bluuebunny/crossref_metadata_2025_split huggingface dataset:
FC 006PP2A PHOSPHATASE INHIBITION IS ANTI-FIBROTIC THROUGH SER77 PHOSPHORYLATION-MEDIATED ARNT/ARNT HOMODIMER FORMATION
Authors: Nyamsuren Gunsmaa , Rapp Gregor Christof , Tampe Björn , Zeisberg Michael 
Published: May 2021

Abstract

Background and Aims
Aryl hydrocarbon receptor nuclear translocator (ARNT) mediates anti-fibrotic activity in kidney and liver through induction of ALK3-receptor expression and subsequently increased Smad1/5/8 signaling. While expression of ARNT can be pharmacologically induced by sub-immunosuppressive doses of FK506 or by GPI1046, its anti-fibrotic activity is only realized when ARNT-ARNT homodimers form, as opposed to formation of ARNT-AHR or ARNT-HIF1α heterodimers. Mechanisms underlying ARNTs dimerization decision to specifically form ARNT-ARNT homodimers and possible cues to specifically induce ARNT homodimerization have been previously unknown. We here aimed to elucidate the molecular mechanisms underlying control of ARNT dimerization decision and to explore its therapeutic potential.

Method
We analyzed dimerization of recombinant and native ARNT by immunoprecipitation, MALDI-TOF mass spectrometry, and LS-MS/MS analysis and proximity ligation assay. Phosphorylation sites were mapped through generation of phosphorylation site mutants and through pharmacological inhibition. For in vivo analysis we challenged mice with model of unilateral ureter obstruction and carbon tetrachloride to induce fibrosis in kidney and liver.

Results
Here we report that inhibition of PP2A phosphatase activity increases intracellular accumulation of ARNT-ARNT homodimers. This effect is dependent on enhanced ARNT-ARNT homodimerization and decreased ARNT proteolytic degradation, but independent of ARNT transcription (which remains unchanged upon PP2A inhibition). We further identify that Ser77 phosphorylation plays a critical role in ARNT homodimerization, as ARNT-ARNT homodimers do not form with Ser77/Asp-mutant ARNT proteins. In light of previous studies which identified anti-fibrotic activity upon increased ARNT expression, we further demonstrate attenuated fibrosis upon monotherapy with the PP2A inhibitor LB100, and additive anti-fibrotic activities upon combination with pharmacological inducers of ARNT expression FK506 or GPI1046 in murine models of kidney and liver fibrosis.

Conclusion
Our study provides additional evidence for the anti-fibrotic activity of ARNT and reveals Ser77 phosphorylation as a novel pharmacological target to realize the therapeutic potential of increased ARNT transactivation activity.
FC 116WEIGHT CHANGE AS A PREDICTOR OF MORTALITY IN CHRONIC HEMODIALYSIS PATIENTS
Authors: Moromizato Takuhiro , Iseki Kunitoshi 
Published: May 2021

Abstract

Background and Aims
Serial decrease in body weight can be a prognostic marker reflecting Protein Energy Wasting (PEW) condition in haemodialysis patients. However, the impact of longitudinal body weight changes on mortality have rarely been evaluated. Therefore, we applied landmark analysis and time-scale mixed regression analyses to clarify the impact of long-term changes in body weight on all-cause mortality.

Method
This study is a post-hoc analysis of the participants in the Olmesartan Clinical Trial in Okinawan Patients Under OKIDS (OCTOPUS) conducted between June 2006 and June 2011. We additionally followed up with the participants until 31 July, 2018. During the OCTOPUS trial, the body weight of surviving participants was repeatedly measured every 6 months. The primary aim of the study was to clarify the association of serial change in body weights and all-cause mortality. The participants were categorized into 4 groups based on weight change slope during the first 2 years (bottom to highest group correspond with the first quartile to the fourth quartile group). We conducted a landmark analysis to evaluate the influence of weight change slope on the subsequent survival with Cox-proportional hazard regression. We also conducted time-scale multilevel regression analyses to draw marginal plots of body weight with a backward time scale to describe the difference in trajectories of body weight between deceased and surviving patients.

