bluuebunny/crossref_metadata_2025 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

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

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<0.01) and PCSK9 (ng/ml, 652.9±230.0 vs 311±116.5, p<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<0.001), serum Cr (mg/dl, 0.48±0.13 vs. 0.18±0.044, p<0.001) and BUN (mg/dl, 80.08±20.22 vs. 46.86±9.60, p<0.05). Compatibly with the clinical data, the severity of glomerulosclerosis score (semi-quantification, 2.44 vs. 1.95, p<0.001) was ameliorated and podocyte density (number of podocyte/glomerulus, 2.61 vs. 7.54, p<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

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

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

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 < 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 < 0.01 and 0.05, respectively). Stiffer arteries were found in patients with diagnosed CVD (p-value < 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

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

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

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 > 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 < 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 >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

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.
MO030PATIENT SAFETY IN A LARGE MULTINATIONAL RENAL SERVICES PROVIDER NETWORK
Authors: Marrón Belén , Silva Israel , Wollheim Charlotta , Lucas Carlos , Torok Marietta , Akdeniz Filiz , Pearce Suzanne , Westesson Ulf , Macário Fernando
Published: June 2020

Background and Aims

Patient safety is considered of paramount importance under any qualified provision of care, but results from routine tracking of incidents have scarcely been reported, even when that may negatively impact survival.

To analyze all types of incidents in a multinational renal service provider network from Jan.1st to Sept. 30th, 2019.

Method

For the last 10 years, our institution has tracked all incidents under a structured process program, as well as, educated our staff in the importance of proactively reporting and analyzing incidents in a quarterly basis at the clinic, by country and globally. Incidents are categorized in 4 different types: A-Patient related; B-Staff and visitors; C-Products and D-Equipment. Different incident codes are assigned to each type.

Results

A total of 68.399 incidents (2.7 incidents/patient/year) have been reported during Q1-Q3 2019 (higher than in 2018: 2.2). This means an increase of 20% in the total number of reported incidents. Total incidents/1000 treatments was 17.1 (12.1 patient-related incidents). Reporting follows a heterogeneous pattern among countries, being lowest in Argentina and highest in the UK. Top 5 reported incidents were as follows: Codes A15 (voluntarily shortened treatment) and A14 (Patient did not show up), both related to patient adherence to treatment, accounted for 36% of total incidents, vascular access (VA) complications (A4) for 10.5%, change of dialyzer and/or blood lines due to clotting (A2) for 8.6% and recurrent minor monitor malfunction (D1) for 6.7% of incidents. Codes related with unexpected death or cardiorespiratory arrest are not present among the total global top 10 incidents.

Conclusion

Detailed tracking of incidents and comparison between countries have potential to increase quality of care. Room for improvement recently made the Corporate Medical Office to launch new strategies on VA management, anticoagulation and patient compliance, among others. This large series may help other institutions to better monitor and standardize patient safety.
MO034ANALYSIS OF A MOUSE MODEL FOR MCTO DUE TO THE MUTATION OF MAFB TRANSACTIVATION DOMAIN
Authors: Usui Toshiaki , Morito Naoki , Tsunakawa Yuki , JEON Hyojung , Hamada Michito , Mizuno Seiya , Takahashi Satoru , Yamagata Kunihiro
Published: June 2020

Background and Aims

Transcription factor MafB in podocytes is essential for podocyte differentiation and maintenance. Previous works identified a missense mutation in the transactivation domain of MAFB as the cause of multicentric carpotarsal osteolysis (MCTO). MCTO is a condition involving progressive osteolysis of the carpal and tarsal bones. MCTO patients also develop with focal segmental glomerulosclerosis (FSGS) and renal failure (MCTO nephropathy). However, the pathogenesis of MCTO in vivo is unclear.

Method

In order to address this question, we generated an MCTO mouse model using the CRISPR/Cas9-mediated genome editing. This mouse has a human MCTO mutation c.176C>T, (p.Pro59Leu). Mafb MCTO/ MCTO mice were obtained by crossing Mafb MCTO/WT mice. Control animals were Mafb WT/WT mice. Sequencing analysis was performed to confirm the integration of the MCTO mutation on F2 generations. We checked urine of these mice every 4 weeks, and biochemical and histological analysis were performed at 26 weeks-ages. RNA-seq analysis of the isolated glomeruli of these mice was performed at 10 weeks-ages.

