bluuebunny/crossref_metadata_2025_split huggingface dataset:
MO039THE 24-WEEK INTERIM ANALYSIS RESULTS OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE II STUDY OF ATACICEPT IN PATIENTS WITH IGA NEPHROPATHY AND PERSISTENT PROTEINURIA
Authors: Barratt Jonathan , Tumlin James A , Suzuki Yusuke , Kao Amy , Aydemir Aida , Zima Yulia , Appel Gerald 
Published: June 2020

Abstract

Background and Aims
IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. Despite being described over 50 years ago, there remains no approved therapy for this common global cause of kidney failure. The central pathogenic feature in IgAN is the formation of circulating IgA containing immune complexes which have the propensity to deposit in the kidneys and trigger glomerular inflammation and tubulointerstitial scarring. The primary substrate for immune complex formation is an excess of poorly O-galactosylated polymeric IgA1 (Gd-IgA1) in the circulation. These IgA1 O-glycoforms are thought to trigger the formation of IgA and IgG autoantibodies. Atacicept is a human TACI-Ig fusion protein that inhibits B cell-stimulating factors, BLyS and APRIL, and has been associated with reductions in levels of serum IgA and IgG, as well as reductions in mature B cells and plasma cells. A number of studies have shown elevated levels of BLyS, APRIL and Gd-IgA1 in IgAN patients which have been linked to worse clinical outcomes. IgAN patients with persistent proteinuria &gt;1 g/day are at increased risk of progression to end-stage renal disease. This Phase II study examines the safety and efficacy of atacicept in reducing pathogenic Gd-IgA1 levels and measures of renal activity in IgAN.

Method
This Phase II study (NCT02808429) enrolled patients with IgAN and proteinuria ≥1 g/day or 0.75 mg/mg on 24-hour urine protein-creatinine ratio (UPCR) despite maximal standard of care therapy (angiotensin converting enzyme inhibitor and/or angiotensin receptor blocker). Enrolled patients were randomized 1:1:1 to receive placebo or atacicept 25mg or 75mg once weekly by subcutaneous injection. The primary endpoint was a change in proteinuria by 24-hour UPCR at Week 48; key secondary endpoints included change in eGFR, serum immunoglobulin and Gd-IgA1 levels.

Results
Data from the 24-week interim analysis are reported here for enrolled patients (placebo=5; atacicept 25mg=6; atacicept 75mg=5). A consistent, dose-dependent reduction in serum immunoglobulins (IgA, IgG and IgM) and, in particular, Gd-IgA1 (Figure) were observed through Week 24. In parallel, proteinuria (24-hour UPCR) showed a higher median % reduction from baseline with atacicept at Week 24: -18.67% and -25.34% with atacicept 25 mg and 75 mg, respectively, vs +0.098% with placebo (Figure). eGFR remained stable over time. TEAEs were reported by 81% of the subjects. TEAEs were mild or moderate in severity, with no severe TEAEs reported. No serious related events, events with severe hypogammaglobulinemia or fatal outcome were reported.

Conclusion
These 24-week interim analysis results provide early proof of concept for the potential treatment of atacicept in patients with IgAN and persistent proteinuria.
MO049EFFECT OF VITAMIN D ON ENDOTHELIAL FUNCTION IN EARLY DIABETIC NEPHROPATHY
Authors: Mahapatra Himansu , Kumar Adarsh , Kulshreshtha Bindu , Chirkara Anubhuti 
Published: June 2020

Abstract

Background and Aims
Diabetic Nephropathy is associated with endothelial dysfunction at an early stage. The benefit of Vitamin D supplementation on endothelial function is supported by a few studies in non-diabetic chronic kidney disease (CKD). However, studies on its effect in early DN is scarce. Hence, the present study was planned to assess the effect of vitamin D supplementation on endothelial function by measuring Flow mediated dilation (FMD) in patient of early DN.

Method
A total of 730 Diabetic subjects were screened for early DN based on Inclusion criteria (eGFR ≥ 120ml/min/1.73m2 with unrestricted ACR value eGFR of 60- 120 mL/min/1.73m2 and ACR 30-300mg) and Exclusion criteria (on ACE I or ARB, eGFR&lt;60ml/min/1.73m2, Hypercalcemia (&gt;11.5mg%), UTI, Pregnancy, Hypertension, HbA1c (&gt;8.0 %), vitamin D supplementation during the last 6 month). Of them 103 included subjects were underwent randomization to receive either Cholecalciferol (54) or matching Placebo (49) in a double blind method. All were subjected to routine investigations, urinary albumin: creatinine (UACR), C reactive protein (CRP), serum 25(OH)vitamin D, intact parathyroid hormone (iPTH) and Flow mediated dilatation at the zero and six months. All subjects were subjected. Comparative results at zero and six months of both groups were compared and analyzed.

