situations that might cause positional or course changes in proximal RRA or LRV due to pathological reasons were excluded from the study. The CT data of LRV compression by different anatomical sources, including but not limited to RRA, was analyzed.

Results

With other anatomical compression sources excluded, there were 22.58% (7/31) and 20.00% (5/25) LRVs compressed by the RRAs in the Renal and Non-renal groups, respectively, with no significant difference (p = 1.0). The distal segments of the LRVs compressed by RRAs have a significantly larger lumen area than those of non-compressed veins (p < 0.01 in both groups). The overall incidence of NCP was calculated as 10.71% (6/56). Complex compressions, namely those LRV compressions by another adjacent structure besides RRA, coincided in 7.14% of the total cases (4/56).

Conclusion

Our study showed that it was not rare for the proximal RRA to compress the end of LRV. The detected incidence of RRA-sourced LRV compression was twice that of the entrapment related to the superior mesenteric artery, the mainstay of NCP. Though this finding came from two relatively small subject populations, it challenged the present connotation of LRV entrapment. Further repetitive studies are needed to test if such a phenomenon prevails in different populations, including healthy individuals.

Legends for all figures: Green thick arrows, RRA; green arrowheads, superior mesenteric artery (SMA); red-edged white arrows, left renal artery (LRA); white short-shafted arrows, LRV; white long-shafted arrows, inferior vena cava (IVC); transparent or white arrowheads, compressed sites.
#565 Renal involvement in solid cancers: epidemiological, clinical and histological characteristics study of 154 onconephrology patients
Authors: Gueutin Victor , Cardineau Aurore , Mathian Alexis , Lanot Antoine , Comoz Francois , Brocheriou Isabelle , Izzedine Hassan
Published: May 2024

Background and Aims

Onconephrology is a growing discipline that aims to improve the management of patients with cancer and kidney disease. If renal histology is an essential key, the anatomopathological data remain weak. We propose an analysis of real-life data from patients managed in onconephrology consultations and had renal biopsy.

Method

Patients with active cancer who had a renal biopsy (RB) between 2015 and 2020 were included, and their clinicobiological and histological data were retrospectively analyzed. Our cohort consisted of 154 patients (83 women) with a mean age of 58 years who went for onconephrology care.

Results

One hundred twelve patients presented with proteinuria, 95 with acute renal failure, and 59 with arterial hypertension. Histologically, interstitial fibrosis was found in 74% of RBs, tubular atrophy in 55.1%, arteriolar hyalinosis in 58.4%, and fibrous endarteritis in 54.4%. Regarding the main acute lesions, thrombotic microangiopathy (TMA) was found in 29.9% of biopsies, acute tubular necrosis (ATN) in 51.3%, and acute interstitial nephritis in 24.8%. The etiological diagnosis most often made was the nephrotoxicity of anticancer drugs (87 patients), followed by a functional cause (15 patients) and renal disease unrelated to cancer (13 patients). Sixty-seven patients presented with at least 2 associated diagnoses. Different clusters were found, highlighting that anti-PD1 and anti-VEGF therapy were the most commonly involved drugs.

Conclusion

The nephrotoxicity of anticancer drugs was the etiology most often determined following RB this a onconephrology population, predominantly with diagnoses of TMA and ATN. Chronic histological lesions were very common. The etiological diagnoses were sometimes mixed, and primary or paraneoplastic glomerulopathies were detected mainly through histology.
#1643 Long-term cohort study on the prognostic impact of mesangial IgM deposition in IgA nephropathy
Authors: Stefan Gabriel , Stancu Simona , Zugravu Adrian Dorin , Terinte-Balcan George
Published: May 2024

Background and Aims

The prognostic importance of mesangial immunoglobulin (Ig) M deposition in IgA nephropathy (IgAN) is not well-understood and is subject to ongoing debate. Moreover, mesangial IgM deposition could also reflect lectin complement system activation. Thus, our study sought to examine the long-term prognostic implications of mesangial IgM deposition in a cohort of IgAN patients.