Results

Interestingly, MafbMCTO/MCTO newborn mice exhibited a 10% lower body weight than control mice. The differences were still observed at 2 weeks, with Mafb MCTO/MCTO mice presenting a 23% lower body weight than control animals. The length of femoral bones in Mafb MCTO/MCTO mice was shorter than that of control. MCTO model mice exhibit growth deficiency. In addition, Mafb MCTO/ MCTO mice resulted in albuminuria at 4 weeks-ages from postnatal periods and became persistent. Renal histological analysis in adult stage revealed FSGS-like glomerular lesions in Mafb MCTO/ MCTO mice. In electron microscope analysis, microvillous transformation of the foot processes of podocytes in Bowman’s space and foot processes effacements were seen in Mafb MCTO/ MCTO mice. These phenotypes are similar to that seen in MCTO nephropathy patients. Subsequently, we performed RNA-seq analysis of isolated glomeruli to gain insight into the molecular mechanism of the MCTO mutation. We found Cldn1, gene expression in mature podocytes caused profound proteinuria, was significantly increased in Mafb MCTO/ MCTO glomeruli.

Conclusion

This study is significant for revealing the mechanism of MCTO and contributes to the development of an alternative treatment against MCTO nephropathy by providing model mice for use.
MO045MITOCHONDRIAL DYSFUNCTION AND MUSCLE ENERGETICS IN CKD PATIENTS
Authors: Gamboa Jorge , Ikizler Alp , Yu Chang , Damon Bruce , Brown Nancy , Towse Theodore
Published: June 2020

Background and Aims

Patients with chronic kidney disease (CKD) suffer from frailty and sarcopenia. Skeletal muscle mitochondria are important for physical function and could be a target to prevent frailty and sarcopenia.

Method

We tested the hypothesis that mitochondrial function worsens with the progression of CKD. We evaluated the interaction between mitochondrial function and co-existing comorbidities such as impaired physical performance, intermuscular adipose tissue (IMAT) infiltration, inflammation, and oxidative stress. We evaluated in-vivo thigh mitochondrial function using 31-phosphorus magnetic resonance spectroscopy to obtain the phosphocreatine (PCr) recovery constant, a measure of mitochondrial function. We measured physical performance using the six-minute walk test, IMAT infiltration and markers of inflammation in plasma.

Results

Sixty-three participants were studied including controls (n=21), patients with CKD not on maintenance hemodialysis (MHD; n=20), and patients on MHD (n=22). We found a prolonged PCr recovery constant in patients on MHD (53.3 (43.4, 70.1) seconds) and with CKD not on MHD (46.3 (40,0, 49.9) seconds) compared to controls (34.2 (28.8, 43.7) seconds) (p<0.001 between groups), Figure 1A-C. Mitochondrial dysfunction was associated with poor physical performance, greater IMAT, and increased markers of inflammation Figure 2A-C.

Conclusion

Mitochondrial function worsens with the progression of CKD and correlates with physical function, IMAT, inflammation, and oxidative stress. These data suggest that therapeutic approaches targeted at mitochondrial dysfunction and dynamics could prevent or treat frailty and sarcopenia in patients CKD.
MO051EFFECTS OF SEMAGLUTIDE ON CHRONIC KIDNEY DISEASE OUTCOMES: A POST HOC POOLED ANALYSIS FROM THE SUSTAIN 6 AND PIONEER 6 TRIALS
Authors: Tuttle Katherine , Cherney David , Hadjadj Samy , Idorn Thomas , Mosenzon Ofri , Perkovic Vlado , Rasmussen Søren , Wolthers Benjamin , Bain Stephen C
Published: June 2020

Background and Aims

The SUSTAIN 6 cardiovascular outcomes trial (CVOT) indicated a renal benefit with subcutaneous (s.c.) once-weekly (OW) semaglutide vs placebo. The PIONEER 6 CVOT reported cardiovascular safety with oral semaglutide in a similar cohort using a similar trial design. In the present post hoc study, eGFR data from the SUSTAIN 6 and PIONEER 6 trials were pooled to evaluate the potential benefit of semaglutide (s.c. or oral) vs placebo on chronic kidney disease (CKD) outcomes.