Results
There was no significant difference between cholecalciferol and placebo group with respect to CRP, iPTH, 25-hydroxyvitamin D (25(OH) D), UACR, FMD at baseline. Median FMD after 6 month was significantly higher in cholecalciferol as compared to placebo group [Median (IQR): 24 % (21.75-26.0) and 22% (18-24) respectively, p= 0.01]. After 6 month UACR was significantly lower in the cholecalciferol group as compared to placebo group (p= 0.04). Significant association of vitamin D level was observed with CRP level. In 25(OH) D &lt; 20 ng/ml subgroup there was significant decrease in CRP level in comparison to 25(OH) D ≥20 ng/ml subgroup (p=0.04).

Conclusion
There was significant improvement in endothelial function as assessed by FMD% following vitamin D supplementation. Vitamin D supplementation given to early diabetic nephropathy patients may have favourable effects on cardiovascular outcome as reflected by improvement in FMD% and decrease in CRP level.
MO060ACUTE KIDNEY INJURY PROMOTES DEVELOPMENT OF A PAPILLARY RENAL CELL ADENOMA-CARCINOMA SEQUENCE FROM RENAL PROGENITORS
Authors: Peired Anna Julie , Allinovi Marco , Antonelli Giulia , Angelotti Maria Lucia , Guzzi Francesco , Romagnani Paola 
Published: June 2020

Abstract

Background and Aims
Renal cell carcinoma (RCC) accounts for 2% of all cancers, with about 190,000 new cases per year worldwide. Risk factors for RCC include obesity, diabetes, hypertension and genetic factors, but the majority of cancers occur in apparent absence of clear risk factors. Acute tissue injury (AKI) causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. We proposed to verify whether AKI plays a role in RCC development, and to identify the cellular origin of RCC.

Method
We used the following techniques: 1. observational, retrospective clinical trial to identify a possible association of AKI with RCC. 2. Experimental AKI induction in wild-type mice to study tumor development over 36 weeks. 3. Analysis of TCGA Research Network dataset on human papillary RCC (pRCC) molecular characterization, focusing on AKI-driven pathways. 4. Development of mouse models in which the intracellular domain of Notch 1 (NICD1), a molecule modulated during AKI, is expressed constitutively by all Pax8+ tubular epithelial cells (Pax8/NICD1) or only by Pax2+ renal progenitors (Pax2/NICD1) upon induction in adult mice. The mice were sacrificed at 36 weeks or 4 weeks after AKI. 5. Clonal analysis of tumoral lesions with Confetti reporter. 6. Examination of single cell RNA sequencing (RNAseq) data from pRCC patients.

Results
We observed that an AKI episode is a major risk factor for pRCC development and recurrence in patients. Wild-type mice subjected to AKI developed pRCC over time in an adenoma-carcinoma sequence, corroborating our human findings. Among AKI-related pathways, Notch1 overexpression in human pRCC associated with worse outcome, prompting us to generate Notch1-overexpressing mice. At 36 weeks o at 4 weeks following AKI, Pax8/NICD1 mice presented a significant decline of renal excretory function as well as type 2 pRCCs. Confetti lineage tracing showed that most of the pRCCs were monoclonal or biclonal, suggesting that they could originate from a local stem cell/progenitor population. Pax2/NICD1 mice presented type 2 pRCCs, and lineage tracing identified single Pax2+ tubular progenitors as the source of pRCCs. Single cell RNAseq analysis confirmed that the molecular signature of the pRCC cell of origin matched the one of human tubular progenitors.

Conclusion
This study expose the link between AKI and pRCC development in patients, with important clinical implications. In mice, AKI promotes long-term development of type 2 papillary tumors by activating the AKI-associated Notch1 pathway. Additionally, pRCC originates from clonal proliferation of renal progenitors in a classical adenoma-carcinoma sequence leading to invasive pRCC growth and metastatization in mice.
MO062CHRONIC KIDNEY DISEASE, INFLAMMATION, AND HEART FAILURE WITH PRESERVED EJECTION FRACTION: A RENAL-CARDIO AXIS?
Authors: Chade Alejandro , Williams Maxx , Engel Jason , Bidwell Gene 
Published: June 2020

Abstract

Background and Aims
Inflammation contributes to progressive renal dysfunction and increases cardiovascular mortality of patients with chronic kidney disease (CKD). The association of CKD and heart failure with preserved ejection fraction (HFpEF) is observed in up to 50%, suggesting the possibility of a shared pathophysiology. CKD and HFpEF are commonly associated with inflammation. Using a novel swine model of CKD and HFpEF, we propose that a renal-cardio inflammatory axis drives diastolic dysfunction and HFpEF in CKD and that targeting renal inflammation will improve cardiac health and reduce cardiovascular risk.

