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Danilo Fliser,1 Maria Mata Lorenzo,2 Katherine Houghton,3 Claire Ainsworth,3 Martin Blogg,2 Elena González de Antona Sánchez,4 Jose Portoles5 1Saarland University Medical Center, Homburg, Germany; 2Astellas Pharma Europe Ltd., Addlestone, UK; 3RTI Health Solutions, Manchester, UK; 4Astellas Pharma España S.A., Madrid, Spain; 5Hospital Universitario Puerta de Hierro, Madrid, SpainCorrespondence: Danilo Fliser, Saarland University Medical Center, Homburg, Germany, Tel +49 – 6841 – 16 15040, Fax +49 – 6841 – 16 15454, Email danilo.fliser@uks.euBackground: Anemia is prevalent among patients with chronic kidney disease (CKD), yet current evidence indicates that treatment may not adhere to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. We aimed to document the management of patients with non-dialysis-dependent (NDD)-CKD receiving erythropoiesis-stimulating agent (ESA) therapy in Europe.Methods: This retrospective, observational study extracted information from medical records in Germany, Spain, and the UK. Eligible patients were adults with NDD-CKD stages 3b– 5 who initiated ESA therapy for anemia between January and December 2015. Anemia was defined as hemoglobin (Hb) < 13.0 g/dL (males) or < 12.0 g/dL (females). Data regarding ESA treatment, treatment response, concomitant iron therapy and blood transfusions were extracted up to 24 months post-ESA initiation, and data on CKD progression until abstraction date.Results: Eight hundred and forty-eight medical records were abstracted. Approximately 40% received no iron therapy prior to ESA initiation. At ESA initiation, mean ± standard deviation Hb level was 9.8 ± 1.0 g/dL. Most patients received darbepoetin alfa, and switching between ESAs was rare (8.5% of patients). Concomitant intravenous and oral iron therapy was prescribed for 36% and 42% of patients, respectively, during initial ESA therapy. Mean Hb levels reached the target level (10– 12 g/dL) within 3– 6 months of ESA initiation. Hb, transferrin saturation, and ferritin levels were infrequently monitored from 3 months post-ESA initiation. Rates of blood transfusion, dialysis, and diagnosis of end-stage renal disease were 16.4%, 19.3%, and 24.6%, respectively. Rates of kidney transplant and death were 4.8% and 8.8%, respectively.Conclusion: Among ESA-treated patients, ESA initiation was in accordance with KDIGO guidelines, but subsequent monitoring of Hb and iron deficiency were suboptimal.Graphical Abstract: Keywords: anemia, chronic kidney disease, clinical care process, erythropoiesis-stimulating agents, iron therapy, real-life management

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a remarkable kidney tropism. While kidney effects are common in severe coronavirus disease 2019 (COVID-19), data on non-severe courses are limited. Here we provide a multilevel analysis of kidney outcomes after non-severe COVID-19 to test for eventual kidney sequela. Methods This cross-sectional study investigates individuals after COVID-19 and matched controls recruited from the Hamburg City Health Study (HCHS) and its COVID-19 program. The HCHS is a prospective population-based cohort study within the city of Hamburg, Germany. During the COVID-19 pandemic the study additionally recruited subjects after polymerase chain reaction–confirmed SARS-CoV-2 infections. Matching was performed by age, sex and education. Main outcomes were estimated glomerular filtration rate (eGFR), albuminuria, Dickkopf3, haematuria and pyuria. Results A total of 443 subjects in a median of 9 months after non-severe COVID-19 were compared with 1328 non-COVID-19 subjects. The mean eGFR was mildly lower in post-COVID-19 than non-COVID-19 subjects, even after adjusting for known risk factors {β = −1.84 [95% confidence interval (CI) −3.16 to −0.52]}. However, chronic kidney disease [odds ratio (OR) 0.90 (95% CI 0.48–1.66)] or severely increased albuminuria [OR 0.76 (95% CI 0.49–1.09)] equally occurred in post-COVID-19 and non-COVID-19 subjects. Haematuria, pyuria and proteinuria were also similar between the two cohorts, suggesting no ongoing kidney injury after non-severe COVID-19. Further, Dickkopf3 was not increased in the post-COVID-19 cohort, indicating no systematic risk for ongoing GFR decline [β = −72.19 (95% CI −130.0 to −14.4)]. Conclusion While mean eGFR was slightly lower in subjects after non-severe COVID-19, there was no evidence for ongoing or progressive kidney sequela.

Medical societies have a social responsibility to disseminate knowledge and inform health authorities on threats to public health posed by various diseases. Advocacy for health protection programmes and for medical research funding is now embedded into the missions of most scientific societies. To promote kidney research funding in Europe, the European Renal Association – European Dialysis and Transplant Association (ERA-EDTA), rather than acting as an individual society advocating for the fight against kidney disease, has actively helped to create an alliance of national associations centred on kidney diseases, the European Kidney Health Alliance (EKHA), and joined the Biomedical Alliance (BMA). The ERA-EDTA is fully committed to supporting its working groups (WGs) and consortia of its members to allow them to produce valuable kidney research. The framing and formalization of projects, and the regulatory issues related to submission to the European Commission, are complex. To help WGs to gain expert advice from agencies with specific know-how, the ERA-EDTA has adopted a competitive approach. The best research projects proposed by WGs and consortia of other European investigators will receive seed funding to cover the costs of consultancy by expert agencies. Via its broader platforms, the EKHA and the BMA, the ERA-EDTA will strive towards broader recognition of kidney disease and related clusters of non-communicable diseases, by European and national agencies, as major threats to the qualities of life of their populations and their economies.

