bluuebunny/crossref_metadata_2025_split huggingface dataset:
#163 Multiome-seq and spatial transcriptomics of refractory PLA2RAb(+) membranous nephropathy reveals importance of immunomodulatory function of B cells
Authors: Park Sehoon , Joo Kwon Wook , Kim Dong Ki 
Published: May 2024

Abstract

Background and Aims
PLA2RAb-associated membranous nephropathy (MN) is a glomerulonephritis that may require immunosuppression to achieve proteinuria remission. However, the disease course is heterogeneous, and some patients exhibit refractory or relapsing nephrotic-range proteinuria. Additional biomarker studies are necessary to dissect the molecular profiles that reflect substantial differences in treatment response and clinical courses. Multiome-seq includes the investigation of gene expression profiles and ATAC-sequencing for open-chromatin regions, which may reveal pathophysiologic gene expression biomarkers and pathways.

Method
We performed multiome-sequencing of peripheral blood mononuclear cells (PBMCs) from 6 refractory or relapsing primary PLA2RAb-associated MN cases, 7 PLA2RAb-associated MN cases that reached complete remission, and disease controls including 6 minimal change disease and 6 diabetic kidney disease cases. We also collected PBMCs from 7 healthy controls. Cell type clustering, comparison of cell type proportions, and differential gene expression analysis were performed. Additionally, we conducted ATAC-sequencing analysis and identified open-chromatin profiles specific to the refractory or relapsing MN group. Lastly, we investigated the glomerular spatial transcriptome using GeoMx digital spatial profiling to determine whether transcriptomic profiles differ based on the disease courses of MN in the initial kidney tissue.

Results
We successfully identified diverse PBMCs in the multiome-seq data. In the DEG analysis, we identified a number of cell-type-specific DEGs in the refractory or relapsing MN cases. Of these, CD83 was the top gene that was lowly expressed in the B cells of refractory/relapsing MN compared to the remission cases. In the ATAC data, among the number of differentially expressed peaks, NFKB2 was the region that consistently showed a low open chromatin profile in the B cells of CD83. When comparing the cell subtype proportions, refractory or relapsing MN cases showed low regulatory T cells in the peripheral blood. Lastly, in the kidney tissue spatial transcriptomic profiling, there were no significant DEGs between the refractory/relapsing MN and MN with remission in the glomerulus.

Conclusion
The clinical course or risk of remission of PLA2RAb-associated MN was more likely a result of differences in systemic immunity rather than differences in the glomerular transcriptome at the initial diagnosis. Both CD83 and NFκB2 are well-known biomarkers of activated B cells that may have immunomodulatory roles leading to the enrichment of regulatory T cells. Such a deficient immunomodulatory status in refractory/relapsing PLA2RAb-associated MN may explain the disease course.
#2095 Genetic kidney disease in pregnancy – experience of tertiary referral hospital
Authors: Marchão Natália , Da Costa José Oliveira , Peres Nadiesda , Godinho Iolanda , Jorge Sofia , Rodrigues Márcia , Gonçalves Sara , Fonseca José Agapito , Centeno Mónica , Lopes José António , Pinto Luisa , Nogueira Estela 
Published: May 2024

Abstract

Background and Aims
Genetic kidney diseases (GKD) are rarely seen in pregnancy and some diagnosis will only be made during gestation, due to a high proportion of chronic kidney diseases (CKD) of unknown etiology and recent advances in genetic testing. Genetic counseling and, when possible, preimplantation genetic testing (PGT) should be offered pre-pregnancy to this specific CKD population.

Method
Retrospective analysis of maternal, obstetric and perinatal outcomes of pregnant women with GKD surveilled at Hospital Santa Maria, at the nephro-obstetric clinic from 2011 to 2023.