Methods
We developed a biopolymer-fused peptide of nuclear-factor kappa (NFk)B (ELP-p50i) that we show it blocks its activity in vitro and in vivo. NFkB is a key pro-inflammatory transcription factor that is upregulated in CKD. To test our hypothesis, we induced CKD in 10 pigs via bilateral renovascular disease and dyslipidemia. Pigs were observed for 6 weeks, renal hemodynamics quantified (multi-detector CT), then randomized to single intra-renal ELP-p50i or placebo (n=5 each), and studies repeated 8 weeks later accompanied by echocardiographic assessment. Blood pressure was continuously measured (telemetry). Blood was collected to measure circulating TNF-α and biomarkers of HF (ANP, BNP). Furthermore, kidneys and hearts were used to quantify expression of factors involved in NFkB signaling.

Results
CKD led to a significant loss of renal function, accompanied by left ventricular hypertrophy and diastolic dysfunction with pEF, increased renal mRNA expression of TNF-α and canonical and non-canonical mediators of NFkB signaling, and elevated systemic TNF-α, ANP, and BNP, indicating renal and cardiac dysfunction. Most of these changes were improved after intra-renal ELP-p50i, although cardiac inflammatory signaling was unchanged (Figure) suggesting the kidney as a source of inflammation that can target the heart in CKD.

Conclusion
We show that a renal anti-inflammatory strategy via targeted inhibition of renal NFkB improves renal and cardiac function in CKD, suggesting an inflammatory renal-cardio axis. The translational pathological features of CKD and HFpEF combined with the predictive power of the model may contribute to advance the field towards new treatments targeting renal inflammation to reduce cardiovascular risk in CKD.
MO064TISSUE-RESIDENT B CELLS DETERMINE SUSCEPTIBILITY TO URINARY TRACT INFECTION BY ORCHESTRATING MACROPHAGE POLARISATION
Authors: Suchanek Ondrej , Wijeyesinghe Sathi , Ferdinand John , Tuong Zewen K , Chandra Anita , Clare Simon , Bashford-Rogers Rachael , Lawley Trevor , Okkenhaug Klaus , Masopust David , Clatworthy Menna 
Published: June 2020

Abstract

Background
Urinary tract infection (UTI) is an important clinical problem. More than half of women and 1 in 10 men will be affected during their lifetime. Many of these affect the lower urinary tract but recurrent pyelonephritis can lead to scarring and chronic kidney disease. There is an increasing appreciation that tissue-resident immune cells, such as macrophages, play an important role in defence against infection, but only little is known about B lymphocytes in this context. Here we sought to address the question of whether B cells reside in the kidney and bladder in homeostasis and to determine their phenotype and contribution to local organ immunity.

Methods and Results
Using intravenous labelling and parabiosis, we identified a population of bona-fide self-renewing, tissue-resident B cells that included non-naïve and innate-like CD5+ B-1 cells, in murine kidneys and urinary bladder (but also in liver and lung). The size and phenotype of this B cell subset was influenced by genetic background, age, and microbiome, with an expanded population evident after co-housing with pet-store mice. Although kidney B cells had less diverse Igh repertoire compared to blood, their seeding was largely independent of their B-cell receptor specificity. In human kidneys we found a similar enrichment for non-naïve B cells compared to blood and spleen.
Using two strains of genetically modified mice with higher (PI3KδE1020K-B) or lower (μMT-) numbers of tissue-resident B cells, we tested the function of these cells during UTI. Surprisingly, the number of tissue-resident B cells inversely correlated with bacterial clearance. We found that these B cells were spatially co-localised with kidney macrophages and skewed their polarization towards an anti-inflammatory M2 phenotype, leading to reduced anti-microbial responses. This effect was, at least in part, driven via IL-10.

