bluuebunny/crossref_metadata_2025_split huggingface dataset:
#2949 Diverse effect of STAT3 inhibition on murine primary tubular epithelial cells
Authors: Manzéger Anna , Szakal Zsofia , Kokeny Gabor 
Published: May 2024

Abstract

Background and Aims
The incidence of chronic kidney diseases increases worldwide, and kidney fibrosis is the final common pathway regardless of the etiology. TGF-β plays a crucial role in the pathogenesis, affecting pro-fibrotic genes and transcription factors. STAT3 (signal transducer and activator of transcription 3) acts via the JAK/STAT signaling. Inhibition of STAT3 in animal studies was shown to attenuate the progression of kidney fibrosis. Yet, the effect of STAT3 inhibition on renal tubular epithelial cells has not been elucidated. We aimed to investigate in vitro the impact of pharmacological STAT3 inhibition with NSC74859 (NSC) and STATTIC on the expression of fibrosis associated genes of primary tubular epithelial cells.

Method
Primary tubular epithelial cells from kidneys of C57Bl6/J mice were isolated and used in our studies. Cells (P10-P15) were seeded on gelatin-coated 6-well culture plates (100000 cells/well) and subjected to treatment with 10 ng/ml TGF-β, 100 µM NSC, 10 µM STATTIC or vehicle (n = 3/group) as follows: Control; NSC; STATTIC; TGF-β; TGF-β+NSC; TGF-β+STATTIC. After 24 h treatment, mRNA and protein expressions were analyzed. Statistical evaluation was performed using Kruskal-Wallis test.

Results
In cells not treated with TGF-β, neither NSC nor STATTIC treatment affected the expression of Tgfb1 (TGF-β) and Acta2 (SMA) genes compared to controls (100%), but reduced Col1a1 expression to 58% and 54%, respectively (p &lt; 0.05). NSC reduced to 54%, while STATTIC tended to increase (169%) the gene expression of Egr2 transcription factor. TGF-β treatment induced STAT3 phosphorylation by 45% accompanied by a fibrotic response and epithelial-to-mesenchymal transition (EMT) as indicated by significantly increased Tgfb1, Acta2, Egr2 and Col1a1 (p &lt; 0.05). NSC treatment did not inhibit the TGF-β-induced Tgfb1 upregulation (178%), but markedly, although not significantly, reduced the expression of Acta2 (100%), Egr2 (98%) and Col1a1 (114%) in the TGF-β+NSC group. Interestingly, although STATTIC treatment dramatically inhibited STAT3 expression (38%, p &lt; 0.05) it significantly enhanced the TGF-β-induced overexpression of Tgfb1 (210%, p &lt; 0.01) and Egr2 (307%, p &lt; 0.05), while markedly reduced Acta2 (64%, p &lt; 0.001) and Col1a1 (81%, p &lt; 0.01) in the TGF-β+STATTIC group.

Conclusion
Our results indicate that in vitro inhibition of STAT3 using two inhibitors with same mode of action lead to diverse responses in primary murine tubular epithelial cells, partially suppressing EMT markers but inducing pro-fibrotic EGR2. Further studies are needed to clarify the underlying mechanisms.
#1894 Disappearance of proteinuria is not a surrogate marker of improvement in IgA nephropathy
Authors: Cho Byoung-Soo , Yun Hyaejin , Jung Sungmin , Cho Won Hee , Lee Hyun-Soon 
Published: May 2024

Abstract

Background and Aims
IgA nephropathy is one of the most common chronic glomerulonephritis and 30-45% falls into chronic kidney disease over a period of 20 to 25 years. Lots of treatment regimens are tried such as RAAS blocker, corticosteroids, complement inhibitors, Nefecon, Atrasentan, SGLT2 inhibitor etc., however disappearance of proteinuria has been regarded as surrogate marker of improvement. We performed follow up renal biopsy to confirm the efficacy of disappearance of proteinuria.

Method
During last 10 years, our clinic performed 1,867 cases of renal biopsies at OPD level. Of which 585 cases (31.3%) were IgA nephropathy.
We performed follow up renal biopsies in 149 cases, who showed improved proteinuria after methylprednisolone pulse therapy.
Follow renal biopsy findings were divided into 3 groups:
One cycle of methylprednisolone pulse therapy consists of methylprednisolone (20-30 mg/kg, max 1 gm/day) for 3 consecutive days. Depends on the pathological grade, we performed 3 to 17 cycles every 2 weeks.