Method

We carried out a single-center retrospective study involving 93 consecutive IgAN patients (median age 41 years, 68% male, eGFR 48.7 mL/min, proteinuria 1.1 g/g) from 2010 to 2015. The follow-up period extended until the onset of end-stage kidney disease (ESKD), death, or January 2021, with a median duration of 7 years. An independent pathologist assessed the IgM immunofluorescence pattern, Oxford MEST-C score, and transmission electron microscopy (TEM) lesions using a detailed protocol.

Results

In our study, 70% (n = 65) of patients exhibited mesangial IgM-positive deposits, while 30% (n = 28) did not show IgM deposition. Both IgM-positive and IgM-negative groups were comparable in terms of age (40 vs 43 years, p 0.6), sex (69 vs 64% male, p 0.6), arterial hypertension prevalence (69 vs 64%, p 0.6), Charlson comorbidity scores (2 vs 1, p 0.3), kidney function (eGFR 46 vs 55 mL/min, p 0.1 and proteinuria 1.2 vs 0.7, p 0.1), pathology findings (including Oxford MEST-C score, IgG and C3 immune deposition), TEM analysis, as well as in their treatment with renin-angiotensin-system inhibitors (63 vs 71%, p 0.4) and immunosuppression (39 vs 39%, p 0.9), and mortality rates (11 vs 7%, p 0.5). However, a notable difference emerged in the progression to ESKD, with 37% of IgM-positive patients advancing to this stage compared to only 11% of those in the IgM-negative group (p 0.01). The multivariate Cox proportional hazards regression analysis identified lower eGFR (HR 0.94, 95% CI: 0.92, 0.97), higher Oxford MEST-C score (HR 1.53, 95% CI: 1.16, 2.02), and mesangial IgM deposits (HR 4.75, 95% CI: 1.25, 17.99) as independent predictors of reduced kidney survival.

Conclusion

Our study identifies mesangial IgM deposition as a potential risk factor for ESKD in advanced IgAN, suggesting a need for further investigation. Future research should explore whether IgM's activation of the lectin complement pathway and resultant damage, as proven in ischemia-reperfusion injury models, are applicable to IgAN.
#2543 Complement receptor C5aR1 correlates with inflammatory responses driven by glomerular uPAR upregulation in renal vasculitides
Authors: Zeisberg Michael , Tampe Björn
Published: May 2024

Background and Aims

Avacopan is a novel promising treatment for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) targeting the complement system by blocking C5a receptor C5aR1. We here pursued a transcriptome array-based approach to dissect molecular signatures associated with C5aR1 in renal vasculitis.

Method

C5aR1 mRNA expression levels (reporter ID: 210845_s_at, platform: Affymetrix Human Genome U133 Plus 2.0 Array, altCDF v10) were extracted from microdissected samples of renal vasculitis (glomerular: n = 23, tubulointerstitial: n = 21). Pathway analysis was performed for gene enrichment associated with PLAUR mRNA expression with a correlation threshold of ≥0.5 by using reactome (http://reactome.org), pathways with a predefined entities value of p≤0.001 were included.

Results

We here identified a predominant glomerular expression of C5aR1 in renal vasculitis as compared to the tubulointerstitial compartment (p < 0.0001). Furthermore, glomerular C5aR1 induction correlated with impaired kidney function (eGFR: 0.0193). Gene set enrichment identified various inflammatory signatures including neutrophil degranulation and innate immunity, and particularly enrichment of urokinase plasminogen activator receptor (uPAR). uPAR itself also correlated with impairment of kidney function in renal vasculitis and particularly active glomerular lesions (cellular crescents and necrosis, p < 0.0001).