Results
We evaluated 34 pregnancies in 28 women, mean maternal age 30±6 years-old [21-37], 89% Caucasian. Molecular genetic testing was performed pre-pregnancy, during and post-pregnancy in 12/19, 2/19 and 5/19 patients, respectively. At baseline, mean serum creatinine (SCr) and proteinuria (Pr) was 1.0±0.9 mg/dL and 222±516 mg/g, with CKD stage 1/2/3/4/5 in 27/2/2/1/2 gestations and chronic hypertension (HTN) in 11/34 pregnancies. Only 1/28 patients performed PGT, while 1/28 patient declined it.
De novo or increased Pr occurred in 10/34 gestations and de novo or worsening HTN in 5/34 gestations. Deterioration of renal function occurred in one patient (CKD3) without recovery and one patient (CKD5) induced dialysis 4 months post-pregnancy. Nephrotic Pr developed in 4/34 gestations. One patient (FSGS APOL1) was treated with tacrolimus and low dose steroids. The patient with TSC re-started sirolimus on week 22 to treat severe fetal ventricular rhabdomyoma. Miscarriage occurred in 2 pregnancies. The C section rate was 21,8%. There were 7 preterm deliveries of which 3 before 32 weeks of pregnancy, mainly due to severe preeclampsia. Mean gestational age at delivery was 37,6 ± 4 weeks (26-41), mean birth weight 2756 ± 831 g (560-3835). Eight newborns were admitted to neonatal ICU due prematurity, fetal TSC, and feeding difficulties. Pulmonary hemorrhage and sepsis caused the death of 2 newborns. We found 1 maternal death, due to rupture of a cerebral aneurism 1 month postpartum (PKD patient).

Conclusion
Our cohort was very heterogenous regarding CKD etiologies, but generally with good kidney function, which allowed overall good obstetric outcomes. Still, maternal, obstetric and fetal complications, namely HTN, Pr, PE and prematurity had an increased incidence compared to pregnancy in healthy patients. This particular population should be approached by an experienced multidisciplinary team in CKD pregnancy care to optimize outcome.
#968 Impact of the presence of acute kidney injury at the time of renal biopsy on long-term prognosis of IgA nephropathy
Authors: Kim Hyun-Jung , Jeon Hyejin , Lee Seunghye , Kim Jin Hyun , Jung Sehyun , Jang Hani , Chang Se-Ho 
Published: May 2024

Abstract

Background and Aims
IgA nephropathy is the most common primary glomerular disease and an important cause of end-stage renal disease. Factors such as decreased renal function, persistent proteinuria, hypertension, and older age predict a poor prognosis in IgA nephropathy. Current international prediction tools for IgA nephropathy determine prognosis based on renal function using estimated glomerular filtration rate (eGFR) at the time of kidney biopsy. However, we observed differences in prognosis between patients with and without concurrent acute kidney injury (AKI) at the time of kidney biopsy. Therefore, we aimed to investigate whether renal function at the time of renal biopsy is a suitable indicator for assessing the long-term prognosis of patients with IgA nephropathy with AKI.

Method
We retrospectively analyzed a total of 185 patients who were diagnosed with IgA nephropathy between 2009 and 2016 at the Gyeongsang National University Hospital. Clinical data, including pathological, demographic, and laboratory findings of patients, were used. We divided the patients into two groups based on the progression rate of kidney function per year, ‘Progression’ or ‘Non-progression group’. AKI was defined according to the KDIGO Clinical Practice Guidelines.

Results
Among a total of 185 patients, 113 showed a sustained decline in eGFR of more than 1 ml/min/1.73 m2 per year. The mean eGFR level of the non-progression group was significantly lower than that of the progression group (p = 0.027). The percentage of patients with AKI in the non-progression group was 25%, which was higher than that in the progression group (p &lt; 0.001). The two groups had no significant differences in comorbid disease, medications at kidney biopsy, and treatment. In sub-analysis, the mean eGFR at kidney biopsy was significantly lower than that in the non-AKI group (p &lt; 0.001). The mean estimated risk, calculated by the international prediction tool, was significantly lower in the AKI group. On the other hand, the mean rate of actual GFR decline per year was higher in the non-AKI group (p &lt; 0.001).

