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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.

Chronic kidney disease (CKD) represents a global public health problem with high disease related morbidity and mortality. Since CKD etiology is heterogeneous, early recognition of patients at risk for progressive kidney injury is important. Here, we evaluated the tubular epithelial derived glycoprotein dickkopf-3 (DKK3) as a urinary marker for the identification of progressive kidney injury in a non-CKD cohort of patients with chronic obstructive pulmonary disease (COPD) and in an experimental model. In COSYCONET, a prospective multicenter trial comprising 2,314 patients with stable COPD (follow-up 37.1 months), baseline urinary DKK3, proteinuria and estimated glomerular filtration rate (eGFR) were tested for their association with the risk of declining eGFR and the COPD marker, forced expiratory volume in one second. Baseline urinary DKK3 but not proteinuria or eGFR identified patients with a significantly higher risk for over a 10% (odds ratio: 1.54, 95% confidence interval: 1.13-2.08) and over a 20% (2.59: 1.28-5.25) decline of eGFR during follow-up. In particular, DKK3 was associated with a significantly higher risk for declining eGFR in patients with eGFR over 90 ml/min/1.73m2 and proteinuria under 30 mg/g. DKK3 was also associated with declining COPD marker (2.90: 1.70-4.68). The impact of DKK3 was further explored in wild-type and Dkk3-/- mice subjected to cigarette smoke-induced lung injury combined with a CKD model. In this model, genetic abrogation of DKK3 resulted in reduced pulmonary inflammation and preserved kidney function. Thus, our data highlight urinary DKK3 as a possible marker for early identification of patients with silent progressive CKD and for adverse outcomes in patients with COPD.

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

Mortality among patients with chronic kidney disease (CKD) is largely a consequence of cardiovascular disease (CVD) and is a particular concern given the increasing prevalence of CKD. Sterile inflammation triggered by activation of the innate immune system is an important driver of both CKD and associated CVD. Several endogenous mediators, including lipoproteins, crystals such as silica, urate and cholesterol crystals, or compounds released from dying cells interact with pattern recognition receptors expressed on a variety of different cell types, leading to the release of pro-inflammatory cytokines. Disturbed regulation of the haematopoietic system by damage-associated molecular patterns, or as a consequence of clonal haematopoiesis or trained innate immunity, also contributes to the development of inflammation. In observational and genetic association studies, inflammation is linked to the progression of CKD and cardiovascular events. In 2017, the CANTOS trial of canakinumab provided evidence that inhibiting inflammation driven by NLRP3-IL-1-IL-6-mediated signalling significantly reduced cardiovascular event rates in individuals with and without CKD. Other approaches to target innate immune pathways are now under investigation for their ability to reduce cardiovascular events and slow disease progression among patients with atherosclerosis and stage 3 and 4 CKD. This Review summarizes current understanding of the role of inflammation in the pathogenesis of CKD and its associated CVD, and how this knowledge may translate into novel therapeutics.

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.

Introduction: High plasma fibroblast growth factor 23 (FGF-23) predicts cardiovascular events in chronic kidney disease (CKD) patients. Experimental evidence suggests FGF receptor 4 (FGFR4) activation by FGF-23, and deficiency of the soluble form of its co-receptor Klotho promotes left-ventricular hypertrophy (LVH). To evaluate the clinical relevance of these findings, a Mendelian randomization study analyzed the association of genetic variants of FGFR4 and Klotho with echocardiographic parameters and cardiac events in CKD patients. Methods: The prospective Cardiovascular and Renal Outcome in CKD 2–4 Patients–The Fourth Homburg Evaluation study recruited CKD G2–G4 patients, of whom 519 consented to SNP genotyping (FGFR4: rs351855; Klotho: rs9536314). Echocardiographic examinations at baseline and 5 years later assessed prevalence of LVH by measurement of left-ventricular mass index (LVMI). Patients were followed for 5.1 ± 2.1 years for the primary endpoints of cardiac decompensation and atherosclerotic cardiovascular disease (ASCVD). Results: Carriers of the different alleles did neither differ in baseline LVMI (rs351855: p = 0.861; rs9536314: p = 0.379) nor in LVMI changes between baseline and follow-up (rs351855: p = 0.181; rs9536314: p = 0.995). Hundred and four patients suffered cardiac decompensation, and 144 patients had ASCVD. Time to cardiac decompensation (rs351855: p = 0.316; rs9536314: p = 0.765) and ASCVD (p = 0.508 and p = 0.800, respectively) did not differ between carriers of different alleles. Discussion/Conclusion: rs351855 and rs9536314 were not associated with LVMI or cardiac events. These findings do not provide evidence for a relevant clinical role of either FGFR4 stimulation or soluble form of Klotho deficiency in LVH development.

