bluuebunny/crossref_metadata_2025_split huggingface dataset:
SO075ADOPTIVE TRANSFER OF GINGIVA-DERIVED MESENCHYMAL STEM CELLS AMELIORATES LUPUS NEPHRITIS VIA INDUCTION OF CD4+HELIOS-FOXP3+ TREG THROUGH TARGETING OF CD39/CD73 SIGNALING PATHWAY
Authors: Xu Zhenjian , Chen Junzhe , Xu Anping 
Published: June 2020

Abstract

Background and Aims
Current approaches offer no cures for lupus nephritis. Accumulating evidence has revealed that manipulation of bone-marrow mesenchymal stem cells (BMSCs) may have the potential to treat lupus nephritis. While BMSC-based therapy faces many challenges such as limited cell availability, BMSCs from patients with autoimmune diseases are dysfunctional, use of BMSCs with long term has a potential risk on tumorigenesis and reduced clinical feasibility, we herein demonstrate that substitution of gingival-derived mesenchymal stem cells (GMSCs) results in significantly improved therapeutic effects on lupus-like disease model.

Method
Lupus-like disease has been induced with female New Zealand mixed (NZM) 2328 mice. In the study of prevention of lupus-like disease, GMSCs were injected i.v. into mice on age of 10 weeks. In some experiments, mice were injected with pre-treatment of GMSCs with CD39 or CD73 inhibitor. In the study of treatment of lupus-like disease, GMSCs were injected i.v. into mice on age of 20 weeks.

Results
In the study of prevention of lupus-like disease, infusion of GMSCs in NZM2328 mice significantly decreased the severity of lupus and kidney pathology scores, and down-regulated Th2, Tfh and Th17 cells. GMSCs significantly suppress activation and differentiation of B cells in vivo. Promotion of CD4+Helios- Foxp3+Treg cells following treatment with GMSCs, these increased Tregs were noted in spleen, LN and Kidney. Pre-treatment of GMSCs with CD39 or CD73 inhibitor significantly reversed the protective effect of GMSCs on lupus-like disease model. In the study of treatment of lupus-like disease, GMSCs can also treat the established disease.

Conclusion
The role of GMSCs in controlling lupus-like disease mostly depends upon CD39/CD73 signals and upon the induction of CD4+ Helios-Foxp3+Treg cells. GMSCs provide a promising approach for the treatment of lupus nephritis.
SO076EVOLOCUMAB HAS THERAPEUTIC EFFECTS ON EXPERIMENTAL MODEL OF FSGS
Authors: Suzuki Taihei , Iyoda Masayuki , Kanazawa Nobuhiro , Wada Yukihiro , Honda Hirokazu 
Published: June 2020

Abstract

Background and Aims
Proprotein convertase subtilisin/kexin type 9 (PCSK9), which accelerates LDL-receptor degradation, plays a central role in dyslipidemia in nephrotic syndrome (NS). Intracellular LDL-C accumulation is supposed to damage podocytes through oxidative stress, foam cell formation, and apoptosis. In the present study, we investigate the effects of evolocumab (EVO), which is anti-PCSK9 monoclonal antibody, on a murine model of adriamycin-induced focal segmental glomerulosclerosis (FSGS) with NS in order to clarify the potential of EVO as a therapeutic agent in FSGS.

Method
Male BALB/c mice aged 9 to 11 weeks were divided into vehicle and intervention groups. The mice underwent subcutaneous injection of normal saline (FSGS-Vehicle group) or EVO (30 mg/kg) (FSGS-EVO group) and immediately after that, they were administered adriamycin (11.5 mg/kg) from tail vein. All mice were sacrificed on Day 14, and then morphological and functional analyses were performed.