Significance Statement Posttranslational guanidinylation of ApoC3, a major constituent of triglyceride-rich lipoproteins, enhances ApoC3?s proinflammatory properties in uremia. Guanidinylated ApoC3 (gApoC3) is generated by guanidine and urea, and accumulates significantly in the plasma of patients with CKD, and in the kidneys of mouse models of CKD. In humanized mice, gApoC3 promotes kidney tissue fibrosis and suppresses regeneration after vascular injury. Importantly, in a large observational trial examining the clinical relevance of this posttranslational modification in patients with CKD, higher plasma gApoC3 intensity was associated with adverse renal and cardiovascular outcomes. Therefore, gApoC3 represents a novel mediator of kidney injury and CKD-associated vascular disease and offers a potential treatment target to halt progression and to prevent vascular disease in patients with CKD.Background Coexistent CKD and cardiovascular diseases are highly prevalent in Western populations and account for substantial mortality. We recently found that apolipoprotein C-3 (ApoC3), a major constituent of triglyceride-rich lipoproteins, induces sterile systemic inflammation by activating the NOD-like receptor protein-3 (NLRP3) inflammasome in human monocytes via an alternative pathway.Methods To identify posttranslational modifications of ApoC3 in patients with CKD, we used mass spectrometry to analyze ApoC3 from such patients and from healthy individuals. We determined the effects of posttranslationally modified ApoC3 on monocyte inflammatory response in vitro, as well as in humanized mice subjected to unilateral ureter ligation (a kidney fibrosis model) and in a humanized mouse model for vascular injury and regeneration. Finally, we conducted a prospective observational trial of 543 patients with CKD to explore the association of posttranslationally modified ApoC3 with renal and cardiovascular events in such patients.Results We identified significant posttranslational guanidinylation of ApoC3 (gApoC3) in patients with CKD. We also found that mechanistically, guanidine and urea induce guanidinylation of ApoC3. A 2D-proteomic analysis revealed that gApoC3 accumulated in kidneys and plasma in a CKD mouse model (mice fed an adenine-rich diet). In addition, gApoC3 augmented the proinflammatory effects of ApoC3 in monocytes in vitro. In humanized mice, gApoC3 promoted kidney tissue fibrosis and impeded vascular regeneration. In CKD patients, higher gApoC3 plasma levels (as determined by mass spectrometry) were associated with increased mortality as well as with renal and cardiovascular events.Conclusions Guanidinylation of ApoC3 represents a novel pathogenic mechanism in CKD and CKD-associated vascular injury, pointing to gApoC3 as a potential therapeutic target.

Lung congestion is a risk factor for all-cause and cardiovascular mortality in patients on chronic hemodialysis, and its estimation by ultrasound may be useful to guide ultrafiltration and drug therapy in this population. In an international, multi-center randomized controlled trial (NCT02310061) we investigated whether a lung ultrasound-guided treatment strategy improved a composite end point (all-cause death, non-fatal myocardial infarction, decompensated heart failure) vs usual care in patients receiving chronic hemodialysis with high cardiovascular risk. Patient-Reported Outcomes (Depression and the Standard Form 36 Quality of Life Questionnaire, SF36) were assessed as secondary outcomes. A total of 367 patients were enrolled: 183 in the active arm and 180 in the control arm. In the active arm, the pre-dialysis lung scan was used to titrate ultrafiltration during dialysis and drug treatment. Three hundred and seven patients completed the study: 152 in the active arm and 155 in the control arm. During a mean follow-up of 1.49 years, lung congestion was significantly more frequently relieved in the active (78%) than in the control (56%) arm and the intervention was safe. The primary composite end point did not significantly differ between the two study arms (Hazard Ratio 0.88; 95% Confidence Interval: 0.63-1.24). The risk for all-cause and cardiovascular hospitalization and the changes of left ventricular mass and function did not differ among the two groups. A post hoc analysis for recurrent episodes of decompensated heart failure (0.37; 0.15-0.93) and cardiovascular events (0.63; 0.41-0.97) showed a risk reduction for these outcomes in the active arm. There were no differences in patient-reported outcomes between groups. Thus, in patients on chronic hemodialysis with high cardiovascular risk, a treatment strategy guided by lung ultrasound effectively relieved lung congestion but was not more effective than usual care in improving the primary or secondary end points of the trial.

Background Since kidney transplant recipients (KTRs) have a high cardiovascular disease burden, adequate risk prediction is of importance. Whether echocardiographic parameters and plasma biomarkers, natriuretic peptides [N-terminal pro-B-type natriuretic peptide (NT-proBNP)] and troponin T provide complementary or overlapping prognostic information on cardiovascular events remains uncertain. Methods The prospective Heterogeneity of Monocytes and Echocardiography Among Allograft Recipients in Nephrology (HOME ALONE) study followed 177 KTRs for 5.4 ± 1.7 years. Predefined endpoints were hospitalization for acute decompensated heart failure or all-cause death (HF/D) and major atherosclerotic cardiovascular events or all-cause death (MACE/D). At baseline, plasma NT-proBNP, plasma troponin T and echocardiographic parameters [left atrial volume index, left ventricular (LV) mass index, LV ejection fraction, and LV filling pressure] were assessed. Results Among all echocardiographic and plasma biomarkers measured, only NT-proBNP was consistently associated with HF/D in univariate and multivariate {third versus first tertile: hazard ratio [HR] 4.20 [95% confidence interval (CI) 1.02–17.27]} analysis, and only troponin T was consistently associated with MACE/D in univariate and multivariate [third versus first tertile: HR 8.15 (95% CI 2.75–24.18)] analysis. Conclusion Our data suggest that plasma biomarkers are robust and independent predictors of heart failure and atherosclerotic cardiovascular events after kidney transplantation, whereas standard echocardiographic follow-up does not add to risk prediction.