Method

Data from 6,480 subjects from SUSTAIN 6 (N=3,297; median follow-up, 2.1 years; mean baseline eGFR, 76 mL/min/1.73 m2) and PIONEER 6 (N=3,183; median follow-up, 1.3 years; mean baseline eGFR, 74 mL/min/1.73 m2) were pooled for semaglutide (0.5 mg s.c. OW, 1.0 mg s.c. OW or 14 mg oral once daily) or placebo. We evaluated time to onset of persistent eGFR reduction (thresholds of ≥30%, ≥40%, ≥50% and ≥57% [57% corresponds to a doubling of serum creatinine]) from baseline in the overall pooled population and by baseline CKD subgroups (≥30–<60 mL/min/1.73 m2, n=1,699; ≥60 mL/min/1.73 m2, n=4,762; data were missing for 19 subjects). Analyses were performed using a Cox proportional-hazards model with treatment group (semaglutide vs placebo) and CKD subgroup as fixed factors and the interaction between both stratified by trial.

Results

In the overall population, the hazard ratios (HRs) for time to onset of persistent eGFR reductions with semaglutide vs placebo were <1.0, but did not achieve statistical significance. In subjects with baseline eGFR ≥30–<60 mL/min/1.73 m2, HRs for semaglutide vs placebo were consistently lower compared with the overall population and, in this subgroup, semaglutide significantly reduced the risk of developing a persistent 30% eGFR reduction vs placebo (Figure; p=0.03). Numerically larger effects were seen with increasing eGFR reduction thresholds in this subgroup, with the exception of the 57% eGFR reduction threshold. No statistically different interactions between treatment and CKD subgroup were observed.

Conclusion

The findings of this post hoc analysis of pooled data from SUSTAIN 6 and PIONEER 6 on clinically relevant outcomes for CKD support a smaller magnitude of eGFR decline with semaglutide vs placebo, despite relatively short follow-up times. The small number of events at both the 50% and 57% thresholds, and the associated broad confidence intervals, limit the interpretability of the results. In line with previous findings, the data suggest a renal benefit of semaglutide vs placebo in subjects with established CKD. The FLOW trial (ClinicalTrials.gov Identifier: NCT03819153), which is dedicated to exploring CKD outcomes with semaglutide treatment, is ongoing to test this hypothesis in patients with CKD at baseline.
MO073ACCELERATION OF KIDNEY FUNCTION DECLINE AFTER INCIDENT HOSPITALIZATION WITH CARDIOVASCULAR DISEASE: THE STOCKHOLM CREATININE MEASUREMENTS (SCREAM) PROJECT
Authors: Ishigami Junichi , Trevisan Marco , Lund Lars , Jernberg Tomas , Coresh Josef , Matsushita Kunihiro , Carrero Juan Jesus
Published: June 2020

Background and Aims

The cardiorenal syndrome refers to a bidirectional relationship between the kidney and the heart. However, epidemiological evidence of cardiovascular disease (CVD) as a risk factor for chronic kidney disease (CKD) progression is actually scarce. We here quantified slopes of kidney function decline before and after the incidence of major CVD.

Method

We examined the slopes of estimated glomerular filtration rate (eGFR) decline in the 2 years before vs. after an incident hospitalization with heart failure (HF) (n=20,420), coronary heart disease (CHD) (n=18,152), or stroke (n=1,808) using data from a complete laboratory data collection in Stockholm, Sweden between 2006 and 2011. We used mixed-effect models with unstructured residual correlation matrix and stratified by index eGFR (≥60, 30-59, <30 ml/min/1.73m2).