Results
Out of 461 patients in the cohort, 404 participants were analysed in the landmark analysis. Of the participants, 168 (41.6%) were deceased, and 236 participants (58.4%) survived. Although baseline body weights and indices about body components such as a creatinine index were similar among the 4 groups, multivariate Cox-proportional hazard regression showed that the higher rate of body weight loss was associated with higher mortality. Hazard ratios were 2.02 (1.28–3.20), 1.77 (1.10–2.85), 1.00 (Reference), and 1.11 (0.67–1.83) for first quartile, second quartile, third quartile (Reference), and fourth quartile group, respectively (P for trend was &lt;0.001). The association was also described using Kaplan-Meier plots, with the P-value of general Log-rank test being 0.015 (Fig 1a). Marginal plots drawn with a multivariate adjusted time-scale multilevel regression model, which included all 461 participants, with a backward time-scale, showed that body weight constantly decreased in deceased patients, while body weight was longitudinally stable in surviving patients (Fig 1b). These trends of weight change have been soundly observed in sensitivity analyses.

Conclusion
In chronic haemodialysis patients, the higher rate of body weight loss, such as a decrease in body weight by 1 kg (1.7%) per 6 months, was significantly associated with higher mortality. Persistent loss of body weight is a significant predictor of death among chronic dialysis patients.
FC 093EFFICACY OF EXPANDED HEMODIALYSIS AT DIFFERENT DIALYSATE FLOWS
Authors: Molano-Triviño Alejandra , Vesga Jasmin , Zuñiga Eduardo , Gutiérrez Juan Felipe , Ramos Carolina , Ronco Claudio 
Published: May 2021

Abstract

Background and Aims
Expanded hemodialysis (HDx) is based on hollow fibre dialyzer focused on improving the clearance of middle molecules as a target for uremia treatment. According to in vitro and in vivo results, High cut off filters have high enough clearance to allow diminishing of dialysate flow. Our aim is to compare clearance of middle molecules at different dialysate flow (Qd) in HDx with TheranovaMR membranes.
Our aim was to Evaluate efficacy of MCO dialyzer in terms of Kt/V and phosphorus levels at different prescribed dialysate flows (Qd) 400 vs 500 ml/min in HD patients from 10 renal clinics in Colombia.

Method
We performed a Prospective, observational, multicenter cohort study.
Prevalent adult HD patients (&gt;90 days), with weight lower or equal to 70 Kg, were included between September to November 2017 and prospectively followed for one year with routine monthly blood tests for HD adequacy and registered at both Qd groups at 1, 3, 6, 9 and 12 months. A mixed-model repeated measures analysis (MMRM) was performed to identify statistical differences over time. Socio-demographic and clinical characteristics of all patients were summarized descriptively by Qd.

Results
462 patients were included: 127 with Qd 400 mL/min. We did not find statistically significative differences in serum levels of albumin, hemoglobin, calcium or phosphorus when comparing Qd 400ml/min vs 500 ml/min. We found statistically higher Kt/V in Qd 400 mL/min patients. (Table 2).
In a sustainability analysis, part of Blue Planet dialysis research group, we calculated important savings in water waste in Qd 400 mL/min group.

Conclusion
MCO dialyzers are at least as effective in reaching HD adequacy parameters (Kt/V, PO4) at Qd 400 as 500 mL/min with interesting savings of potable water: 24 Liters were saved in each session per patient.
FC 094THREE VERSUS TWICE-WEEKLY HEMODIALYSIS SESSIONS: A COMMUNITY EXPERIENCE
Authors: Bonagiri Paavan , Owen Meagan , Mohandas Shreya , Sharma Simrun , Ejaz Abutaleb 
Published: May 2021

Abstract

Background and Aims
We investigated the feasibilty of converting stable end stage renal disease (ESRD) patients from three to twice weekly hemodialysis (HD) sessions based on published criteria.

Method
ESRD patients on three times weekly (3xwkly) HD sessions for at least 3 months duration were screened for eligibility for conversion to twice weekly (2xwkly) maintenace HD schedule in a university-affiliated community dialysis program. Eligibility criteria were: residual renal function &gt; 3ml/min; urine output &gt;500mL/day; intradialytic weight gain &lt;2.5kg; hemoglobin &gt;8gm/dL; manageable phosphorus and potasium levels. Clinical parameters on 3xwkly vs. 2xwkly HD sessions were then performed in the eligible patients.

Results
7/71 (9.8%) of the patients met criteria for conversion to 2xwkly HD sessions. Baseline patient characteristics are shown in Table 1. Major indication for HD initiation was symptomatic progression of disease. Less than 50% of patients had a functioning arteriovenous fistula at initiation of HD. In the current cohort, residual renal function &gt; 3mL/min was maintainedfor &gt;200 days after initiation of HD. There were no significant changes in electrolytes, hemoglobin, nutrition staus or adequacy of dialysis. PTH levels were not significantly different: 3xwkly, 625.7 + 546.2pg/mL vs. 2xwkly, 399 + 344.2pg/mL; p=0.374). Karnofsky Performance Status Scale improved post conversion but did not achieve statistical significance (3xwkly, 57.1 vs. 2xwkly, 70; p=0.316). There were no hospital admissions since conversion to 2xwkly schedule during the study period.