Background Graft survival in transplant recipients depends on pharmacokinetics and on individual susceptibility towards immunosuppressive drugs. Nevertheless, pharmacodynamic changes in T-cell functionality in response to drugs and in relation to pharmacokinetics are poorly characterized. We therefore investigated the immunosuppressive effect of calcineurin inhibitors and steroids on general T-cell functionality after polyclonal stimulation of whole blood samples. Methods General T-cell functionality in the absence or presence of immunosuppressive drugs was determined in vitro directly from whole blood based on cytokine induction after stimulation with the polyclonal stimulus Staphylococcus aureus enterotoxin B. In addition, diurnal changes in leukocyte and lymphocyte subsets, and on T-cell function after intake of immunosuppressive drugs were analyzed in 19 patients during one day and compared to respective kinetics in six immunocompetent controls. Statistical analysis was performed using non-parametric and parametric tests. Results Susceptibility towards calcineurin inhibitors showed interindividual differences. When combined with steroids, tacrolimus led to more pronounced increase in the inhibitory activity as compared to cyclosporine A. While circadian alterations in leukocyte subpopulations and T-cell function in controls were related to endogenous cortisol levels, T-cell functionality in transplant recipients decreased after intake of the morning medication, which was more pronounced in patients with higher drug-dosages. Interestingly, calcineurin inhibitors differentially affected circadian rhythm of T-cell function, as patients on cyclosporine A showed a biphasic decrease in T-cell reactivity after drug-intake in the morning and evening, whereas T-cell reactivity in patients on tacrolimus remained rather stable. Conclusions The whole blood assay allows assessment of the inhibitory activity of immunosuppressive drugs in clinically relevant concentrations. Circadian alterations in T-cell function are determined by dose and type of immunosuppressive drugs and show distinct differences between cyclosporine A and tacrolimus. In future these findings may have practical implications to estimate the net immunosuppressive effect of a given drug-regimen that daily acts in an individual patient, and may contribute to individualize immunosuppression.

International audience; No abstract available

Rationale: The renin–angiotensin–aldosterone system is a major pathway in regulating blood pressure, glomerular filtration, and fluid homeostasis. During inflammatory diseases, generation of angiot...

BACKGROUND AND AIMS Cardiovascular diseases (CVD) and chronic kidney diseases (CKD) are highly prevalent in Western populations and account for a substantial proportion of mortality. We recently found that apolipoprotein C-3 (ApoC3), a constituent of triglyceride-rich lipoproteins, induces alternative NLRP3 inflammasome activation leading to sterile inflammation. In the present study, we aimed to assess post-translational modifications (PTMs) of ApoC3 in patients with CKD, to determine the effects of post-translationally modified ApoC3 in vitro and in vivo, and to test the relevance in a prospective clinical trial. METHOD Using mass-spectrometry, we screened ApoC3 for PTMs We determined the effects of modified ApoC3 on monocyte inflammatory response in vitro and assessed its effects in humanized mice subjected to a vascular injury model and unilateral ureter ligation. Finally, we assessed the association of post-translationally modified ApoC3 and cardiovascular and renal events in a prospective clinical trial of 543 CKD patients. RESULTS We identified post-translational guanidinylation of ApoC3 (gApoC3) in patients with CKD, which augments the proinflammatory effects of ApoC3. Mechanistically, guanidine and urea induced guanidinylation of ApoC3. gApoC3 accumulates in kidneys and plasma of mice subjected to a CKD model as determined by 2D-proteomic analyses. In humanized mice, gApoC3 promotes kidney fibrosis and impedes vascular regeneration. In the clinical trial, higher gApoC3 blood levels as determined by mass spectrometry were associated with increased mortality as well as cardiovascular and renal events. CONCLUSION Guanidinylation of ApoC3 represents a novel pathogenic mechanism in CKD and CKD-associated vascular injury, rendering gApoC3 a potential therapeutic target.

Background Acute kidney injury (AKI) is an often neglected but crucial element of clinical nephrology. The aim of the Nephrology and Public Policy Committee (NPPC) of the European Renal Association–European Dialysis and Transplant Association is to promote several key aspects of European nephrology. One of the targets proposed by the NPPC was to advance European nephrology involvement in AKI. Methods We undertook a literature analysis to define the current position of European nephrology in the field of AKI compared with other regions and to determine how different European countries compare with each other. Results It appeared that vis-à-vis countries with a comparable socio-economic status (the USA, Australia, New Zealand and Canada), the European contribution was almost 50% less. Within Europe, Central and Eastern Europe and countries with a lower gross domestic product showed lower scientific output. Nephrologists contributed to less than half of the output. There was no trend of a change over the last decade. Conclusions There is room to improve the contribution of European nephrology in the field of AKI. We propose a model on how to promote clinical collaboration on AKI across Europe and the creation of a pan-European nephrology network of interested units to improve clinical outcomes, increase nephrologist involvement and awareness outside nephrology and stimulate research on AKI in Europe. Accordingly, we also propose a list of research priorities and stress the need for more European funding of AKI research.

For heart failure patients with reduced ejection fraction, optimised medication improves symptom control and reduces mortality. Substances influencing the renin-angiotensin-aldosteron-system, so-called RAAS-inhibitors, are the cornerstone of heart failure treatment. This article summarises a consensus between experts in cardiology and in nephrology on a pragmatic approach to manage a drop in glomerular filtration rate and incident hyperkalaemia - the two most common reasons for reducing or discontinuing heart failure medication.Bei Patienten mit Herzinsuffizienz und reduzierter Ejektionsfraktion wird durch eine optimierte medikamentöse Therapie sowohl die Symptomkontrolle verbessert als auch die Mortalität gesenkt. Eckpfeiler der Herzinsuffizienztherapie sind dabei Medikamente mit Einfluss auf das Renin-Angiotensin-Aldosteron-System, sogenannte RAAS-Inhibitoren. Dieser Artikel stellt einen kardiologisch-nephrologischen Konsens zur praxisorientierten Hilfestellung bei abnehmender glomerulärer Filtrationsrate oder Anstieg des Serum-Kaliumspiegels vor. Dies sind die 2 häufigsten Gründe für eine Dosisreduktion oder das Absetzen von prognoseverbessernden Medikamenten bei Herzinsuffizienzpatienten.