Results
Male to female ratio was 0.96(73:76), Mean age was 38.4 years old. Of the 149 follow up biopsies, 75 cases (50%) showed improved pathology (Group A), 60 cases (40%) showed no pathological changes (Group B) and 14 cases (10%) showed aggravated pathology (Group C).

Conclusion
Normalized proteinuria could not be a surrogate marker of renal improvement, because only 50% showed pathological improvement. Follow up renal biopsy might be a mandatory procedure to define the efficacy of treatment in IgA nephropathy.
#1153 Short course of steroids as a treatment for immune checkpoint inhibitors-associated acute kidney injury
Authors: Escribano Teresa Cavero , Lopes Vanessa , Ordoñez Katherine Peña , Soto Mara Serrano , Pérez Mariana Rivera , Valdivia Verónica Ruth Mercado , Moliz Candela , Macia Manuel , Gutiérrez Eduardo , Auñón Pilar 
Published: May 2024

Abstract

Background and Aims
Immune checkpoint inhibitors (ICPi) have been a revolution in oncology. Due to their mechanism of action they can produce inflammatory adverse events, called “immune related adverse events” (IrAEs). Immune-mediated renal toxicity appears to be infrequent (2.2-5%), with acute tubulointerstitial nephritis being the most common form, clinically manifested as acute kidney injury (AKI). Corticosteroids are a highly effective treatment. However, the most suitable regimen has not been established.

Method
Retrospective multicenter study to evaluate the efficacy and safety of a short course of steroids (Group A) versus a long course (Group B) in patients with a clinical or histologic diagnosis of ICPi-associated acute kidney injury (ICPi-AKI). Short-duration regimen was considered to be that with a duration ≤3 months. Renal response was assessed 3 months after initiation of steroid therapy. Partial and complete renal response rates were compared in both groups, as well as relapses of ICPi-AKI with the lowering or suspension of steroid treatment. The development of adverse effects attributable to corticosteroids and the evolution of the oncologic disease were also evaluated.

Results
Sixty-three patients were included, 30 (48%) of whom received a short course of corticosteroids. Type of malignancy and oncologic treatment were similar in both groups. Baseline serum creatinine (1.1 mg/dL Group A and 0.9 mg/dL Group B; p = 0.53) and at ICPi-AKI diagnosis (3.0 mg/dL in Group A and 2.8 mg/dL in Group B; p = 0.43) were comparable. As shown in the table below, cumulative prednisone dose was lower in Group A than in Group B (1654 mg vs 4030 mg; p = 0.001). The overall renal response was 92% (87% Group A and 97% Group B; p = 0.2). There were no differences in complete response (40% Group A and 40% Group B; p = 1) or partial response (47% Group A and 57% Group B; p = 0.4). There were no recurrences of AKI after rechallenge of ICPi treatment. Adverse events related to corticosteroids were similar. There was a trend towards greater progression of oncologic disease in group B (64% versus 40%; p = 0.08).

Conclusion
A short course of steroids (&lt; 3 months) is equally effective as a treatment for ICPi-AKI as longer courses, both in terms of renal response and relapse rate of ICPi-AKI. Adverse events related to steroid treatment were comparable in both groups. There appeared to be greater oncologic progression in the prolonged steroid treatment group.
#1472 Prevalence of Mendelian and non-Mendelian forms of genetic disease in a Swiss cohort of adult kidney stone formers
Authors: Anderegg Manuel , Olinger Eric , Bargagli Matteo , Geraghty Rob , Pohlmeier Lea , Nater Alexander , Sayer John , Vogt Bruno , Halbritter Jan , Schaller André , Fuster Daniel 
Published: May 2024

Abstract

Background and Aims
Molecular mechanisms of kidney stone formation remain unknown in most patients. Previous studies showed high heritability of nephrolithiasis, but analysis of Mendelian disease in selected cohorts and genome-wide analysis were yet unable to entirely explain heritability. While prevalence of Mendelian disease in selected nephrolithiasis cohorts has already been studied, data on prevalence and characteristics of genetic disease in unselected adults with nephrolithiasis are lacking. This study was conducted to fill this important knowledge gap.

Method
We performed whole exome sequencing in 787 participants of the Bern Kidney Stone Registry, an unselected cohort of adults with ≥1 past kidney stone episode (KSF), and 114 non-stone-forming individuals (NKSF). An exome-based panel of 34 established nephrolithiasis genes was analyzed and variants assessed according to ACMG criteria. Pathogenic (P) or likely pathogenic (LP) variants were considered diagnostic.