Results
EVO treatment significantly reduced serum levels of LDL-C (mg/dl, 305.3±77.1 vs. 159.1±31.7, p&lt;0.01) and PCSK9 (ng/ml, 652.9±230.0 vs 311±116.5, p&lt;0.001). In addition, EVO treatment significantly improved renal function, including albuminuria (albumin/creatinine (Cr), 15.73±1.26 vs. 7.32±1.02, p&lt;0.001), serum Cr (mg/dl, 0.48±0.13 vs. 0.18±0.044, p&lt;0.001) and BUN (mg/dl, 80.08±20.22 vs. 46.86±9.60, p&lt;0.05). Compatibly with the clinical data, the severity of glomerulosclerosis score (semi-quantification, 2.44 vs. 1.95, p&lt;0.001) was ameliorated and podocyte density (number of podocyte/glomerulus, 2.61 vs. 7.54, p&lt;0.001) was maintained in the FSGS-EVO mice compared with the FSGS-Vehicle mice.

Conclusion
Our findings provided novel insights into the protective effects of EVO on adriamycin nephropathy, indicating EVO as a potent therapeutic agent for FSGS.
SO080NOVEL EVIDENCE OF THE “PULMO-RENAL INTERACTION” AS A DISEASE DRIVER IN PATIENTS WITH CKD AND COPD
Authors: Schunk Stefan , Beisswenger Christoph , Herr Christian , Ritzmann Felix , Sarah Triem , Schmit David , Omlor Albert , Jörres Rudolf , Watz Henrik , Welte Tobias , Vogelmeier Claus , Zewinger Stephen , Fliser Danilo , Bals Robert , Speer Thimoteus 
Published: June 2020

Abstract

Background and Aims
Chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD) represent a global public health problem worldwide. As such, both conditions are associated with high disease-related morbidity and mortality. However, it is unclear whether the presence of CKD aggravates the clinical course of COPD and vice versa.

Method
In a novel murine model of cigarette smoke (CS)-induced lung injury combined with an adenine nephropathy model, kidney and lung inflammation, and fibrosis were studied. Moreover, in 2,314 patients with stable COPD enrolled in the prospective, multi-centre COSYCONET study, urinary Dickkopf-3 (DKK3), a biomarker of kidney injury and CKD progression was quantified. The association between urinary DKK3 and trajectories of forced expiratory pressure in 1 second (FEV1) and estimated glomerular filtration rate (eGFR) during a median follow-up of 37.1 months, exercise capacity, risk of exacerbation, and mortality was determined.

Results
In the CKD-COPD animal model, the presence of kidney injury was associated with increased systemic and pulmonary inflammation, impaired pulmonary function, as well as more severe damage of the lung architecture. Moreover, CS enhanced kidney fibrosis. Accordingly, in the COPD patients from the COSYCONET study, higher urinary DKK3 was associated with declining FEV1 during follow-up (OR 3.36, 95% CI 2.22-5.08). Moreover, high urinary DKK3 was associated with higher risk for exacerbation (OR 1.24, 95% CI 1.03-1.50), lower 6-minute walking distance, and higher all-cause mortality (HR 1.49, 95% CI 1.08-2.05). Importantly, high urinary DKK3 was associated with declining eGFR during follow-up (OR 2.23, 95% CI 1.22-4.07) independently from baseline kidney function and proteinuria, which was confirmed by a machine learning approach.

Conclusion
These data uncover a novel pathophysiological link between CKD and COPD. Patient with COPD and concomitant CKD are at high risk for worsening pulmonary function and adverse outcomes. Elevated urinary DKK3 allows identification of COPD patients with progressive CKD. Measurement of urinary DKK3 in patients with COPD may therefore represent a novel tool for risk stratification and the identification of patients, who might in particular benefit from preventive therapeutic strategies to prevent progression of COPD and CKD as well.
SO082LATENT TRANSFORMING GROWTH FACTOR BETA BINDING PROTEIN (LTBP4) CAN REGULATE RENAL FIBROSIS AND ALTER INFLAMMATION AND MITOCHONDRIAL DYSFUNCTION IN CHRONIC KIDNEY DISEASE (CKD)
Authors: Su Chi-Ting , Jao Tzu-Ming , Huang Jenq-Wen 
Published: June 2020