Conclusion
In a community-based dialysis program, 10% of total HD patients qualified for conversion from 3xwkly to 2xwkly maintenance HD without significant changes to their laboratory or clinical performance measures. These observations stimulate discussion regarding increased application of incremental dialysis initiation strategies to preserve residual renal function, increase dialysis-free days and alleviate transportation and care provider-related burden to patients and families.
FC 096THE EFFECT OF INCREMENTAL START OF HAEMODIALYSIS ON BLOOD PRESSURE AND INTERDIALYTIC WEIGHT GAIN: PRELIMINARY FINDINGS FROM THE ENDURE STUDY
Authors: Hazara Adil , Allgar Victoria , Twiddy Maureen , Bhandari Sunil 
Published: May 2021

Abstract

Background and Aims
Mortality rates are high in patients starting haemodialysis/haemodiafiltration (HD) therapy. Incremental HD may help reduce this risk by reducing the burden of early treatment whilst patients are still adapting to long-term HD therapy. A feasibility study (ENDURE study – Clinical trials ID: NCT04268264) is being conducted with the primary objectives of evaluating the acceptability and tolerance of a new incremental HD regime. Its secondary aims are to evaluate the impact of this form of incremental HD on indicators of patient safety and wellbeing. These indicators include blood pressure (BP) control and interdialytic weight gains (IDWG) which are independently associated with adverse cardiovascular outcomes in patients on long-term HD. We present preliminary findings from the study related to systolic BP and IDWG.

Method
The ENDURE study is being carried out at a tertiary care hospital in the United Kingdom. Patients aged &gt; 18 years known to renal services for at least 90 days, referred for start of HD, were eligible for participation. Following approved consenting procedures, they are started on a new regime of incremental HD starting dialysis twice weekly with progressive increases in the duration and frequency of sessions over 15 weeks. This period is split in to four phases; phase 1 representing the first two days of dialysis (baseline) whereas phases 2 – 4 representing the pre-specified incremental steps. Propensity scores were calculated to match each participant (incremental HD group) with two controls from a database of patients who previously started HD at our centres using the standard protocol of 3 times weekly, 4hr long sessions. The matching criteria accounted for 14 key demographic, clinical and laboratory characteristics. Results were analysed as intention to treat. In comparing BP and IDWG between the two groups, only readings taken pre-dialysis at the first session of the week was considered. This study has been approved by the West of Scotland Research Ethics committee-4 (Ref: 19/WS/0019).

Results
Baseline characteristics of the first 15 participants (target 20) and their matched controls are presented in table 1. The proportion of females and duration of previous specialist input was higher in the incremental HD group.

Conclusion
The ENDURE study tests the feasibility of starting patients on a novel incremental HD regime. Early data suggest that control of systolic BP and IDWG are comparable to patients who start dialysis at 3 times weekly. Further work is needed to understand the impact of reducing dialysis frequency on BP control correlating the findings with changes residual renal function and objective measures of fluid overload.
FC 012PRIMARY KIDNEY DISEASE IMPACTS OUTCOME IN CKD PREGNANCIES: COMPLICATIONS IN COL4A3-5 RELATED DISEASE (ALPORT SYNDROME) VS OTHER CKD PREGNANCIES
Authors: Snoek Rozemarijn , Gosselink Margriet , Vogt Liffert , De Jong Margriet , Cerkauskaite Agne , Vollenberg Renee , Knoers Nine , Lely Titia , Van Eerde Albertien M 
Published: May 2021

Abstract

Background and Aims
Chronic kidney disease (CKD) affects approximately 3% of pregnant women. CKD increases the risk of pregnancy complications such as prematurity, low birthweight and pre-eclampsia. Also, kidney function can deteriorate more quickly due to pregnancy. There is limited knowledge on pregnancy outcomes in specific kidney diseases. The aim of the ALPART network is to study pregnancy outcomes differentiated by CKD aetiology. We have started with COLA3-5 related disease (Alport syndrome), which is one of the most prevalent monogenic kidney diseases. Comparing outcomes in COLA3-5 related disease to pregnancies with other CKD aetiologies allows us to investigate whether this specific diagnosis impacts outcome in CKD pregnancies.