International audience; Objective: Conflicting findings and knowledge gaps exist regarding links between anemia, physical activity, health-related quality of life (HRQOL), chronic kidney disease (CKD) progression, and mortality in moderate-to-advanced CKD. Using the CKD Outcomes and Practice Patterns Study, we report associations of hemoglobin (Hgb) with HRQOL and physical activity, and associations of Hgb and physical activity with CKD progression and mortality in stage 3-5 nondialysis (ND)-CKD patients. Design and Methods: Prospectively collected data were analyzed from 2,121 ND-CKD stage 3-5 patients, aged ≥18 years, at 43 nephrologist-run US and Brazil CKD Outcomes and Practice Patterns Study–participating clinics. Cross-sectional associations were assessed of Hgb levels with HRQOL and physical activity levels (from validated Kidney Disease Quality of Life Instrument and Rapid Assessment of Physical Activity surveys). CKD progression (first of ≥40% estimated glomerular filtration rate [eGFR] decline, eGFR12 g/dL. Odds of being highly physically active were substantially greater at Hgb>10.5 g/dL. Lower Hgb was strongly associated with greater CKD progression and mortality, even after extensive adjustment. Physical inactivity was strongly associated with greater mortality and weakly associated with CKD progression. Possible residual confounding is a limitation. Conclusion: This multicenter international study provides real-world observational evidence for greater HRQOL, physical activity, lower CKD progression, and greater survival in ND-CKD patients with Hgb levels >12 g/dL, exceeding current treatment guideline recommendations. These findings help inform future studies aimed at understanding the impact of new anemia therapies and physical activity regimens on improving particular dimensions of ND-CKD patient well-being and clinical outcomes.

Plasma exchange (PE) and immunoadsorption (IA) are standard therapeutic options of immune-mediated neurological disorders. This study evaluates the relation of the relative quantity of applied dose of PE and/ or IA and its achieved therapeutic effectiveness within the treated underlying neurological disorders. In a retrospective study, we evaluated data from PE and IA carried out 09/2009-06/2014 in neurological patients at the University-Hospital of Saarland, Germany. Apheresis dose was defined as the ratio of the extracorporeal treated plasma volume to the patient’s plasma volume. Effectiveness was assessed through disease-specific tests and scores by the attending neurologist(s); results were classified into response or no response. 1101 apheresis (PE:238, IA:863), in 153 hospital-stays were carried out, averaged, 7.0 treatments per patients, 82% responded, 18% not. Mean applied apheresis dose per treatment was 0.91 with mean doses of 1.16 for PE and 0.81 for IA. The totally applied mean dose per stay was 5.6 (PE:5.01, IA:5.81). No correlation was seen between apheresis dosing and treatment effectiveness (PE:R2 = 0.074, IA:R2 = 0.0023). PE and IA in therapy-refractory immune-mediated neurological disorders majorly achieved a measurable severity improvement – without correlation to the applied dose. Moreover, our data rather suggest, that effectiveness may be given with volumes below currently recommended volumes.

Chronic kidney disease (CKD) is a global public health problem accompanied by substantial comorbidities and reduced life expectancy. In this respect, progressive CKD leading to uraemia can be seen as a systemic disease with a critical impact on virtually all organ systems. Therefore, it is of particular importance to identify patients with ongoing CKD progression, which is challenging, because the individual course of CKD is difficult to predict. Patterns of progression in CKD patients include linear and non-linear trajectories of GFR loss, but kidney function can also remain stable for years. Moreover, a substantial GFR decline may occur in the absence of higher-grade albuminuria (non-proteinuric CKD), rendering the measurement of albuminuria less reliable for progression prediction in such individuals. In the present review, we focus on the recently identified glycoprotein Dickkopf-3 (DKK3) as a stress-induced, renal tubular epithelial cell-derived, pro-fibrotic molecule. In experimental CKD models, DKK3 promoted renal tubulointerstitial fibrosis through modulation of the canonical Wnt/β-catenin signalling pathway. In clinical studies, increased urinary DKK3 levels identified patients at high risk for short-term CKD progression, regardless of the cause of kidney disease, baseline kidney function and albuminuria. Moreover, increased urinary DKK3 levels are associated with a high risk for acute kidney injury and the subsequent loss of kidney function after cardiac surgery. These findings highlight DKK3 as a mediator of renal tubular cell damage in kidney injury and short-term progression of kidney disease, with potential therapeutic implications.

Background Chronic kidney disease (CKD) progression among German patients in a representative setting has not been described previously. The Verband Deutsche Nierenzentren and Chronic Kidney Disease Outcomes and Practice Patterns Study established a longitudinal observational cohort among German CKD patients to research variations in patient care and outcomes in real-world nephrology practices. Methods A cohort of CKD Stages 3 (25%) and 4 (75%) patients was established from German nephrologist-run CKD clinics in 2013–16. Linear models were used to determine the estimated glomerular filtration rate (eGFR) slope during follow-up and Cox models were used to assess outcomes of end-stage kidney disease (ESKD) and death. Results A total of 1834 patients (median age 75 years, 58% male, 42% diabetics, median baseline eGFR 25 mL/min/1.73 m2) were followed for a median of 29 months. More than 50% had slow or no decline and 17% declined ≥5 mL/min/1.73 m2/year. After 4.5 years, the incidence of ESKD was 8% and of deaths without ESKD 16% among patients with eGFR ≥30 mL/min/1.73 m2 and 37% and 19% for eGFR Conclusions Routine nephrology care of patients in Germany comprises mostly elderly patients, many with slow CKD progression. Identification of risk factors for CKD progression and mortality may help guide resources by closer follow-up of high-risk patients.

Aims Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. Methods and results We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.