Abstract
Background and Aims: Transforming growth factor beta (TGF-beta) has been well known as a key factor for fibrosis and inflammation. LTBPs regulate TGF-beta signalling in complicated ways. Disruption and loss of LTBP4 expression is associated with abnormal accumulation of extracellular matrix (ECM) and altered TGF-beta activation. However, the role of LTBP4 in chronic kidney disease remains largely unknown. We aim to explore the mechanisms of LTBP4-related regulation in kidney disease.
Method: To investigate the impact of LTBP4 on tubulointeresitial fibrosis (TIF), we generated LTBP4-overexpression human renal proximal tubule cells (HK-2), treated with exogenous TGF-beta and established a fibroblasts-HK-2 co-culture system using rat fibroblasts (NRK-49F) and HK-2 cells. Moreover, to create TIF model, we performed unilateral ureteral ligation (UUO) in Ltbp4S-/- mice and wild-type (WT) mice to check ECM deposition and phenotypic alterations. In addition, we performed RNA-Sequencing analysis to understand transcriptomic changes associate with LTBP4 overexpression.
Results: Up-regulation of Ltbp4 in fibrotic kidney was noted in TIF model with UUO and in renal tissue with diabetic nephropathy. LTBP4-overexpression reduced epithelial-mesenchymal transition (EMT) with showing increased epithelial-cadherin, reduced vimentin and collagen I in the co-culture system. Moreover, higher expression of fibronectin, collagen I and alpha-smooth muscle actin (alpha-SMA) were noted in fibrotic kidneys in Ltbp4S-/- mice compared with changes in WT mice, suggesting inflammation condition could be altered by the absence of Ltbp4S. The inflammatory change in renal tissue in UUO model was studied with F4/80 stain. Increased macrophage infiltration and increased monocyte chemoattractant protein-1 (MCP-1) expression were detected in Ltbp4S-/- mice compared with that in WT mice. In addition, LTBP4-overexpression reduced mitochondrial biogenesis.
Conclusion: Ltbp4 acted as a regulator of fibrosis and inflammation in fibrotic kidneys. TGF-beta- induced EMT were clearly enhanced in ltbp4 deficient environments, accompanied with reduced macrophage infiltration, which could be the major mechanism related to LTBP4/TGF-beta pathways. Furthermore, altered ATP production and usage as well as mitochondria respiration could be regulated by LTBP4 in renal failure.
SO083VASCULAR STIFFNESS ESTIMATED NON-INVASIVELY USING PULSE WAVE PROPAGATION CORRESPONDS TO VASCULAR BIOPSY FINDINGS
Authors: Debowska Malgorzata , Lindholm Bengt , Dai Lu , Waniewski Jacek , Qureshi Abdul Rashid Tony , Stenvinkel Peter , Poleszczuk Jan 
Published: June 2020

Abstract

Background and Aims
Patients with chronic kidney disease (CKD) are at high risk of cardiovascular disease (CVD) due to complex processes in the uremic milieu linked to CKD - mineral and bone disorders (CKD-MBD). These processes alter structure and function of heart and vasculature e.g. by causing ectopic calcification that makes vessels stiffer thus affecting pulse (pressure) wave profiles. Our study aimed to derive patient-specific parameters using pulse wave propagation model including arterial stiffness and compare those parameters with cardiovascular status including biopsy proven severity of vascular calcification.

Method
In a group of 81 CKD (stage 5) patients undergoing living donor kidney transplantation, the degree of medial calcification in epigastric artery was histologically graded as 0 (n=22), 1 (n=31), 2 (n=21) and 3 (n=7) representing no, minimal, moderate and extensive signs of vascular calcification, respectively. Concomitantly 82 features were determined including demographic and anthropometric features, blood biomarkers related to CKD - MBD and other measurements. Pressure profiles (circles in Fig. 1) in radial artery were recorded using applanation tonometer (SphygmoCor, AtCor Medical, Australia) and used to derive patient-specific parameters from a mathematical model describing blood flow and pressure in 55 major arteries.