Method
The ALPART network is an international 15-center network, which aims to include ∼200 COLA3-5 related disease pregnancies. In this intermediary analysis, we present data on 109 pregnancies from 68 women with COLA3-5 related disease. We compared outcomes to a cohort of 457 CKD stage 1-2 patients (a similar CKD stage as our cohort) of diverse aetiology from a 2015 Italian study and 159,924 women from the general Dutch population.

Results
The main pregnancy and kidney outcomes are presented in Figure 1. Foetal outcomes were better in COLA3-5 pregnancies than in pregnancies of women with CKD stage 1-2 of diverse aetiology. We saw less prematurity (17% vs 36% respectively) and a higher mean birthweight of 3216 ± 663 gram compared to 2768 ± 680 in the Italian cohort. Maternal kidney outcomes should be interpreted with caution (&gt;30% missing data): proteinuria (73%) and hypertension (30%) were more frequent in COLA3-5 pregnancies than the Italian cohort. In the ALPART cohort, 10% developed severe hypertension. Median eGFR was not impacted by pregnancy and decline of eGFR before and after pregnancy were not significantly different between groups.

Conclusion
Fetal outcomes in pregnancies with COLA3-5 related disease seem to be more favorable than in a cohort with mixed cause of CKD. In this intermediary analysis, proteinuria levels and frequency of new-onset hypertension in pregnancy are higher. There is no significant eGFR loss during pregnancy or increased eGFR deterioration in the long-term. The differences between COLA3-5 and general CKD pregnancies underscore the importance of investigating pregnancy outcomes in specific kidney disease phenotypes to ensure adequate (pre-) pregnancy counselling and care.
FC 019PROTEOMIC PROFILING OF GLOMERULI FROM KIDNEYS WITH HYPERTENSIVE NEPHROPATHY REVEALS SIGNATURE OF DISEASE PROGRESSION
Authors: Mikkelsen Håvard , Vikse Bjørn Egil , Scherer Andreas , Finne Kenneth , Marti Hans-Peter 
Published: May 2021

Abstract

Background and Aims
Hypertensive nephropathy (HN) often represents an unspecific clinical diagnosis applied to non-diabetic, chronic kidney disease (CKD) patients with low-level proteinuria and elevated blood pressure. Kidney biopsy-based findings are the diagnostic gold standard, but they are not entirely specific and there is a need for prognostic markers. We aimed at defining candidate markers that predict disease progression based on protein signatures.

Method
We included adult patients (n=17) with an eGFR &gt;30 ml/min/1.73m2 and proteinuria &lt;3g/d from the Norwegian Kidney Biopsy Registry (NKBR). Subjects were divided into two groups: stable patients (n=9) and subjects with HN progression (n=8) leading to end-stage renal disease (ESRD) within 20 years of follow-up. Glomerular cross-sections were microdissected from 10 μm whole archival kidney biopsy sections and processed for protein extraction. Proteomic analyses were performed at our local facility PROBE in Bergen using a Q-exactive HF mass spectrometer. Abundances of glomerular proteins were compared between the two groups.

Results
Amongst a total of 1870 quality filtered proteins, we identified 58 proteins with absolute fold change (FC) ≥1.5, p≤0.05, including 17 proteins with absolute FC ≥2, indicative of HN progression (highest FC: Cadherin 16 and UDP-glucuronosyl-transferase 2B7). Hierarchical cluster and principal component analysis (PCA) with the 17 proteins showed clear separation of samples into these two disease clusters of HN progressors and non-progressors. To find proteins as biomarkers for the identification of progressors, we employed unsupervised K nearest neighbors validation algorithm coupled with leave-one-out internal cross-validation. Thereby, a set of five proteins (incl. cadherin 16) performed best and separated the two groups in a PCA, as shown in Figure 1. This classifier classified 16 of 17 samples correctly (AUC 0.993), misclassifying only one progressor sample. Applying Geneset Enrichment Analysis (GSEA; The Broad Institute, USA), in general metabolic pathways were up-regulated in progressors and structural cell pathways up-regulated in non-progressors. Ingenuity Pathway Analysis (IPA; Qiagen, USA) identified Epithelial Adherens Junction Signaling as the most affected canonical pathway (p=1.95E-06); five of six member proteins were down-regulated in progressors.