Conclusion

The therapeutic implications of targeting uPAR in renal vasculitis are promising, and ongoing research endeavors are aimed at unraveling the complexities of uPAR as a potential diagnostic marker and therapeutic target for this challenging renal pathology. We here expand our current knowledge and link C5aR1 to inflammatory responses driven by glomerular uPAR upregulation in renal vasculitis.
#1804 Long-term outcomes of CKD patients with lupus nephritis: a nationwide cohort study
Authors: Chrysostomou Charikleia , Faustini Francesca , Gunnarsson Iva , Carrero Juan-Jesus , Barany Franz Peter , Evans Marie , Faucon Anne-Laure
Published: May 2024

Background and Aims

Health trajectories of patients with lupus nephritis (LN) are poorly understood in the setting of moderate and advanced chronic kidney disease (CKD). Furthermore, data on comparison of outcomes of LN to other forms of CKD are scarce. Therefore, the aim of this study was to compare long-term outcomes between LN and CKD from other etiologies.

Method

Using data from the Swedish Renal Registry (2006-2021), we compared clinical outcomes between patients with moderate and advanced CKD related to LN (LN-CKD), and patients with CKD due to primary glomerular diseases (PGD-CKD, i.e. IgA nephropathy, focal segmental glomerulosclerosis, membranous nephropathy), and due to other common CKD etiologies with high cardiovascular risk (Other-CKD, mostly diabetes and nephrosclerosis). Cox proportional hazard models were used to estimate the adjusted hazard ratios of mortality, major cardiovascular events (MACE), heart failure (HF), kidney replacement therapy (KRT) and acute kidney injury (AKI). Models were adjusted for age, sex, comorbidities, clinical and biological data including kidney function, medications and healthcare utilization.

Results

At baseline, patients with LN-CKD (N = 317, 61 years, 76% women, median eGFR 30 mL/min per 1.73 m²) and PGD-CKD (N = 2296, 57 years, 30% women, eGFR 29 mL/min per 1.73 m²), were younger and had lower prevalence of cardiovascular disease than patients with Other-CKD (N = 34778, 75 years, 36% women, eGFR 25 mL/min per 1.73 m²).

Over a median follow-up of 6.2 [3.3; 9.8] years, 19029 deaths (51%), 15768 (42%) MACE and 8390 (22%) KRT events occurred. The unadjusted 5-year absolute risks of death and MACE were high both in patients with LN-CKD (27% and 25%) and Other-CKD (50% and 44%), but lower in those with PGD-CKD (16% and 14%), whereas the 5-year absolute KRT risk was higher in patients with PGD-CKD (PGD-CKD: 37%, LN-CKD: 23%, Other-CKD: 23%).

In multivariable analyses and as compared to PGD-CKD, patients with LN-CKD had a higher risk of death (adjusted HR: 1.63 [95% CI: 1.32-2.02]), MACE (1.65 [1.31-2.08]), HF (1.68 [1.31-2.14]) and AKI (1.45 [1.02-2.05]) and showed a lower risk of KRT (HR: 0.81 [0.64-1.02]), although the 95% CI slightly overlapped (Figure, panel A).

In contrast, the risks of adverse events were similar between patients with LN-CKD and those with Other-CKD (Figure, panel B).

Conclusion

While LN-CKD had a lower risk of KRT than PGD-CKD, they exhibited a higher risk of death, MACE, KRT, HF and AKI, reaching the risk magnitude of patients with high cardiovascular burden (Other-CKD). Our findings may inform decisions for care planning in patients with advanced CKD and LN.
#953 Preliminary results of the peripheral T follicular cells and their subsets in ANCA associated glomerulonephritis
Authors: Christodoulou Michalis , Moysidou Eleni , Stai Stamatia , Bantis Konstantinos , Fylaktou Asimina , Sarafidis Pantelis , Stangou Maria
Published: May 2024

Background and Aims

T cells play crucial role in the pathogenesis of autoimmune diseases such as ANCA associated vasculitis-glomerulonephritis (AAV/GN) by secreting immune mediators and helping B cell-mediated long-lived humoral immunity development. Specific T and B cells subsets can be used as biomarkers of patients with AAV/GN. We aimed to prospectively compare the predictive ability of such subpopulations in patients with active AAV/GN.