Results
The model was able to reproduce all recorded pressure profiles with high accuracy with average relative error less than 8% (compare solid line and circles in Fig. 1). Vascular stiffness, derived from the model, in arterial branches located in the area of artery for which calcification was histologically quantified, was significantly higher for higher calcification score (p-value &lt; 0.001). The estimated stiffness correlated with the level of troponin T (rho=0.65**), advanced glycation end-products (by skin autofluorescence, rho=0.55*), osteoprotegerin (rho=0.44**), hepcidin 25 (rho=0.32*, interleukin 6 (rho=0.29*) and choline (rho=0.28**), (‘**’ and ‘*’ denote p-value &lt; 0.01 and 0.05, respectively). Stiffer arteries were found in patients with diagnosed CVD (p-value &lt; 0.01).

Conclusion
We demonstrate that a mathematical model based on a single peripheral recording of pulse pressure profile has the potential to provide information about cardiovascular status in the individual patient. Also, the estimated stiffness correlates well with several well-established CVD risk factors. Our mathematical model of the arterial tree, if validated in larger cohorts of patients, may be used as computational tool to predict vascular stiffness without need of arterial biopsy.
MO008B LYMPHOCYTE SUBSET CHANGES IN PRIMARY MEMBRANEOUS NEPHROPATHY
Authors: Dalili Nooshin , Pour-Reza Gholi Fatemeh , Hasanzadeh Katayoun , Assadiasl Sara 
Published: June 2020

Abstract

Background and Aims
Primary membranous nephropathy (PMN) is the most common cause of nephrotic syndrome (NS) in adults. Rituximab a chimeric monoclonal anti-CD20 antibody has been supposed to eliminate autoantibody-producing B cells via direct signaling, complement-mediated cytotoxicity (CMC), and antibody-dependent cellular cytotoxicity (ADCC). According to the fact that a wide range of B lymphocytes may carry this marker, we aimed to identify which subset is more (or less) frequent in PMN patients and which one is more affected by rituximab administration.

Method
Three groups were enrolled in the present study. They included a healthy control group and two patient groups having the clinical, laboratory, and pathological diagnostic criteria of PMN, comprising either patients on standard treatment or patients on standard treatment plus rituximab. The latter group was studied just before receiving rituximab (pre-rituximab) and two months later (post rituximab). Peripheral blood mononuclear cells (PBMCs) were isolated using Ficoll-hypaque (inno-train, Germany) gradient. Afterward, cells were adjusted to a concentration of 1 _ 106 cells/mL and stained with mouse antihuman CD19-Cy5-conjugated antibody (Cytognos, Spain), mouse antihuman CD24-PE-conjugated antibody (Cytognos, Spain), and mouse antihuman CD38-FITC-conjugated antibody (Cytognos, Spain). Flow cytometry performed by FACS Calibur (BDFacs Calibur Becton Dickinson, USA).

Results
The total lymphocyte percentage was higher in PMN patients receiving either standard treatment or rituximab than in healthy controls (standard-treatment vs. control: P value = 0.001, pre-rituximab vs. control: P value =0.001). In post-rituximab analysis, CD19+ cell count showed notable reduction (P value = 0.003)
B CD19+CD24+CD38- cells, representing the memory B cell population, did not show any significant difference between healthy controls and patients. Furthermore, the count of these cells did not decrease significantly two months after rituximab administration. The subset of CD19+CD24-CD38+ B lymphocytes, a class of naïve/mature lymphocytes with normal function, was significantly higher in the control group than in standard treatment patients (P value = 0.01). However, no statistically significant difference was found in CD19+CD24-CD38+B lymphocytes neither between the rituximab and control groups nor between pre-rituximab and post-rituximab patients.

Conclusion
The number of regulatory B cells decreased in both standard treatment and rituximab-receiving PMN patients and the proportion of naïve/mature B-lymphocytes was lower in the former group. Moreover, the memory B cells count did not reduce significantly two months after rituximab administration. Hence, it might be the best choice to target the memory B cell subset in immunosuppressive therapy while avoiding the Breg or naïve/mature B lymphocyte depletion to obtain more favorable sustained outcomes.
MO011A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF VITAMIN K SUPPLEMENTATION TO IMPROVE VASCULAR HEALTH IN KIDNEY TRANSPLANT RECIPIENTS
Authors: Lees Jennifer , Rankin Alastair , Gillis Keith , Zhu Luke , Rutherford Elaine , Roditi Giles , Witham Miles , Jardine Alan G , Mark Patrick 
Published: June 2020

Abstract

Background and Aims
Vascular stiffness (VS) and calcification (VC) are markers of cardiovascular disease which are prevalent in kidney transplant recipients (KTR) and associated with subclinical vitamin K deficiency. We tested the hypothesis that vitamin K supplementation would reduce VS and VC in prevalent KTR in the Vitamin K for kidney Transplant Organ Recipients: Investigating vEssel Stiffness (ViKTORIES) trial.