Results
Mean age of KSF was 47 ± 15 years, and 18% were first time KSF. A Mendelian kidney stone disease was present in 2.9% (23 of 787) of KSF. The most common genetic diagnoses were cystinuria (SLC3A1, SLC7A9; n = 13), Vitamin D-24 hydroxylase deficiency (CYP24A1; n = 5) and primary hyperoxaluria (AGXT, GRHPR, HOGA1; n = 3). 8.1% (64 of 787) of KSF were monoallelic for LP/P variants predisposing to nephrolithiasis, most frequently in SLC34A1/A3 or SLC9A3R1 (n = 37), CLDN16 (n = 8) and CYP24A1 (n = 8). KSF with Mendelian disease had a lower age at the first stone event (30 ± 14 years vs. 36 ± 14 years, p = 0.003), were more likely to have cystine stones (23.4% vs. 1.4%) and less likely to have calcium oxalate monohydrates stones (31.9% vs. 52.5%) compared to KSF without genetic diagnosis. The phenotype of KSF with variants predisposing to nephrolithiasis was subtle and showed significant overlap with KSF without diagnostic variants. In NKSF, no Mendelian disease was detected, and LP/P variants were significantly less prevalent compared to KSF (1.8% vs. 8.1%).

Conclusion
Mendelian disease is uncommon in unselected adult KSF, yet variants predisposing to nephrolithiasis are significantly enriched in adult KSF. While the identified variants predisposing to nephrolithiasis may explain some of the unresolved heritability, likely additional intermediate effect size variants in known and yet unknown kidney stone genes remain to be discovered for us to fully understand the genetic factors leading to the high heritability of nephrolithiasis.
#1028 Experience with ravulizumab in atypical hemolytic uremic syndrome
Authors: Saiz Víctor Joaquín Escudero , Chillarón Marta Martínez , Morantes Laura , Grau Julia Ollé , Guillen-Olmos Elena , Xipell Marc , Molina-Andujar Alicia , Piñeiro Gaston , Poch Esteban , Bastida Carla , Porras Luis Fernando Quintana , Pelicano Miquel Blasco 
Published: May 2024

Abstract

Background and Aims
The arrival of eculizumab revolutionized the treatment of Atypical Hemolytic Uremic Syndrome (aHUS). Ravulizumab also offers C5 inhibition, but with 3-4 times longer half- life. We describe the experience with ravulizumab in patients with aHUS in two scenarios: 1. Switching from another C5 inhibitor in stable patients; 2. Direct initiation of therapy with ravulizumab (naïve).

Method
We present 9 patients with an average age of 42 ± 13 years and weight of 81 ± 12.4 kg. The switch to ravulizumab was initiated 2 weeks after the last dose of eculizumab in switch patients, while in naïve patients it was initiated after excluding other causes of aHUS. The initial dose was 2700 mg, followed by a second dose of 3300 mg after 2 weeks, and subsequently every 2 months. Analytical variables of renal function, hematological parameters, and complement were collected.

Results
Switch : 6 patients (50% females), 4/6 were transplant recipients (3 on prophylactic treatment). Regarding renal function, 5/6 patients had a complete response with eculizumab (creatinine 1.33 ± 0.32 mg/dL, eGFR 59.5 ± 34.3 mL/min/1.73 m2, proteinuria 115 ± 91.5 mg/g), and all of them had a complete hematological response. After the switch, all patients maintained a complete hematological response, stability of renal function, and serum complement levels.
Naïve : 3 cases (2 males); 2/3 required hemodialysis (HD) at presentation. The renal response was complete in two patients and partial in the third (who discontinued HD after 90 days and currently remains stable with stage G3b chronic kidney disease). All three patients had a complete hematological response.
Only 3 adverse effects were documented (arthralgia, headache, and rhinitis), with no cases of infection.

Conclusion
The use of ravulizumab is effective both in maintaining a complete response after switching from eculizumab and as a first-line therapy. The safety profile is comparable, with the main difference being the dosing regimen, as ravulizumab requires fewer administrations and leads to a reduction in direct and indirect costs.
#2167 Polyclonal immunoglobulin free light chains: an evidence of cardiac remodeling in patients with glomerular diseases
Authors: Churko Anna , Rumyantsev Aleksander 
Published: May 2024

Abstract

Background and Aims
It was previously shown, that polyclonal immunoglobulin free light chains (FLC) are the independent predictor of mortality in patients with decompensated heart failure, chronic kidney disease (CKD) and also in general population. Mechanisms of this phenomenon are still unknown. The aim of our study is to reveal the possible relationships between FLC and cardiac remodeling in patients with glomerular diseases.