Conclusion
In conclusion, our data identify a critical role for tissue-resident B cells in modulating local immunity in the urinary tract, determining the inflammatory ‘set-point’ of resident and recruited myeloid cells, with important clinical implications for the use of B-cell depleting therapies and conditions such as infection, transplant rejection, fibrosis or autoimmunity.

Graphical Abstract
MO065TUBULAR EPITHELIAL CELL POLYPLOIDIZATION IS REQUIRED TO SURVIVE AKI BUT PROMOTES CKD DEVELOPMENT
Authors: De Chiara Letizia , Lazzeri Elena , Angelotti Maria Lucia , Conte Carolina , Peired Anna Julie , Antonelli Giulia , Melica Maria Elena , Mazzinghi Benedetta , Lasagni Laura , Romagnani Paola 
Published: June 2020

Abstract

Background and Aims
Acute kidney injury (AKI) is a global health concern. If not lethal in the acute phase, AKI is considered reversible based on the capacity of surviving tubular cells (TECs) to re-enter cell cycle. However, even mild AKI episodes carry a substantial risk of developing chronic kidney disease (CKD). The pathophysiological basis for this phenomenon remains unclear. Recently, we demonstrated that tubular epithelial cells (TECs) can undergo endoreplication-mediated hypertrophy after AKI. Endoreplications are incomplete cell cycles that lead to the formation of polyploid cells. As polyploid cells can provide increased cell function without restoring tissue integrity, we hypothesized that this mechanism is essential to survive AKI but it can be potentially maladaptive.

Method
To address this hypothesis, we employed a series of in vitro and in vivo transgenic models based on the Fluorescence Ubiquitin Cell Cycle Indicator (FUCCI) technology to monitor cell cycle phasing in combination with YAP1 overexpression or downregulation. In the in vivo models, YAP1 overexpressing mice and YAP1 knock-out mice were subjected to unilateral ischemia reperfusion injury (IRI) or glycerol-induced rhabdomyolysis to induce AKI. Polyploid cells have been then characterized by microarray analysis, cell sorting, super-resolution STED microscopy and transmission electron microscopy.

Results
In vitro, human renal tubular cells undergo polyploidization. The fraction of polyploid cells significantly decreases when YAP1 nuclear translocation is blocked, suggesting a possible involvement of YAP1 in regulating TEC polyploidization. After AKI in mice, the inhibition of YAP1 significantly reduces the number of polyploid cells and worsens kidney function resulting in a dramatic decrease of mouse survival. In contrast, YAP1 overexpression leads to an increase in the number of polyploid cells up to 20% of all TECs, further confirming the role of YAP1 in controlling TEC polyploidization. In YAP1 overexpressing mice, electron microscopy and STED analysis revealed the presence of both mononucleated and binucleated polyploid cells. Strikingly, these mice appear to be more prone to develop tubulointerstitial fibrosis acquiring a marked senescent phenotype along with significant decline in renal function thus suggesting an association between polyploidization and CKD development. Indeed, isolation of polyploid cells proved that these cells actively transcribe and secrete pro-fibrotic and senescent factors confirming their role in CKD progression.

Conclusion
These data suggest that: 1) polyploidization after AKI is required to preserve renal function in the acute phase of damage and it is essential for survival 2) polyploid cells are pro-fibrotic and senescent leading in the long run to the progression of AKI to CKD.
MO066GASDERMIND MUTATION IS PROTECTIVE AGAINST RENAL ISCHEMIA REPERFUSION INJURY
Authors: Rogers Natasha , Li Jennifer , Alexander Stephen 
Published: June 2020

Abstract

Background and Aims
Ischemia reperfusion injury (IRI) is an important contributor to acute kidney injury (AKI) and manifests as delayed graft function following kidney transplantation. Limiting the damage of IRI has implications on graft outcomes and has driven further exploration of the underlying pathophysiology. We hypothesize that pyroptosis, a pro-inflammatory form of cell death, has an important role in IRI and AKI. The pyroptosis pathway converges to the cleavage and release of N-terminal of the Gasdermin-D protein, leading to pore formation in the cell membrane and cell death. We examined the effects of Gasdermin-D mutation on inflammation in acute kidney injury.

Method
Male C57BL/6 mice were exposed to ethyl-N-nitrosourea mutagenesis, leading to a loss-of-function, single nucleotide polymorphism (isoleucine to asparagine mutation, I105N) in the Gasdermin-D gene. Age- and gender-matched littermate control wild-type, heterozygous and homozygous Gasdermin-DI105N mice were subjected to bilateral renal IRI (36°C, 22mins) and sacrificed 24-hours post-reperfusion for analysis of renal function, histology and biomolecular phenotyping. To delineate if the GasderminD mutation in renal parenchymal or hematopoietic cells were key drivers of IRI, we generated chimeric mice with whole body irradiation and infusion of syngeneic donor bone marrow. Following 8 weeks of engraftment, bilateral renal IRI was performed with analysis at 24 h reperfusion.