Method
In a single-centre, phase II, parallel-group, randomised, double-blind, placebo-controlled trial (ISRCTN22012044), KTR were randomised 1:1 to vitamin K (menadiol diphosphate 5mg) or placebo thrice weekly for one year. The primary outcome was between-group difference in VS (ascending aortic distensibility by cardiac magnetic resonance imaging) at 1 year by ANCOVA adjusted for the baseline value, age and duration of end-stage kidney disease. Secondary outcomes included VC (coronary artery calcium score on non-contrast computed tomography), cardiac structure and function (on cardiac magnetic resonance imaging), blood pressure, eGFR, proteinuria and quality of life. All outcomes were assessed by intention-to-treat with secondary per-protocol analyses. Missing data were multiply imputed as a sensitivity analysis for the main outcomes. The trial was conducted in accordance with the Declaration of Helsinki and was approved by the West of Scotland Research Ethics Committee 4 (Ref: 17/WS/0101). The results were combined in a meta-analysis with other published data.

Results
Ninety participants were randomised to vitamin K (n=45) or placebo (n=45) and included in the analysis. Baseline demographics, clinical history and immunosuppression regimens were similar between groups: mean age 57.6 ± 9.6 years, 70% male, with median time after transplantation 7.8 (IQR 3.5 - 13.9) years. There was no impact of vitamin K versus placebo on VS after 12 months (-0.2 (-0.5 - 0.2) vs. -0.3 (-0.6 - 0.1) x10-3 mmHg-1; p=0.60), nor on VC (184 (52 - 315) vs 44 (-89 - 177) units; p=0.11), nor on any other outcome measure. Medication adherence was very good in both groups (90 vs. 95%; p=0.58). Achieved power was 85%. Serious adverse events were common (vitamin K: 26.7 vs. placebo: 60.0%): all serious adverse events were classified as expected. Multiple imputation of missing data had no impact on results of VS or VC outcomes. Combining these with other published results, vitamin K supplementation has no significant observed effect on VS or VC, though with few available studies for analysis.

Conclusion
In this heterogeneous cohort of prevalent KTR, vitamin K supplementation did not reduce VS or VC over 1 year. Improving vascular health in patients with established kidney disease is likely to require a multifaceted approach.
MO019AURORA PHASE 3 TRIAL DEMONSTRATES VOCLOSPORIN STATISTICAL SUPERIORITY OVER STANDARD OF CARE IN LUPUS NEPHRITIS (LN)
Authors: Caster Dawn J , Solomons Neil , Randhawa Simrat , Huizinga Robert B 
Published: June 2020

Abstract

Background and Aims
Voclosporin (VCS) is a novel high potency calcineurin inhibitor (CNI) with a favorable metabolic profile and a consistent predictable dose response potentially eliminating the need for therapeutic drug monitoring. The Aurinia Renal Response in Active Lupus with Voclosporin (AURORA) study, involving 357 patients with active LN, was a Phase 3 global, double-blind, placebo-controlled RCT designed to evaluate the efficacy and safety of VCS (23.7mg BID) vs placebo in combination with mycophenolate (MMF, 2 g/day) and rapidly tapered low dose oral steroids.

Method
The primary endpoint was renal response (RR) at 52 weeks. RR was defined as UPCR of ≤ 0.5 mg/mg, eGFR ≥ 60 mL/min, or no confirmed decrease from baseline in eGFR of &gt; 20%, presence of sustained, low dose steroids and no administration of rescue medication.