Method

Flow cytometry was applied in the peripheral blood of 29 subjects. 15 AAV/GN patients (M/F 6/9), age: 62.1(28-82)years, MPO/PR3/Negative ANCA: 10/4/1) and 14 healthy controls (HC), to estimate T-cells subsets: CD4, T-folicular cells (Tfol), T-regulatory cells (Tregs), Tfh, Tfh1, Tfh2, Tfh17, and T-folicular regulatory cells(Tfr) and B-cells subsets: CD19, IgD(+)CD127(-), IgD(+)CD127(+), IgD(-)CD127(+) and IgD(-)CD127(-).

Results

Compared to HC, AAV/GN patients had reduced CD4 (698.8 Vs 368.8, p = 0.04) but increased proportion of Tfol, and both Tfh1 and Tfh2 cells (7% vs 12%, p = 0.05, 8.4 vs 11.2, p = 0.03, 13.3 vs. 45.9, p = 0.09, respectively). Both Tfr (p = 0.048) and Tfh (p = 0.023) were also significantly higher in group A, compared to group HC.

CD19 levels were lower in AAV/GN compared to HC, with reduced all subpopulation, though of not-statistical significance.

Conclusion

Specific T-cells subsets can be measured in AAV/GN patients’ peripheral blood. Subpopulations such as Tfh and Tfr can be used as biomarkers to diagnose patients with active disease and their role in the pathogenesis of AAV/GN must be studied in detail to determine if they can become targets for new therapies in the future.
#3068 Fibrosis and CD-163+ macrophages: making a difference between MPO-AAV and PR3-AAV
Authors: Benito-García Silvia , Vilardell Jordi , Arce Yolanda , Barros Xoana , Marco Helena , Guirado Lluis , Encarnacion Montserrat Mercedes Diaz
Published: May 2024

Background and Aims

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a necrotizing vasculitis characterized by inflammation of small blood vessels, with the kidney being one of the most affected organs. Its pathogenesis is a complex, multifactorial process involving inflammation and fibrosis in which macrophages play a crucial role. Macrophages are plastic cells that can change their phenotype in response to their environment. Infiltration of CD163+ macrophages (anti-inflammatory) in the interstitium and glomeruli is observed in AAV patients. Clinical and demographic differences between PR3-AAV and MPO-AAV were observed. We observed that interstitial fibrosis (IFTA) is more pronounced in MPO-AAV than in PR3-AAV.

We aimed to investigate the differences in CD163+ macrophage infiltration and interstitial fibrosis between PR3-AAV and MPO-AAV.

Method

Retrospective single-center study of 80 AAV patients (66 MPO-AAV and 14 PR3-AAV) diagnosed by renal biopsy with at least 1 year of follow-up. Clinical and laboratory variables, ANCA type and renal/patient survival were evaluated. 26 human kidney tissue samples (13 MPO-AAV and 13 PR3-AAV) were stained for CD163+ by immunohistochemistry and immunofluorescence, and trichrome-stained biopsy slides were used to measure the degree of fibrosis. Histomorphometric quantification was performed using MetaMorph® software in both cases. Data analysis was performed under standard conditions. Statistical significance was defined as P values less than 0.05. All P values were 2-sided.

Results

CD163+ macrophages infiltration in the interstitial space was greater in MPO-AAV than PR3-AAV with statistical significance (p < 0.001), observing an average infiltration area of 0.333% in MPO-AAV than 0.116% in PR3-AAV. Furthermore, IFTA was higher at diagnosis in MPO-AAV (35.35%) than in PR3-AAV (31.21%) at the diagnosis with a p = 0.03. However, a correlation between IF and CD163+ macrophages infiltration was not possible to stablish.

Conclusion

We have observed an increased macrophage infiltrate with an anti-inflammatory and reparative phenotype that is higher at diagnosis in ANCAS-MPO compared to ANCAS-PR3, the same difference occurs with respect to interstitial fibrosis. Since the study population is small, no correlations between fibrosis and CD163 macrophage infiltration have yet been found.