Background and Aims Cardiovascular diseases (CVD) and chronic kidney disease (CKD) are highly prevalent, aggravate each other, and account for substantial mortality. Both conditions are characterized by activation of the innate immune system. The alarmin IL-1α is expressed in a variety of cell types promoting (sterile) systemic inflammation. The aim of the present study is to examine the role of IL-1α in mediating inflammation in the setting of cardiorenal diseases. Method We assessed the expression of IL-1α on the surface of monocytes from patients with acute myocardial infarction (AMI) and patients with CKD and determined its association with atherosclerotic CVD events during follow-up in an explorative clinical study. Furthermore, we assessed the inflammatory effects of IL-1α in several organ injury models in Il1a -/- and Il1b -/- mice and investigated the underlying mechanisms in vitro in monocytes and endothelial cells. Results IL-1α is strongly expressed on the surface of monocytes from patients with AMI and CKD compared to healthy controls. Higher IL-1α surface expression on monocytes from patients with AMI was associated with a higher risk for atherosclerotic CVD events, which underlines the clinical relevance of IL-1α. In mice, IL-1α, but not IL-1β, mediates leukocyte-endothelial adhesion as determined by intravital microscopy. IL-1α promotes accumulation of macrophages and neutrophils in inflamed tissue in-vivo . Furthermore, IL-1α on monocytes stimulates their homing at sites of vascular injury. A variety of stimuli such as free fatty acids or oxalate crystals induce IL-1α surface expression and release by monocytes, which then mediates their adhesion to the endothelium via IL-1 receptor-1. Besides, IL-1α promotes expression of the vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells thereby fostering the adhesion of circulating leukocytes. IL-1α induces inflammatory injury after experimental AMI and abrogation of IL-1α prevents the development of CKD in oxalate or adenine-fed mice. Conclusion IL-1α represents a key mediator of leukocyte-endothelial adhesion and inflammation in cardiorenal diseases. Inhibition of IL-1α may serve as a novel anti-inflammatory treatment strategy.

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 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.

Background and Aims Among patients with CKD, prevalence of anaemia increases with CKD severity,1 and is accompanied by elevated risk of hospitalisation and mortality.2 Treatment options include iron therapy and ESAs; international guidelines recommend initiating ESA therapy when haemoglobin (Hb) declines Method This was a non-interventional, retrospective cohort study of adults with NDD-CKD stages 3b–5 (as defined in KDIGO 2012 guidelines)1 diagnosed with anaemia (Hb Results In total, 848 patient records (Germany, 211; Spain, 430; UK, 207) were included. Average age was 66 years (Table). Most patients were white and almost half had >2 comorbidities. Prior to ESA initiation, at least half of all patients in each country received either oral or intravenous (IV) iron therapy. The average (mean ± SD) number of months between anaemia diagnosis and initiation of ESA therapy was 8.4 ± 19.2. Hb levels were recorded at ESA initiation for almost all (91.3%) patients and averaged 9.8 ± 1.0 g/dL for the total cohort; this initial Hb level was similar between countries (Table). Mean ± SD estimated glomerular filtration rate (eGFR) at ESA initiation was 28.0 ± 10.4 ml/min/1.73m2. Across countries, 72–88% of patients received ESAs at home. The mean ± SD duration of therapy (at the time of data collection) was 41.2 ± 18.2 months, and the median weekly dose of short-acting and long-acting ESAs was 3238 IU and 20 μg, respectively. During their initial course of therapy, three-quarters of patients had either an increase or decrease in ESA dose. Less than 10% of patients switched ESAs, while approximately one-third discontinued within 2 years of initiation. At 3 and 6 months post-ESA initiation, only 64.7% of the sample had a documented Hb measurement despite continuing ESA treatment; this proportion was further reduced to 60.0% by 12 months after initiation. The Hb target was maintained by 88.7%, 74.6% and 49.4% of patients at 3, 6 and 12 months, respectively. Mean ferritin levels were 167.3 ng/mL at initiation and 198.7 ng/mL at 12 months (among the 85% and 48% of the sample, respectively, with recorded data). Mean TSAT was 22.1% at initiation and 25.6% at 12 months (among the 67% and 38%, respectively, with recorded data). Approximately three-quarters of patients (77.3%) received iron therapy concomitantly with ESA treatment; in the UK, most of these received IV iron, while in Germany and Spain, a majority received oral iron (Table). Blood transfusions were more common in Spain (24.2%) than in Germany (5.1%) or the UK (8.4%). Approximately one-fifth of patients required dialysis. Conclusion Initiation of ESAs to treat anaemia among patients with NDD-CKD in Germany, Spain and the UK follows current guidelines. However, recommendations to regularly monitor Hb were not routinely followed or were poorly documented. As most patients with NDD-CKD anaemia were treated at home, oral therapies may be of benefit to these patients

Background and Aims Prescription of anticoagulants in patients with chronic kidney disease (CKD) is challenging, since these patients are at high risk of thromboembolic episodes, but are also prone to bleeding events. Based on a number of pivotal trials, four direct oral anticoagulants (DOACs) have been approved for use in non-valvular atrial fibrillation (AF) since 2010. These DOACs have now supplanted vitamin K antagonists (VKAs) as first-line treatment in non-CKD patients. Following post-hoc analyses of randomized clinical trials of DOACs in CKD patients performed between 2011 and 2016, a 2018 Kidney Disease Improving Global Outcomes Controversies Conference stated that although there is not enough evidence to recommend DOACs in patients with advanced CKD, these medications are safer than VKAs and not inferior for stroke preventing in patients with AF and an estimated glomerular filtration rate (eGFR) between 30 and 50 ml/min/1.73 m2. Here, in a study of stage 3 to 5 CKD patients, we sought to describe multinational prescription patterns for oral anticoagulants in general and for VKAs vs. DOACs in particular. Method We analyzed data from the international CKD Outcomes and Practice Patterns Study (CKDopps) of non-dialysis CKD patients ≥ 18 years of age with an eGFR Results Of the 8154 patients enrolled, 7092 had drug prescriptions data available at baseline, and 1080 (15%) of these had at least one prescription of an oral anticoagulant. At baseline, VKAs were the most frequently prescribed oral anticoagulants (n=984, 91%), and only 97 of the 1080 patients (9%) were on DOACs (91 on a direct factor Xa inhibitor and 6 on a direct thrombin inhibitor). This low DOAC prescription rate was observed in France, the USA, Brazil and Germany. There was an upward trend in DOAC prescription (relative to VKAs) over the course of the study. Over a median [interquartile range] follow-up period of 3 years [1.5-4.5], 287 incident oral anticoagulant prescriptions were reported, 177 started on VKAs and 110 started on DOACs. Among the patients receiving a VKA at baseline, only 44 switched to a DOAC. Conclusion In an international sample of non-dialysis CKD patients (eGFR