Results
AURORA met its primary endpoint, achieving statistically superior RR rates of 40.8% for voclosporin vs. 22.5% for the control (OR 2.65, 95% CI; p &lt; 0.001). The benefits of VCS were also seen for all predetermined secondary endpoints, achieving statistical significance in favor of VCS for RR at 24 weeks, partial renal response (PRR) at 24 and 52 weeks, time to achieve UPCR ≤ 0.5, and time to 50% reduction in UPCR. Prespecified confirmed eGFR decreases &gt;30% were similar in both groups, with 10.1% reported in the VCS group and 10.2% in the control arm (p= 0.971). No significant differences were seen at any timepoints in the study. Furthermore, all pre-specified subgroup analyses (age, sex, race, biopsy class, region, and prior MMF use) also favored VCS. VCS was well tolerated with no unexpected safety signals. Similar SAEs were reported in the VCS group (20.8%) and in the control arm (21.3%). Infection was the most commonly reported SAE with 10.1% of VCS patients versus 11.2% of patients in the control arm. Overall mortality in the trial was low, with 6 deaths observed; 1 in the VCS arm and 5 in the control group. Additionally, the VCS arm showed no significant decrease at week 52 in eGFR or increase in BP, lipids or glucose.

Conclusion
While maintaining a comparable safety profile, VCS plus standard therapy achieved a statistically superior RR over one year compared to placebo plus standard therapy in adults with active LN.
MO021GALECTIN 3 LEVEL IS REDUCED BY TREATMENT WITH SODIUM BICARBONATE IN PATIENTS WITH CHRONIC KIDNEY DISEASE
Authors: Dobre Mirela , Patel Neil , Sapa Hima , Horwitz Edward , Melamed Michal , Hostetter Thomas 
Published: June 2020

Abstract

Background and Aims
Circulating cardiac biomarkers implicated in the pathogenesis of heart disease are a non-invasive platform to assess the cardiovascular disease (CVD) burden in individuals with chronic kidney disease (CKD). Galectin 3 is a 26 kDa β-galactoside-binding lectin that has a graded and positive association with CKD stages. In animal models, inhibition of galectin-3 prevents myocardial fibrosis. These pre-clinical findings have not been replicated in randomized controlled studies in humans. Metabolic acidosis of CKD has been shown to be associated with adverse CVD outcomes. We sought to examine whether correction of metabolic acidosis of CKD leads to lower circulating levels of Galectin 3, as an expression of myocardial fibrosis.

Method
A total of 95 participants with stages 3 and 4 CKD and a serum bicarbonate level between 21-25 mEq/L, were randomized to receive sodium bicarbonate at a dose of 0.4 mEq/kg/day once a day or placebo for two years at two clinical sites in US. Galectin 3, was measured at study baseline and after one year.

Results
Fifty participants were randomized to sodium bicarbonate and 45 to placebo. Mean age (SD) was 61.4 (10.2) years, 48% were women, 57% were non-Hispanic black, and 40% were non-Hispanic white, 61% had diabetes mellitus and 90% had hypertension at baseline. Mean baseline serum bicarbonate level was 23.5 (SD 1.7), mean (SD) baseline eGFR was 38.8 (11.2) ml/min/1.7m2 and mean (SD) baseline systolic BP was 130 (17) mmHg. There were no differences in baseline characteristics between treatment groups.
Compared to the placebo group, participants randomized to sodium bicarbonate had statistically significant change in the levels of Galectin 3 after one year of treatment (-7.12% vs 7.76% and -1.25 vs 1.54 ng/ml, p=0.03 in the sodium bicarbonate vs. placebo group, respectively, Figure). In subgroup analyses by CKD stages, participants with stage 3A randomized to sodium bicarbonate observed the highest decrement in Galectin 3 levels (-19.2% vs 14.7%, p=0.01; -3.3% vs -4.8%, p=0.49; and -7.4% vs 29.1%, p=0.09; for CKD 3B, 3B and 4, respectively).

Conclusion
The level of Galectin 3 was reduced in patients with CKD 3 and 4 treated with sodium bicarbonate. This provides a framework for future therapeutic interventions aimed at reduction of myocardial fibrosis in patients with CKD and metabolic acidosis.