Results

Overall, patients who had HF were older, and had more comorbidities (e.g., diabetes, hypertension) and lower eGFR compared to those who had CHD or stroke. Incident hospitalization with HF and CHD, but not stroke, was significantly associated with a subsequent accelerated decline in eGFR, with a faster eGFR decline and greater slope change after HF than CHD. In the overall population, the pre-event vs. post-event eGFR slopes (ml/min/1.73m2 per year) were -1.67 (-1.77 to -1.57) vs. -2.76 (-2.82 to -2.71), with a Δslope of -1.09 (-1.16 to -1.02) for HF; -1.09 (-1.20 to -0.98) vs. -1.87 (-1.92 to -1.81), with a Δslope of -0.78 (-0.85 to -0.70) for CHD; and -1.00 (-1.37 to -0.63) vs. -0.99 (-1.19 to -0.78), with a Δslope of 0.02 (-0.24 to 0.27) for stroke (Figure 1A). The accelerated declines in eGFR after HF and CHD were consistent across the spectrum of eGFR, although pre-event eGFR slopes were steeper in lower eGFR (e.g., pre-event eGFR slope for HF -0.64 (-0.76 to -0.53) for eGFR ≥60, -1.43 (-1.57 to -1.30) for eGFR 30-59, and -2.42 (-2.71 to -2.12) for eGFR <30 ml/min/1.73m2) (Figure B-D).

Conclusion

Incident hospitalization with cardiac diseases (i.e., HF and CHD) was significantly associated with a subsequent acceleration of eGFR decline.
MO074RENAL FUNCTION DECLINE IN OLDER MEN AND WOMEN WITH ADVANCED CKD - RESULTS FROM THE EQUAL STUDY
Authors: Chesnaye Nicholas , Dekker Friedo W , Evans Marie , Caskey Fergus , Torino Claudia , Postorino Maurizio , Szymczak Maciej , Ramspek Chava , Drechsler Christiane , Wanner Christoph , Jager Kitty J
Published: June 2020

Background and Aims

Understanding the mechanisms underlying the differences in renal decline between men and women may improve sex-specific clinical monitoring and management. To this end, we aimed to compare the slope of renal function decline in older men and women in CKD 4-5, taking into account informative censoring related to the sex-specific risks of mortality and dialysis initiation.

Method

The EQUAL study is an observational prospective cohort study in stage 4-5 CKD patients ≥65 years not on dialysis. Data on clinical and demographic patient characteristics were collected between April 2012 to December 2018. eGFR was calculated using the CKD-EPI equation. Linear mixed models were used to model the eGFR trajectory by sex, and joint models were applied to deal with informative censoring.

Results

We included 7801 eGFR measurements in 1682 patients over 2911 years of follow-up. Renal function declined 14.0% (95% CI 12.9%-15.1%) on average each year. Renal function declined faster in men (16.2% per year, 95% CI 15.9%-17.1%) compared with women (9.6% per year, 95% CI 6.3%-12.1%), which remained largely unchanged after accounting for various mediators, and for informative censoring due to mortality and dialysis initiation. We identified effect modification by diabetes, with faster declines in renal function found especially in women with diabetes.

Conclusion

In conclusion, renal function declines faster in men compared with women, which remained similar after adjustment for mediators, and despite a higher risk of informative censoring in men. We demonstrate a disproportional negative impact of diabetes specifically in women.
MO075DNA METHYLATION AND RESPONSE TO STEROIDS IN CHILDREN WITH NEPHROTIC SYNDROME
Authors: Hayward Samantha , Suderman Matthew , Bierzynska Agnieszka , Welsh Gavin I , Saleem Moin A
Published: June 2020

Background and Aims

Historically, paediatric patients with nephrotic syndrome (NS) have been crudely categorised by their response to steroids: steroid resistant (SRNS), steroid sensitive (SSNS) and secondary SRNS. However, growing evidence that these categories do not correspond to single diseases has led to a demand that they be re-defined based on biological mechanisms involved in the disease process. Indeed, next generation sequencing has identified causative mutations in up to 30% of paediatric NS patients (‘monogenic’ NS); however, specific disease mechanisms in the remaining patients remain unknown.