Background and Aims Hyperkalemia (HK) (serum K>5.0 mEq/L) is a chronic condition in patients with chronic kidney disease (CKD) associated with high morbidity and mortality, and it is a frequent reasons for renin angiotensin aldosterone inhibition (RAASi) discontinuation. Patiromer is a non-absorbed, sodium-free, K+ binder that has been shown to reduce serum K+ in patients with HK, and thereby enable RAASi therapy, which is supported by randomized trial evidence. The description of patiromer utilization in patients with moderate to advanced CKD in the real-world setting in Europe is lacking. The objective of this analysis was to describe predictors of patiromer initiation and time to discontinuation among CKD patients using contemporary (April 2018-October 2020) data from German participants in CKD Outcomes and Practice Patterns Study (CKDopps). Method We identified 136 patiromer users (116 with matching K measurement) during the observation period. Patients with eGFR Results Patiromer was prescribed to ≥2 patients in 11 clinics, one patient in 19 clinics, and zero patients in 57 clinics. Patients prescribed patiromer had lower eGFR (23.2 [15.8, 28.6] vs 36.9 [27.7, 46.3]ml/min) and higher serum K levels (5.6 [5.4, 6.1] vs 4.6 [4.3, 5.0]ml/min). There were no major differences according to patiromer use in other demographic, clinical, and biochemical characteristics. Despite the differences in serum K, use of RAAS inhibitors was similar in patiromer users (83%) versus non-users (80%). Thirty three percent of patiromer users were prescribed polystyrene sulfonate (SPS) before patiromer initiation. In a multiple logistic regression models (including serum K, CKD stage, gender, age, prescription of RAASi, diabetes, coronary artery disease, heart failure), patiromer use was strongly associated more advanced CKD stage (independently of high serum K), with odds ratios of initiation >3 for CKD stage 4 or 5 versus CKD stage 3. Among new users, 90% of patients had active prescription at 30 days and about one-half had active prescription at one year (Figure). Conclusion The main predictors of Patiromer initiation were advanced CKD stage and hyperkalemia. Treatment decisions did not appear to be based on other patient or clinical characteristics. Patiromer was often prescribed to patients already receiving alternative HK treatment (SPS), suggesting use for chronic hyperkalemia rather than response to acute event. Further analysis with a larger population and measurements of K+ before and after patiromer initiation may improve the understanding of its pharmacoutilization in moderate to advanced CKD.

Renin‐angiotensin‐aldosterone system inhibitors (RAASi) are recommended for chronic kidney disease (CKD) patients. In this study, we describe RAASi prescription patterns in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) in Brazil, Germany, France, and the United States (US). 5870 patients (mean age 66‐72 years; congestive heart failure [CHF] in 11%‐19%; diabetes in 43%‐54%; serum potassium ≥5 in 20%‐35%) were included. RAASi prescription was more common in Germany (80%) and France (77%) than Brazil (66%) and the United States (52%), where the prevalence of prescription decreases particularly in patients with CKD stage 5. In the multivariable regression model, RAASi prescription was least common in the United States and more common in patients who were younger, had diabetes, hypertension, or less advanced CKD. In conclusion, RAASi prescription patterns vary by country, and by demographic and clinical characteristics. RAASi appear to be underused, even among patients with strong class‐specific recommendations. Although the reasons for this variation could not be fully identified in this cross‐sectional observation, our data indicate that the risk of hyperkalemia may contribute to the underuse of this class of agents in moderate to advanced CKD.

Circulation : an official journal of the American Heart Association 143(11), 1157-1172 (2021). doi:10.1161/CIRCULATIONAHA.120.050686, Published by Lippincott, Williams & Wilkins, Philadelphia, Pa.

The adrenal glands participate in cardiovascular (CV) physiology and the pathophysiology of CV diseases through their effects on sodium and water metabolism, vascular tone and cardiac function. In the present study, we identified a new adrenal compound controlling mesenchymal cell differentiation that regulates osteoblastic differentiation in the context of vascular calcification. This peptide was named the “calcification blocking factor” (CBF) due to its protective effect against vascular calcification and is released from chromogranin A via enzymatic cleavage by calpain 1 and kallikrein. CBF reduced the calcium content of cells and thoracic aortic rings under calcifying culture conditions, as well as in aortas from animals treated with vitamin D and nicotine (VDN animals). Furthermore, CBF prevented vascular smooth muscle cell (VSMC) transdifferentiation into osteoblast-like cells within the vascular wall via the sodium-dependent phosphate transporter PIT-1 and by inhibition of NF-κB activation and the subsequent BMP2/p-SMAD pathway. Pulse pressure, a marker of arterial stiffness, was significantly decreased in VDN animals treated with CBF. In line with our preclinical data, CBF concentration is significantly reduced in diseases characterized by increased calcification, as shown in patients with chronic kidney disease. In preparation for clinical translation, the active site of the native 19-AS long native CBF was identified as EGQEEEED. In conclusion, we have identified the new peptide CBF, which is secreted from the adrenal glands and might prevent vascular calcification by inhibition of osteogenic transdifferentiation. The anti-calcific effects of CBF and short active site may therefore promote the development of new tools for the prevention and/or treatment of vascular calcification. Supplementary Information The online version contains supplementary material available at 10.1007/s00395-021-00899-z.

International audience

Progressive chronic kidney disease (CKD) in individuals with type 2 diabetes mellitus is a global public health problem accompanied by substantial comorbidities and reduced life expectancy. In this respect, CKD leading to uremia can be seen as a systemic disease with a critical impact on virtually all organ systems. Thus it is of particular importance to identify patients with incipient CKD and ongoing CKD progression, but the individual course of CKD is challenging to predict. Patterns of progression in persons with CKD include linear and nonlinear trajectories of glomerular filtration rate (GFR) loss. Kidney function can also remain stable for years, especially in the elderly. In particular, one-fifth of individuals show a substantial GFR decline in the absence of high albuminuria (nonproteinuric CKD), rendering albuminuria less suitable for predicting the progression in such individuals.