Conclusion
We confirmed a discrepancy between the predicted prognosis and the actual decline in GFR, particularly in the AKI group. We found that AKI at the time of renal biopsy was a good long-term prognostic factor. There is a need to conduct further research to confirm whether this is due to early detection of AKI and early active treatment.
#3108 Rituximab in adult-onset IgA vasculitis
Authors: Trivioli Giorgio , Fenoglio Roberta , Pillebout Evangeline , Hocevar Alojzija , Bruchfeld Annette , Lundberg Sigrid , Mohammad Aladdin , Maritati Federica , Jayne David R W , Mcadoo Stephen , Roccatello Dario , Vaglio Augusto 
Published: May 2024

Abstract

Background and Aims
Adult-onset IgA Vasculitis (IgAV) is poorly responsive to glucocorticoids (GC) and conventional immunosuppressive therapies, such as cyclophosphamide. Rituximab has been successfully used in a few cases and may represent a safer and potentially more effective option [1]. Crescentic IgA Nephropathy (cIgAN), a rare entity that shares features of renal vasculitis with IgAV, is also frequently refractory to cyclophosphamide, while response to rituximab is unknown. We investigated outcomes after rituximab in a multicentre European cohort of adult-onset IgAV and cIgAN.

Method
We screened clinical records of patients followed at 18 European consorted centres who were ≥18 years old at the onset of IgAV and received ≥1 rituximab dose. Furthermore, we identified patients with cIgAN (≥25% crescentic glomeruli and rapidly progressive glomerulonephritis), who were treated with rituximab. Remission was defined as Birmingham Vasculitis Activity Score (BVAS) &lt;3 at month 6 after rituximab and renal response as stable or improved eGFR and ≥50% proteinuria reduction. Relapse was defined as an increase in BVAS requiring a change in immunosuppressive therapy. Outcomes of IgAV with severe nephritis (eGFR &lt;60 mL/min) were compared with those of cIgAN.

Results
We included 61 patients with IgAV and 15 with cIgAN (Table). Rituximab was administered as initial therapy in 23/61 (38%) patients with IgAV and 13/15 with cIgAN (87%), while the remainder had refractory or relapsing disease. Active skin involvement was present in 49 patients (80%) and nephritis in 55 patients (90%) with IgAV at the time of starting rituximab. This was given alone in 13/61 (21%) or combined with GC in 48 (79%) patients with IgAV and in all those with cIgAN. Furthermore, cyclophosphamide was used in 15% of patients with IgAV and 40% of those with cIgAN. Remission at 6 months was achieved by 52 (85%) patients with IgAV and 12/13 (92%) of those treated with rituximab alone. A renal response was observed among 49/55 (89%) of those with nephritis. Patients with IgAV and severe nephritis had similar eGFR to those with cIgAN at the time of starting rituximab, but the latter had lower rate of remission and a higher frequency of kidney failure. A relapse occurred in 15/52 patients (29%) who achieved remission a median of 13 months (10-15) after rituximab. Eight patients resumed rituximab and achieved again remission.

Conclusion
Rituximab alone or in combination with GC and immunosuppressants appeared to achieve a high rate of remission in this cohort of adult-onset IgAV. Renal response among those with severe nephritis was also good, while this was worse among patients with cIgAN, suggesting substantial differences among these conditions despite similar histological appearances.
#1917 SGLT2-Inhibition in patients with Alport syndrome – an international, retrospective and in parts prospective observational large cohort study
Authors: Boeckhaus Jan , Gross Oliver 
Published: May 2024

Abstract

Background and Aims
Large-scale trials showed positive outcomes of SGLT2-inhibitors (SGLT2i) in elderly patients with CKD. Patients with Alport syndrome, a type IV collagen disease, develop CKD early in life. Whether the use of SGLT2i is safe and effective in patients with the type IV collagen disease Alport syndrome (and thus a different pathogenesis) has not yet been investigated specifically besides case reports.

Method
For the first time, this observational, multicenter, international study (NCT02378805) assessed 112 patients with AS from nine countries and 21 trial sites after start of SGLT2i at early stages of their chronic kidney disease (CKD). The study's primary endpoint was change of albuminuria in albumin/g creatinine after start of therapy with SGLT2i.

Results
Compared to the large randomized trials investigating the effect of SGLT2i in CKD, the adult patients in this trial were much younger (38 ± 14 years; n = 101), had a better eGFR (63 ± 35 ml/min/1.73m2; n = 98) and had a higher albuminuria (1699 ± 1472 mg/g creatinine; n = 51). At a mean time on SGLT2i-therapy of 6 ± 1 months, albuminuria decreased significantly (1727 ± 1564 vs. 1203 ± 1165 mg/g creatinine; n = 33; p = 0.01). Compared to baseline, at the first three follow-up visits after initiation of SGLT2i-therapy, a significant reduction of albuminuria &gt;30% was observed. Mean loss of eGFR was 9 ± 12 ml/min/1.73 m² almost one year after initiation of SGLT2i-therapy (n = 35). At a mean follow up of 12 ± 2 month after initiation of SGLT2i-therapy, serum-albumin increased significantly from 3.7 ± 0.7 to 4.0 ± 0.4 g/dL (n = 18; p = 0.019). At a total of 68 patient-years at risk, adverse events occurred in 11/85 patients (13%). Two very serious adverse events (acute necrotizing pancreatitis and Fournier's gangrene) occurred.