Conclusion
Glomerular proteomic profiling can be used to distinct progressors from non-progressors in HN.
FC 131OFATUMUMAB OR RITUXIMAB FOR CHILDREN WITH STEROID-DEPENDENT NEPHROTIC SYNDROME. A RANDOMIZED CONTROLLED TRIAL
Authors: Ravani Pietro , Colucci Manuela , Bruschi Maurizio , Vivarelli Marina , Cioni Michela , Di Donato Armando , Cravedi Paolo , Lugani Francesca , Emma Francesco , Angeletti Andrea , Ghiggeri Gian Marco 
Published: May 2021

Abstract

Background and Aims
The chimeric anti-CD20 monoclonal antibody rituximab has been successfully used in steroid-dependent forms of nephrotic syndrome (SDNS) to maintain oral-drug-free remission, but relapses at one year occur in almost half of the patients. Ofatumumab, a fully human anti-CD20 monoclonal antibody, may be superior to rituximab in maintaining remission of SDNS. We compared the efficacy and safety of ofatumumab vs. rituximab in children and young adults with SDNS (NCT02394119) and evaluated the risk of relapse following steroid and calcineurin-inhibitor tapering and withdrawal.

Method
We randomly assigned 140 children and younger adults (age 2-24 years) with SDNS maintained in remission with steroids and calcineurin-inhibitors to receive intravenous ofatumumab (1.500 mg/1.73 m2; intervention) or rituximab (375 mg/m2; control). Following infusions, oral drugs were tapered and withdrawn. Participants were followed for 24 months. The primary outcome was relapse at one year, defined by protein-creatinine ratio ≥2000 mg/g or &gt;3+ protein on urine dipstick for 3 consecutive days. Cellular and safety data were also assessed.

Results
At 12 months, 36 patients (51.4%) relapsed in the rituximab arm and 37 (52.8%) in the ofatumumab arm (Odds Ratio [OR] 1.06; 95% confidence interval [CI] 0.55 to 2.06). At 24 months, 46 children relapsed in the rituximab arm (65.7%) and 53 in the ofatumumab arm (75.7%). In both arms, circulating B cell levels declined following treatment and recovered between 3 and 9 months. Higher pretreatment levels and faster recovery after decline of memory B cells predicted relapse.

Conclusion
In children and younger adults with SDNS, ofatumumab is not superior to the chimeric anti-CD20 antibody rituximab. Immune phenotyping data indicate that anti-CD20 therapies alter the course of the disease by interfering with memory B cell populations and can be used to predict response to anti-CD20 treatment.
FC 066DICKKOPF-3 (DKK3) LINKS RECIPROCAL LUNG AND KIDNEY INJURY IN MICE AND HUMANS
Authors: Schunk Stefan , Beisswenger Christoph , Sarah Triem , Hütter Gregor , Sarakpi Tamim , Boor Peter , Jörres Rudolf , Watz Henrik , Welte Tobias , Vogelmeier Claus , Gröne Hermann , Fliser Danilo , Bals Robert , Speer Thimoteus 
Published: May 2021

Abstract

Background and Aims
Chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD) represent global public health problems with high disease-related morbidity and mortality. However, the interaction between both diseases remains unclear.

Method
In a novel murine model, cigarette smoke (CS)-induced lung injury was combined with a CKD model (CS-CKD model). In 2,314 patients of the prospective multi-center COSYCONET study, urinary Dickkopf-3 (DKK3), a renal tubular stress marker, was quantified. The association between urinary DKK3 and trajectories of FEV1 and estimated glomerular filtration rate (eGFR), exercise capacity, risk of exacerbation, and mortality was determined (follow-up 37.1 months).

Results
In the CS-CKD model, CKD was associated with higher systemic and pulmonary inflammation, and the combination of CKD and CS significantly aggravated kidney inflammation as well as fibrosis and increased renal expression of DKK3. Abrogation of Dkk3 attenuated kidney injury and pulmonary inflammation alike. In COPD patients, higher urinary DKK3 was associated with rapidly declining FEV1 (OR 3.36, P&lt;0.0001), higher risk for exacerbation, lower 6-minute walking distance, and higher all-cause mortality (HR 1.49, P=0.015). Importantly, higher urinary DKK3 was also associated with declining eGFR during follow-up (OR 2.23, P=0.0005). Neither eGFR nor proteinuria were associated with lung or kidney dysfunction during follow-up.

Conclusion
In summary, the present study identified a strong pathophysiological link between lung and kidney dysfunction, which is at least partially mediated by DKK3. Urinary DKK3 allows identification of COPD patients at increased risk for deteriorating pulmonary and kidney function as well as adverse outcomes. These patients might particularly benefit from preventive therapeutic strategies as a personalized-medicine approach.