Results
Homozygote and heterozygote Gasdermin-DI105N mice were protected from renal IRI in a gene dose-dependent manner when compared to wild-type, with lower mean serum creatinine (15.7, 48.1 and 85.5µmol/L respectively, p&lt;0.001), less histological tubular injury and cell death (1.8, 3.6 and 5.1 TUNEL+ cells/hpf, p&lt;0.01) and significantly decreased expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, RANTES). Homozygote GasderminDI105N chimeric mice (reconstituted with wild-type donor bone marrow) were more susceptible to IRI, and serum creatinine was similar to that of wild-type chimeric control mice, indicating that hematopoietic cells rather than parenchymal cells, are likely predominant drivers of injury. Similarly, adoptive transfer of CpG-activated CD11c+ dendritic cells into homozygous Gasdermin-DI105N mice augmented renal injury compared to GpC-treated cells.

Conclusion
GasderminDI105N mice were protected from IRI and demonstrates the importance of the pyroptosis pathway on acute kidney injury. Manipulation of GasderminD is potentially an attractive target to mitigate inflammation and cellular death following injury.
MO078HEMODIAFILTRATION MAINTAINS A SUSTAINED IMPROVEMENT IN BP COMPARED TO CONVENTIONAL HEMODIALYSIS IN CHILDREN - THE HDF, HEART AND HEIGHT (3H) STUDY
Authors: De Zan Francesca , Bayazit Aysun Karabay , Azukaitis Karolis , Canpolat Nur , Bakkaloglu Sevcan , Krid Saoussen , Litwin Mieczysław , Paglialonga Fabio , Samaille Charlotte , Shenoy Mohan , Sinha Manish , Spasojevic Brankica , Schmitt Claus , Schaefer Franz , Vidal Enrico , Shroff Rukshana 
Published: June 2020

Abstract

Background and Aims
Hypertension is prevalent in children on dialysis and associated with left ventricular hypertrophy, cardiovascular disease and mortality. We studied the effect of different dialysis modalities (conventional hemodialysis [HD] vs hemodiafiltration [HDF]) on BP and risk factors affecting the evolution of BP over a one-year follow-up.

Method
This is a post-hoc analysis of the “3H - HDF-Hearts-Height” dataset, a multicenter, non-randomized, parallel-arm intervention study. The time–averaged 24-h mean arterial pressure (MAP) was used for the analyses and hypertension defined as 24-h MAP standard deviation score exceeding the 95th percentile.

Results
All 133 children who completed 12 months follow-up in the 3H study were included in this post - hoc analysis. 78 (74%) were on HD and 55 (77%) on HDF. At baseline MAP-SDS was &gt; 95th percentile in 64 (82%) of children on HD and 23 (41.8%) patients on HDF, but these data are skewed by a high percentage of prevalent dialysis patients in the study. 43 (55%) of HD patients and 23 (42%) of HDF patients were on antihypertensive medications, and uncontrolled hypertension (BP&gt;95th centile on medications) was present in 38 (88%) of HD patients and 6 (25%) of HDF patients. In the stepwise logistic regression at baseline, independent risk factors for hypertension were gender (OR 2.29; 95%CI 1.06–4.96; p=0.04) and inter-dialytic weight gain at baseline (OR 1.3; 95%CI 1.1–1.55; p=0.004). Over the one-year study period, MAP-SDS increased by 39% in HD patients and 12% in HDF patients (p&lt; 0.001) (Figure). Significant risk factors for hypertension over time were dialysis modality (OR for HD compared to HDF 7.65; 95% CI 3.23 – 18.12; p&lt; 0.001), inter-dialytic weight gain (OR 1.21; 95% CI 1.05 – 1.39; p=0.007), and dialysate sodium (for 1 mmol/L increase in dialysate sodium MAP-SDS increased by 1.1mmHg ; 95% CI 1.01 – 1.21; p=0.04).

Conclusion
Children on HD compared to HDF had a 7.6-fold higher 24-hr MAP-SDS and a sustained increase in BP over the one-year study period. Higher inter-dialytic weight gain and higher dialysate sodium levels were associated with a higher MAP-SDS in both groups.