Method
We included 97 patients with biopsy-proven diagnosis of different immune-mediated glomerular diseases, 53% were men, mean age was 48 ± 14.6 years. Serum Freelite FLC levels were measured as well as standard clinical and laboratory investigation. At the time of biopsy transthoracic echocardiography was also performed. Glomerular filtration rate (eGFR) was estimated by “2021 CKD-EPI Creatinine” equation.

Results
Median of eGFR was 46.8 ml/min/1.73 m² (28.7-80.0), FLC-kappa level was 27.4 mg/l (16.8- 48.4), FLC-lambda level was 28.2 mg/l (20.8-43.3). FLC-kappa levels were above reference range in 65%, FLC-lambda levels – in 54%. LV diastolic dysfunction (DD) was present in 68%. Comparison in groups showed that the elevation of FLC-kappa more than 19.4 mg/l was associated with bigger LV mass index (LVMI) – 138.3 ± 30.2 g/m² vs 99.9 ± 31.2 g/m² р = 0.022, the parallel correlation was found between LVMI and levels of FLC-lambda higher than 26.3 mg/l (136.2 ± 64.8 g/m² vs 104.0 ± 36.6 g/m², р = 0.023). Spearman analysis has shown statistically significant correlations between FLC levels and E/e’- Rs = 0.501 p = 0.0001 for FLC-kappa, Rs = 0.343 p = 0.012 for FLC-lambda. Combined FLC level higher than 52.9 mg/l was a significant predictor of DD with area under the ROC curve (AUC) 0.703 (sensitivity 76.5%, specificity 62.5%).

Conclusion
Elevation of serum pFLC level could be a promising marker of cardiac remodeling, especially, of DD in patients with glomerular diseases. Possible pathogenic role of FLC in cardiorenal relationships may be revealed in further studies.
#2111 Prediction of ESRD in IgA nephropathy using IgA: C3 ratio at diagnosis. 10 year cohort
Authors: Ker Robert , Rankin Alistair , Doyle Arthur 
Published: May 2024

Abstract

Background and Aims
IgA Nephropathy is the commonest glomerular pathology with a wide range of outcomes depending on the severity of the circulating serological pathophysiology and on the resulting inflammatory response in the kidney. Prediction of kidney loss, which results in renal failure in 20-40% of cases -versus very benign disease, has largely used traditional clinical parameters such as proteinuria, hypertension and already established renal decline at the point of diagnosis. There has been variable utility from biopsy severity scoring. Pathogenicity of IgA immune complexes may result from activation of complement via the alternative pathway and assessment of serum IgA and complement C3 has been suggested as a marker of pathogenicity. We examined the utility of IgA to C3 ratio in predicting outcomes in a cohort over 10 years

Method
We examined all the electronic records of biopsy proven IgA cases from 2010 onwards when serum electrophoresis and serum complement became been widely tested at all new renal presentations. These cases were followed to end stage kidney disease or death. A subset of diagnosed patients also had MEST-C score.

Results
Of 319 biopsy proven IgA cases between 2010 and 2023, 216 had serum IgA and complement studies at diagnosis, with median PCR 309 and median serum creatinine 177. 56 patients had IgA:C3 &gt;4. Outcome of “death or renal replacement therapy” rather than the surrogate “RRT or doubling serum creatinine” was possible due to the length of follow up. Median follow up was 4.5 years, during which 101 (46%) died or reached ESRD. Among those with IgA:C3 &gt; 4, 35 (61%) median survival 5 years, versus 67(42%) of those &lt; 4 (median survival 10 years). Hazard ratio for IgA:C3 &gt;4 was 1.9 (1.2-3.2) Cox Proportional Hazard show this to be independent from presenting creatinine, proteinuria, but not independent of age.
A cohort of 107 biopsy proven IgA cases between 2010 and 2015 had data on CMEST score. 62 of this cohort also had IgA and complement measured. There was no correlation with CMEST score, or occurrence of crescents present on biopsy
There were no differences in the treatments used following diagnosis of IgA Nephropathy. Similar proportions receiving steroid, calcineurin or mycophenolate.

Conclusion
IgA to C3 ratio is readily available result which powerfully predicts IgA outcome independently from pathology score and traditional clinical severity estimates. It may well become a useful indicator to target novel immune/complement therapies.
#2684 Free light chains levels in ANCA associated vasculitis: a new potential inflammatory biomarker
Authors: Kronbichler Andreas , Barnini Cecilia , Matyjek Anna 
Published: May 2024

Abstract

Background and Aims
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic disease characterized by an immune-mediated process where inflammation plays a central role. The widely available serum biomarkers of inflammation are not always able to detect ongoing disease activity in ANCA-associated vasculitis (AAV) patients. Free light chains (FLCs) expression levels have been proposed as new promising biomarker in some immune-mediated and inflammatory diseases. The aim of this study is to evaluate the expression levels of FLCs in patients affected by AAV and investigate the potential effect of rituximab treatment on FLCs levels.