We propose that the remaining phenotype variation in NS may be explained by DNA methylation, the reversible but heritable addition of methyl groups to DNA that change how the underlying DNA sequence is interpreted.
MO076LONGITUDINAL CHANGES AND OUTCOME OF HIGH BLOOD PRESSURE IN EUROPEAN CHILDREN ON RENAL REPLACEMENT THERAPY
Authors: Vidal Enrico , Bonthuis Marjolein , Jager Kitty J , Harambat Jerome
Published: June 2020

Background and Aims

Few studies have focused on trends of hypertension (HTN) and status of blood pressure (BP) control over time in children on renal replacement therapy (RRT). In this study, we aimed to evaluate the 5-year trend in BP antihypertensive medications (AHs) use, as well as the association between HTN and mortality among RRT patients enrolled within the ESPN/ERA-EDTA Registry.

Method

25.223 BP measurements from 5.032 patients who started RRT before 20 years of age, between 2007-2016, were included. Mixed models were used to analyse trends of BP, the JointPoint regression to assess prevalence of uncontrolled HTN (uHTN) over time, and multivariable Cox proportional hazard models to evaluate association of BP with mortality.

Results

Mean systolic BP (SBP) at RRT initiation was 1.66(+0.15), 1.05(+0.15) and 1.09(+0.08) SDS in HD, PD and transplanted (Tx) patients, respectively, while it was 1.41(+0.19), 1.12(+0.18), and 0.79(+0.06) SDS in the corresponding RRT categories after 5 years. Patients on HD showed a significant decrease in the prevalence of uHTN over time (57.1% at dialysis start vs 41.4% after 5 years; annual percentage change [APC] -4%; 95% CI: -5.7;-2.2; p<0.05), coupled with a significant reduction in AHs use (APC -3.5%; 95% CI: -6.7;-0.2). PD patients showed a similar reduction in uHTN prevalence (APC -4.9%; 95% CI: -7.2;-2.6; p<0.05), but a significant increase in AHs use (APC +3.6%; 95% CI: 0.6;6.6; p<0.05). After 5 years, Tx patients showed a significant reduction in both prevalence of uHTN (APC -4.8%; 95% CI: -7.8;-1.7; p<0.05) and use of AHs (APC -2.2%; 95% CI: -4.1;-0.3%; p<0.05). Having uHTN was not associated with mortality (HR 0.95; 95% CI: 0.68-1.33).

Conclusion

A more adequate control of BP over time seemed to be obtained in children on RRT. Findings in PD patients suggest that this requires a progressive increase in the use of AHs.
TO004IMPACT OF RENAL TRANSPLANT ON COGNITIVE FUNCTION AMONG ESRD PATIENTS ON DIALYSIS
Authors: Kaul Anupma , Bhaduria Dharmendra , Prasad Narayan , Gupta Amit
Published: June 2020

Background and Aims

Kidney transplantation can help in mitigating neuropsychological (NP) impairments in end-stage renal disease (ESRD). Evidences have shown mixed responses on the the nature of cognitive function in patients who have undergone renal transplantation.Present study looked into the factors impacting cognitive domains and impact post transplant.

Method

43 patients who were stable ESRD on thrice a week hemodialysis were investigated 6 months pre and post transplant using a battery of neurophysiological testing assessing attention–concentration, psychomotor ability and memory.

Formal kinetic modelling of dialysis delivery ensured adequate renal replacement therapy. Transplant function was assessed on regular interval and following a stable graft function and on stable doses of immunosuppressive medication 6 months post transplant were reassessed

Results

Within-subject comparisons showed statistically significant improvement in memory performance after kidney transplant. Other NP measures (attention– concentration and psychomotor abilities) showed non-significant improvements. Normative comparisons showed NP impairments on dialysis, which were not apparent after transplant

Conclusion

These data demonstrate improvements in cognition following kidney TX and emphasize the reversibility of the memory problems evidenced in dialysis
TO018ACUTE KIDNEY INJURY IDENTIFICATION: USE OF ELECTRONIC AKI ALERTS VERSUS ELECTRONIC HEALTH RECORDS IN HOSPITAL EPISODE STATISTICS
Authors: Savino Manuela , Casula Anna , Wong Esther , Kolhe Nitin , Medcalf James , Nitsch Dorothea
Published: June 2020

Background and Aims

Acute kidney injury (AKI) refers to an abrupt decline in the glomerular filtration rate (GFR) which may be associated with significant morbidity and mortality. Since April 2015, an automated real-time electronic alert system for AKI has been introduced and progressively implemented in England, with alert data being sent to the UK Renal Registry (UKRR) for collection into a master patient index (MPI). Historically, the only way to routinely measure AKI incidence in hospital was to analyse the Hospital Episode Statistics (HES). The introduction of the MPI allows for the first time a comparison between warning-test score defined AKI and clinical coding. This project aims to determine whether episodes of AKI identified in the UKRR MPI correspond to coded diagnoses on the discharge record held in HES.