Conclusion
This study demonstrated that SGLT2i, when added to RASi, have the potential to reduce the rate of albuminuria in adult patients with Alport Syndrome. The study will be continued to provide valuable data on the long-term course of CKD under SGLT2i-therapy in AS to investigate if the promising reduction of albuminuria results in a clinical relevant delay in renal failure. This observational study successfully formed the scientific basis for the current randomized controlled trial with SGLT2i in children and young adults with AS Double Protect Alport.
#1392 MEST-C score correlation with proteinuria reduction after SGLT2i treatment in patients with IgA nephropathy
Authors: Xydakis Dimitris , Antonaki Ergini , Tzali Eleni , Papapanagiotou Michalis , Petra Christina , Kostakis Kostantinos , Vardaki Eleftheria 
Published: May 2024

Abstract

Background and Aims
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are associated with better cardiovascular outcomes and with nephroprotection independent of diabetes status. Recent data suggest that SGLT2i significantly reduce proteinuria in patients with IgA nephropathy (IgAN). Data available for the use of the MEST-C score to determine if treatment would benefit IgAN patients is scarce. The aim of our study was to assess the degree of proteinuria reduction after SGLT2i treatment in IgAN and its possible association with the MEST-C score.

Method
63 adult patients with biopsy-proven IgA nephropathy, eGFR ≥ 30 mL/min/1.73 m2 (CKD-epi), and total urine protein of &gt;0.5 grams/day at screening were included. Patients with secondary IgAN and crescents were excluded. All receiving maximally tolerated RASi for at least 12 weeks. All patients started dapagliflozin 10 mg once per day after baseline data were registered. The total follow-up was 12 months. The main outcome was the decline in eGFR and the reduction in 24-hour proteinuria from SGLT2i initiation to 1,3, 6, 9, 12 months, end-stage renal disease, or kidney or cardiovascular death. Three repeated measurements of proteinuria (mg/24H) were performed, 90 days before SGLT2i treatment initiation, and only patients with stable proteinuria were enrolled in the study.

Results
49 patients (35/14 M/F), with mean age of 41,9 ± 19,6 years, completed follow up. 8 patients discontinued treatment due to adverse events attributed to dapagliflozin. At baseline eGFR was 68.21±18,1 ml/min/1.73 m2 and Upr: 2196±1091 mg/24H. The MEST-C scores were correlated with the serum creatinine level, proteinuria, and hematuria. The mean serum creatinine level was higher in M1, E1, S1, and T1 compared with score “0”. It was statistically significant (p = 0.03) only in the T-score. The mean proteinuria level was again higher in M1, S1, and T1 but reached statistical significance (p = 0.037) in only the T1-score. E1 has higher hematuria.
The Upr/24H difference for dapagliflozin was −24.7% (95% CI −27.5, −23.2; p &lt; 0.001) at the end of follow-up (month 12). Proteinuria reduction was similar across all eGFRs, age, and baseline proteinuria.
Among MEST-C score parameters, T1 had a negative impact on the antiproteinuric effect of dapagliflozin (p = 0.01)
No hypoglycemic events were reported and no deaths occurred.

Conclusion
In the present study, the use of SGLT2i was associated with a significant reduction of proteinuria in patients with IgA nephropathy and maximally tolerated RASi. We analyzed renal outcomes in association with pathologic features. We established that the presence of the T1 score has a negative impact on proteinuria reduction after SGLT2i treatment. Further studies are needed to investigate the impact of the use of the Oxford Classification score for developing individual treatment therapies.
#751 Noninvasive evaluation of histopathology in immunoglobulin A nephropathy by contrast-enhanced ultrasonography
Authors: Zheng Ke , Wang Gangan , Li Xuemei 
Published: May 2024

Abstract

Background and Aims
IgA nephropathy is a common primary glomerulonephritis. Renal pathology provides a visual reflection of renal lesions, but percutaneous renal biopsy carries risks This study explores a non-invasive method for evaluating the renal pathological changes in IgA nephropathy patients. We attempt to correlate contrast-enhanced ultrasonography parameters with IgA nephropathy pathological changes, discussing the potential value of this approach in assisting the assessment of IgA nephropathy renal pathology.