Method
We conducted a retrospective multicenter study enrolling AAV patients in complete remission of AAV (defined as BVAS/GPA = 0); those with clinical suspicion of underlying hematologic malignancy were excluded. We analyzed κ and λ FLCs serum concentrations and evaluated their correlation with biomarkers of immune system activation, such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum immunoglobulin (Ig) levels, serum C3 and C4 complement and albumin levels (which has a negative correlation with acute inflammatory phase). We assessed impact of rituximab (RTX) therapy within the last 6 months on the same laboratory parameters.

Results
A total of 137 patients with AAV were recruited, who were gender balanced, had an average age of 68 years and an estimated glomerular filtration rate of 68 (43-89) mL/min/1.73 m2. Fifty-one patients received rituximab treatment (RTX group), while 86 patients were on other immunosuppressive maintenance therapies (non-RTX group). In comparison to non-RTX group, patients treated with RTX experienced higher complement C3 levels, lower ESR levels and lower FLCs κ (p = 0.063) and λ (p = 0.013) levels. The differences between RTX and non-RTX groups in terms of FLCs were even more prominent after correction to total Ig concentration (p = 0.004 for κ /Ig and p = 0.003 for λ /Ig, respectively). Both, serum free κ and λ levels were found to correlate significantly with ESR (R = 0.55 and p &lt; 0.001 for κ; R = 0.53 and p &lt; 0.001 for λ) and albumin (R = ‒0.38 and p &lt; 0.001 for κ; R = ‒0.33 and p &lt; 0.001 for λ). Additionally, serum free κ levels showed an inverse association with C3 (R = ‒0.18 and p = 0.041).

Conclusion
In subjects with AAV, FLC levels were found to be associated with markers of inflammation and complement activation; hence FLCs levels may represent a promising biomarker for detection of subclinical inflammation in AAV patients on maintenance therapy. Rituximab therapy showed a potential to reduce the levels of markers of subclinical inflammation, including FLCs.
#1532 Correlation between TNF-alpha, IL-4 and IL-6 levels and vitamin D in patients with SLE lupus nephritis
Authors: Khusankhodjaeva Feruza , Sharapov Olimkhon , Daminova Kamola 
Published: May 2024

Abstract

Background and Aims
Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease characterized by multisystem organ damage and high titers of autoantibodies to a number of nuclear and cytoplasmic antigens. Numerous abnormalities of the cytokine network have been observed in patients suffering from SLE. However, the relationship between cytokines and vitamin D in damage to the kidneys and various organs has not been studied enough.

Aim
To determine whether interleukin-6.4 (IL-6.4) and tumor necrosis factor (TNF-alpha) levels correlate with vitamin D deficiency in patients with SLE/FN.

Method
We determined the levels of TNF-alpha, IL-6, IL-4 and vitamin D in the blood of patients with SLE/FN in 108 people.

Results
Levels of TNF-alpha, IL-4 and IL-6 were higher in SLE/FN patients with vitamin D deficiency. Further analysis showed that this association was dependent on an inverse correlation (P = 0.017, r = ‒0, 49) for IL-6, (P = 0.023, r = ‒0.42) for IL-4, and (P = 0.76, r = ‒0.243) for TNF-alpha. The average level of TNF-alpha was (3.2+/-6.92 pg/ml), IL-4 and IL-6 showed results (2.13+/-8.72 pg/ml) and 5.02+ /-7.22 pg/ml) respectively for patients with vitamin D deficiency, while it was for IL-6, for IL-4 (3.5+/-6.43 pg/ml) and TNF- alpha (4.33+/-8.61 pg/ml) for patients with normal concentrations of vitamin D in the blood and IL-6, (1.02+/-5.1 pg/ml), IL-4 (2.13+/- 6.4 pg/ml), TNF-alpha (1.45+/-5.28 pg/ml), for the healthy control group, respectively. The difference was statistically significant (P = 0.002). We found a significant positive correlation between TNF-alpha, IL-4 and IL-6 and low vitamin D levels, respectively, and with the SLE Disease Activity Index (SLEDAI). (r = +0.743 and +0.772, respectively).

Conclusion
Increased levels of IL-4, IL-6 and TNF-alpha may influence the development and progression of nephritis in patients with SLE, in addition, the production of large amounts of IL-4, IL-6 and TNF-alpha correlates with low levels of vitamin D in the blood.