Background In dialysis patients statins are less effective than in other high risk patients due to a shift from cholesterol synthesis towards cholesterol absorption. The CARE FOR HOMe study investigates whether a shift towards cholesterol absorption occurs in non-dialysis chronic kidney disease (CKD), and whether the ratio of campesterol-to-lathosterol predicts cardiovascular outcomes in non-dialysis CKD patients. Methods In this analysis 251 participants suffering from CKD (KDIGO 2–4) without lipid-lowering drugs were included and followed for major atherosclerotic events (MACE). Additionally, all-cause death and the composite endpoint MACE and all-cause death were explored. We performed univariate and multivariate Cox regression analysis, adjusting for age, gender, estimated glomerular filtration rate (eGFR), log-transformed albuminuria, prevalent cardiovascular disease, current smoking, diabetes mellitus, systolic blood pressure and body mass index. The primary hypothesis was that patients with a high campesterol-to-lathosterol ratio had a higher event rate. Results Neither lathosterol-to-cholesterol (r=0.022; p=0.730), nor campesterol-to-cholesterol (r=0.041; p=0.519) nor campesterol-to-lathosterol (r=−0.103; p=0.105) correlated with eGFR. During follow-up of 5.1±2.1 years, 47 participants suffered from MACE, 46 participants died and 61 reached the composite endpoint of MACE or all-cause death. In univariate Cox regression analysis, campesterol-to-lathosterol did not predict atherosclerotic cardiovascular events (HR 0.740; 0.368–1.487), all-cause death (HR 0.564; 0.277–1.145) or the composite endpoint (HR 0.652; 0.355–1.196). After full adjustment: campesterol-to-lathosterol was not associated with all three endpoints; MACE (HR 1.064; 0.507–2.231), all-cause death (HR 0.818; 0.420–1.594) and MACE and all-cause death (HR 0.956; 0.525–1.744). Conclusion Markers of cholesterol metabolism were not associated with eGFR in patients with impaired renal function (KDIGO 2–4). Campesterol-to-lathosterol did not predict future MACE or all-cause death in non-dialysis CKD. These findings do not support the concept that patients with impaired renal function (KDIGO 2–4) benefit in particular from ezetimibe treatment. Further research is required to address this hypothesis in dialysis patients. Funding Acknowledgement Type of funding source: None

Chronic kidney disease (CKD) is associated with high cardiovascular risk. CKD patients exhibit a specific lipoprotein pattern termed ‘uraemic dyslipidaemia’, which is characterized by rather normal low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol, and high triglyceride plasma levels. All three lipoprotein classes are involved in the pathogenesis of CKD-associated cardiovascular diseases (CVDs). Uraemia leads to several modifications of the structure of lipoproteins such as changes of the proteome and the lipidome, post-translational protein modifications (e.g. carbamylation) and accumulation of small-molecular substances within the lipoprotein moieties, which affect their functionality. Lipoproteins from CKD patients interfere with lipid transport and promote inflammation, oxidative stress, endothelial dysfunction as well as other features of atherogenesis, thus contributing to the development of CKD-associated CVD. While, lipid-modifying therapies play an important role in the management of CKD patients, their efficacy is modulated by kidney function. Novel therapeutic agents to prevent the adverse remodelling of lipoproteins in CKD and to improve their functional properties are highly desirable and partially under development.

Background In patients with iron deficiency anemia, ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) allow high-dose iron repletion. While FCM is reported to induce hypophosphatemia, the frequency of hypophosphatemia after an equivalent dosage of FDI had not been assessed prospectively. Methods In the prospective, single-center, double-blind HOMe aFers study, 26 women with iron deficiency anemia (hemoglobin Results Hypophosphatemia occurred more frequently in women treated with FCM (9 out of 12 [75%]) than in those treated with FDI (1 out of 13 [8%]; p = 0.001). Within 24 h after iron supplementation, women in the FCM group had significant higher plasma intact FGF23 (p p p = 0.021 at day 7 ± 2 after iron supplementation). We did not observe differences in skeletal and cardiovascular markers, potentially because of the limited number of participants. Conclusions While both FCM and FDI provide efficient iron repletion in participants with iron deficiency anemia, FCM induced hypophosphatemia more often than FDI. Trial registration Clinical Trials.gov NCT02905539. Registered on 8 September 2016. 2015-004808-36 (EudraCT Number) U1111-1176-4563 (WHO Universal Trial Number) DRKS00010766 (Deutsches Register Klinischer Studien)

Background and Aims In dialysis patients, cholesterol-lowering therapy with statins is less effective than in other high-risk patients. This may partly be explained by a shift from cholesterol synthesis, which is inhibited by statin treatment, towards cholesterol absorption, which is inhibited by ezetimibe. In line, markers of cholesterol absorption – such as campesterol - better predict atherosclerotic cardiovascular events than markers of cholesterol synthesis – such as lathosterol - in dialysis patients. We now investigated in our CARE FOR HOMe study whether a similar shift towards cholesterol absorption occurs in non-dialysis chronic kidney disease (CKD), and whether the campesterol / lathosterol ratio predicts outcome in non-dialysis CKD patients. Method Since 2008, 599 participants suffering from chronic kidney disease have been included into the CARE FOR HOME study, an observational cohort study. 555 patients had baseline samples available for analyses of the lathosterol / cholesterol ratio as a marker for cholesterol synthesis, and the campesterol / cholesterol ratio as a marker for cholesterol absorption. We excluded those participants who were currently treated with statins or other lipid lowering drugs, leaving 251 patients for this analysis. Participants were followed annually for major atherosclerotic cardiovascular events (MACE), defined as non-fatal acute myocardial infarction, non-fatal ischemic stroke, cerebrovascular / peripheral arterial or coronary revascularization, major amputation above the ankle and cardiovascular death. Additionally, all-cause death and the composite endpoint MACE and all-cause death were explored. We performed univariate (Model 1) and multivariate Cox regression analysis, adjusting for age, gender (Model 2), estimated glomerular filtration rate (eGFR), log-transformed albuminuria (Model 3), prevalent cardiovascular disease, current smoking, diabetes mellitus, systolic blood pressure and body mass index (Model 4). The primary hypothesis was that patients with a high campesterol / lathosterol ratio had a higher event rate. Results Neither lathosterol / cholesterol ratio (r = 0.022, p = 0.730), nor campesterol / cholesterol ratio (r = 0.042; p = 0.519) nor the campesterol / lathosterol ratio (r = -0.103; p = 0.105) correlated significantly with eGFR. During follow-up of 5.1 ± 2.1 years, 47 participants suffered from MACE, 46 participants died and 61 participants reached the composite endpoint of MACE or all-cause death. In univariate Cox regression analysis, campesterol / lathosterol ratio did not significantly predict atherosclerotic cardiovascular events (HR 0.740; 0.368 – 1.487), all-cause death (HR 0.564; 0.277 – 1.145) or the composite endpoint (HR 0.652; 0.355 – 1.196). After full adjustment, results were not different: Campesterol / lathosterol ratio was not significantly associated with all three endpoints: MACE (HR 1.064; 0.507 – 2.231), all-cause death (HR 0.818; 0.420 – 1.594) and MACE and all-cause death (HR 0.956; 0.525 – 1.744). Conclusion We did not observe a shift from cholesterol synthesis to cholesterol absorption across the spectrum of non-dialysis CKD. Campesterol / lathosterol ratio did not predict future MACE or all-cause death in non-dialysis CKD. These findings do not support the concept that CKD patients may preferentially benefit from ezetimibe rather than from statin treatment.