Method
This prospective study included 26 IgAN cases eventually confirmed through renal pathology. Prior to renal biopsy, patients underwent contrast-enhanced ultrasound examination and conventional renal ultrasound. Ultrasound contrast parameters, including time-intensity curve (TIC) peak intensity, time to peak, rise time, and mean transit time, were recorded. Correlation analyses were conducted between conventional ultrasound, contrast-enhanced ultrasound parameters, clinical data, and pathology scores.

Results
Significant differences in peak intensity were observed between different Oxford C scores, with significant statistical differences between C0 and C1, as well as C0 and C2 (P &lt; 0.05). Quantitative analysis revealed correlations between peak intensity, time to peak, and C scores (r = −0.571, P &lt; 0.05; r = 0.498, P &lt; 0.05). Time to peak correlated with T scores (r = −0.445, P &lt; 0.05). No correlations were found between other contrast-enhanced ultrasound parameters and Lee's grading, Oxford MEST-C M, E, or S scores.

Conclusion
Contrast-enhanced ultrasonography parameters, specifically time-intensity curve peak intensity and time to peak, correlate with renal pathology C scores. Contrast-enhanced ultrasound holds clinical significance in the non-invasive assessment of renal pathological changes in IgA nephropathy patients.
#2423 Molecular classification of lupus nephritis based on immune pathway profiling—correlations with histological class and clinical manifestations
Authors: Zhang Danting , Xie Ruiyan , Yap Desmond 
Published: May 2024

Abstract

Background and Aims
The ISN/RPS 2003 classification is the current gold standard histopathological classification for lupus nephritis (LN), and has important roles in guiding treatment and predicting prognosis. The classification system, largely based on light microscopy features, does not inform the underlying immunological aberrations. A classification based on molecular typing of immune-related pathways may better stratify LN patients and help select treatments that target specific immune cascades.

Method
The normalized expression matrix and clinical data were extracted from Gene Expression Omnibus database, Human Cell Atlas (Hacohen-Human-CELseq2) and Nephroseq. Four chip datasets (GSE127797, 32591, 69438 and 37463) and one single cell dataset were analyzed. Sample gene set enrichment analysis (ssGSEA) method was used to derive immune phenotype with gene expression data. The hierarchical clustering with ssGSEA scores of selected gene sets was used to classify LN tissues. Functional characterization and protein-protein interactions of the differential expression genes (DEGs) of three groups were compared with healthy donors using Metascape (absolute log FC &gt; 1 and adjusted P-value &lt; .05). Kruskal-Walli test and chi-square test were performed to compare the clinical parameters of the different groups.

Results
We analyzed 96 immune-related gene sets in the glomerular and tubulointerstitial regions of LN kidney biopsy samples. The immune-related genes were categorized into three clusters (Immune-Mild, Immune-Moderate and Immune-Severe) based on the degree of immune pathway activation. Interferon-stimulated genes are a hallmark of LN, with high signals in all three clusters. When compared to other groups, the Immune-Mild cluster from the glomerular region showed no T-cell activation or T cell receptor pathway. Also, the Immune-Mild (tubulointerstitial) group also showed minimal lymphocyte activation or migration. Protein-protein interactions networks with MOCDE components further suggested that STAT1 and ISG15 the hub genes in different clusters. The gene expressions of hub genes were then compared among epithelial cells and 21 immune cells from LN and heath controls. Immune clusters are correlated with clinical phenotypes, in which Immune-Mild Group (Glomerular) showed high prevalence of Class II and V LN, and Immune-Mild (Tubulointerstitial) showed more Class V LN. Immune-Severe group also showed higher degree of proteinuria and blood pressure but lower eGFR compared to Immune-Moderate and Immune-Mild groups.

Conclusion
A new molecular classification of LN based on the degree of immune pathway activation shows correlation with clinical manifestations and may potentially guide personalized therapy in LN patients.