Method

The UKRR MPI of all AKI electronic alerts (AKI stages 1, 2 and 3) in patients ≥18 years of age, between 01/01/2017 and 31/12/2017 were linked to HES data to identify a hospitalised AKI population. Descriptive analyses were conducted to describe the demographics and to investigate whether those with electronic AKI alert also had an International Classification of Diseases (ICD)-10 code for AKI (N17) in HES.

Results

From 01/01/2017 to 31/12/2017, 301,504 hospitalised adults received an AKI electronic alert. AKI severity was positively associated with the percentage of AKI alerts which were coded in HES. There was also a significant variation in HES coding between hospitals, but generally, variation was most pronounced for AKI stage 1, with a mean of 48.2% [SD 14], versus AKI stage 3, with a mean of 83.3 % [SD 7.3] (figures 1, 2 and 3). There was an inverse trend with age in that younger adults AKI staging warning scores were less often coded in HES and this was true for all the three AKI stages (33% of AKI episodes coded in HES for people aged 18-29 versus 64% for people ≥ 85 years old) (Table 1).

Conclusion

In 2017, earlier stages AKI warning scores were poorly coded in HES. There was also high degree of inter-hospital variability, particularly for AKI warning score 1, reflecting potentially poor clinical recognition and documentation in medical record and subsequent clinical coding. AKI warning scores were poorly captured in HES for younger adults in comparison to those of older age; reasons for which need to be identified. Use of HES to identify cases of AKI is likely to underestimate the incidence of AKI, especially for AKI stage 1, though a high proportion of the most severe cases will be captured.
TO021LONG-TERM OUTCOMES OF COMMUNITY- VERSUS HOSPITAL-AQUIRED ACUTE KIDNEY INJURY: A RETROSPECTIVE ANALYSIS OF A LARGE COHORT IN A GERMAN TERTIARY CARE CENTER
Authors: Khadzhynov Dmytro , Schmidt Danilo , Eckardt Kai-Uwe , Schmidt-Ott Kai M
Published: June 2020

Background and Aims

This study compared epidemiology, short- and long-term outcomes for patients with community-acquired (CA) and hospital-acquired (HA) acute kidney injury (AKI).

Method

We retrospectively analyzed all episodes of AKI over a period of 3.5 years (2014–2017) on the basis of routinely obtained serum creatinine measurements in 103,161 patients whose creatinine had been measured at least twice and who had been in the hospital for at least two days. We used the “Kidney Disease: Improving Global Outcomes” (KDIGO) criteria for AKI and analyzed the first hospital admission. A total of 103161 were admitted in hospital and fulfilled the inclusion criteria. Average observation period per patient was 248 days.

Results

The incidence of CA-AKI among included hospital admissions was 9.7% compared with an incidence of 8.6% of HA-AKI, giving an overall AKI incidence of 18,3%. Patients with CA-AKI were younger than patients with HAAKI (64 vs 66,2y) and had significantly less comorbidities, including preexisting cardiac failure, ischemic heart disease, hypertension, diabetes. Patients with CA-AKI were more likely to have stage 1 AKI (69,3 vs 58,4%, p<0.001) and had significantly shorter lengths of hospital stay than patients with HA-AKI (14 vs 24d, p<0.001).

Those with CA-AKI had better survival than patients with HA-AKI (Figure 1; p<0.001). Patiens with CA-AKI were less likely dialysis dependent before discharge (1,9 vs 4,8% in HA-AKI; p<0.001) Patients with HA-AKI received more often administrative coding of AKI (29,3% vs 26,5% in CA-AKI patients; p<0.001)

Conclusion

Patients with CA-AKI sustain less severe AKI than patients with HA-AKI, accordigly showing better short- and long-term outcomes. However, patiens with CA-AKI are at risk of inadequate clinical perception of AKI.