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.

Background and Aims Chronic kidney disease (CKD) represents one of the strongest cardiovascular risk factors. Recently, we have shown that activation of the NOD-like receptor protein-3 (NLRP3) inflammasome mediates progression of kidney injury and CKD-associated vascular disease (Zewinger et al. Nat Immunol 2013). Components of the NLRP3 inflammasome pathway such as interleukin-1β (IL-1β) can therapeutically be targeted. Associations of genetically determined life-long inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. Method We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 3,061 patients enrolled in the LURIC study undergoing coronary angiography in a gene-centric approach. Functional relevance of the rs10754555 NLRP3 variant was studied in freshly isolated human monocytes. Findings were validated in 39,755 participants from eight independent studies (CV risk populations) as well as in 483,258 participants of the UKBiobank study (general population). Results Genetic analyses identified the highly prevalent (MAF 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Expression of NLRP3 mRNA and inflammasome-dependent effector responses of isolated human monocytes from rs10754555 carriers were significantly higher as compared to non-carriers. In homozygous rs10754555 carriers, the prevalence of coronary artery disease (CAD) was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age in LURIC and in UKBiobank. Importantly, in LURIC and in UKBiobank, homozygous rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up (HR 1.37, 95%-CI 1.08-1.74 and HR 1.13, 95%-CI 1.02-1.25, respectively). Consistently, rs10754555 was associated with higher cardiovascular mortality (HR 1.11, 95%-CI 1.05-1.16; P Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent CAD and mortality. This study provides evidence for a substantial role of life-long, genetically-driven systemic inflammation in cardiovascular disease and highlights the NLRP3 inflammasome as a therapeutic target in the general population and particular in patients with CKD.

Introduction Circular RNAs (circRNAs) have recently been described as novel noncoding regulators of gene expression. They might have an impact on microRNA expression by their sponging activity. The detectability in blood of these RNA transcripts has been demonstrated in patients with cancer and cardiovascular disease. We tested the hypothesis that circulating circRNAs in blood of critically ill patients with acute kidney injury (AKI) at inception of renal replacement therapy may also be dysregulated and associated with patient survival. Methods We performed a global circRNA expression analysis using RNA isolated from blood of patients with AKI as well as controls. This global screen revealed several dysregulated circRNAs in patients with AKI. Most highly increased circRNA-array−based transcripts as well as expression of the circRNA target miR-126-5p were confirmed in blood of 109 patients with AKI, 30 age-matched healthy controls, 25 critically ill non-AKI patients, and 20 patients on maintenance hemodialysis by quantitative real-time polymerase chain reaction. Results Circulating concentrations of 3 novel circRNAs were amplified in blood of patients with AKI and in controls. Circular RNA sponge of miR-126 (or ciRs-126) was most highly altered compared to healthy controls and disease controls (fold change of 52.1). ciRs-126 was shown to bioinformatically sponge miR-126-5p, which was found to be highly suppressed in AKI patients and hypoxic endothelial cells. Cox regression and Kaplan−Meier curve analysis revealed ciRs-126 as an independent predictor of 28-day survival (P Conclusion Circulating concentrations of circRNAs in patients with AKI are detectable. ciRs-126 may potentially sponge miR-126-5p and acts as a predictor of mortality in this patient cohort.

In January 2019, the ERA-EDTA surveyed nephrologists with questions on kidney care and kidney research designed to explore comprehension of the impact of alterations to organization of renal care and of advancements in technology and knowledge of kidney disease. Eight hundred and twenty-five ERA-EDTA members, ∼13% of the whole ERA-EDTA membership, replied to an ad hoc questionnaire. More than half of the respondents argued that kidney centres will be increasingly owned by large dialysis providers, nearly a quarter of respondents felt that many medical aspects of dialysis will be increasingly overseen by non-nephrologists and a quarter (24%) also believed that the care and long-term follow-up of kidney transplant patients will be increasingly under the responsibility of transplant physicians caring for patients with any organ transplant. Nearly half of the participants (45%, n = 367) use fully electronic clinical files integrating the clinical ward, the outpatient clinics, the haemodialysis and peritoneal dialysis units, as well as transplantation. Smartphone-based self-management programmes for the care of chronic kidney disease (CKD) patients are scarcely applied (only 11% of surveyed nephrologists), but a substantial proportion of respondents (74%) are eager to know more about the potential usefulness of these apps. Finally, European nephrologists expressed a cautious optimism about the application of omic sciences to nephrology and on wearable and implantable kidneys, but their expectations for the medium term are limited.