Chronic kidney disease (CKD) is associated with substantial cardiovascular morbidity and mortality. This is mediated by highly prevalent traditional cardiovascular risk factors such as arterial hypertension and diabetes mellitus in patients with CKD, but also by the presence of CKD-specific so-called nontraditional cardiovascular risk factors such as vascular calcification, uremic toxins, uremic dyslipidemia, inflammation, and oxidative stress. Therefore, the primary and secondary prevention of cardiovascular disease represents an important part of the care of patients with CKD. This entails optimal control of blood pressure and diabetes, treatment of the uremic dyslipidemia, as well as life-style modifying factors such as weight reduction and smoking cessation.Die chronische Nierenerkrankung ist mit einer erheblichen kardiovaskulären Morbidität und Mortalität assoziiert. Ursächlich hierfür ist zum einen die hohe Prävalenz traditioneller kardiovaskulärer Risikofaktoren wie arterielle Hypertonie und Diabetes mellitus bei Nierenkranken und zum anderen niereninsuffizienzspezifische, sog. nichttraditionelle kardiovaskuläre Risikofaktoren. Hierzu gehören vaskuläre Kalzifikation, Urämietoxine, die urämische Dyslipidämie sowie Inflammation und oxidativer Stress. Deshalb kommt der Primär- und Sekundärprävention kardiovaskulärer Erkrankungen in der Nephrologie eine zentrale Rolle zu. Hierzu gehören eine optimale Blutdruck- und Blutzuckereinstellung, die Therapie der urämischen Dyslipidämie sowie lebensstilmodifizierende Faktoren wie Gewichtsreduktion und Nikotinkarenz.

The WNT–β-catenin system is an evolutionary conserved signalling pathway that is of particular importance for morphogenesis and cell organization during embryogenesis. The system is usually suppressed in adulthood; however, it can be re-activated in organ injury and regeneration. WNT-deficient mice display severe kidney defects at birth. Transient WNT–β-catenin activation stimulates tissue regeneration after acute kidney injury, whereas sustained (uncontrolled) WNT–β-catenin signalling promotes kidney fibrosis in chronic kidney disease (CKD), podocyte injury and proteinuria, persistent tissue damage during acute kidney injury and cystic kidney diseases. Additionally, WNT–β-catenin signalling is involved in CKD-associated vascular calcification and mineral bone disease. The WNT–β-catenin pathway is tightly regulated, for example, by proteins of the Dickkopf (DKK) family. In particular, DKK3 is released by ‘stressed’ tubular epithelial cells; DKK3 drives kidney fibrosis and is associated with short-term risk of CKD progression and acute kidney injury. Thus, targeting the WNT–β-catenin pathway might represent a promising therapeutic strategy in kidney injury and associated complications. This Review discusses advances in the understanding of WNT–β-catenin signalling and its regulation during kidney injury, along with its potential diagnostic and therapeutic implications.

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.

Die Pravalenz der chronischen Nierenerkrankungen (CKD) nimmt weltweit stetig zu. Chronisch Nierenkranke weisen eine massiv erhohte kardiovaskulare Mortalitat auf. Unter anderem spielen Lipoproteine eine wichtige Rolle bei der Entstehung atherosklerotischer kardiovaskularer Erkrankungen. Bei uramischen Patienten sind Lipoproteine in ihrer Struktur verandert, was Auswirkungen auf deren biologische Funktion hat. Dies betrifft nicht nur LDL („low-denity lipoprotein“), sondern auch HDL („high-density lipoprotein“), dessen vasoprotektive Eigenschaften in der Uramie verloren gehen, sodass es in ein gefasschadigendes Lipoprotein transformiert wird. Daruber hinaus induzieren triglyzeridreiche Lipoproteine eine sterile Inflammationsreaktion, woraus ebenfalls Gefas- und Organschadigungen resultieren konnen. 2019 wurden von der European Society of Cardiology (ESC) und der European Atherosclerosis Society (EAS) neue Leitlinien zur Therapie von Dyslipidamien mit neuen LDL-Cholesterin(LDL-C)-Zielwerten vorgestellt. Insgesamt wird eine deutlich striktere LDL-C-Einstellung empfohlen. Neben lebensstilmodifizierenden Masnahmen und Statinen/Ezetimibe, steht mit den PCSK9(Proproteinkonvertase Subtilisin/Kexin Typ 9)-Inhibitoren eine vielversprechende zusatzliche therapeutische Option zur Verfugung. Bei Patienten mit gering- oder mittelgradig eingeschrankter Nierenfunktion ist die Therapie mit PCSK9-Inhibitoren ahnlich erfolgreich und sicher wie in der Allgemeinbevolkerung. Leider fehlen entsprechende Daten fur Patienten mit fortgeschrittener Nierenfunktionseinschrankung. Insgesamt spielt bei Nierenkranken die Senkung von LDL‑C eine zentrale Rolle in der kardiovaskularen Primar- und Sekundarpravention.

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.

Introduction Since infammation alters vascular permeability, including vascular permeability in the lung, we hypothesized that it can be an amplifer of lung congestion in a category of patients at high risk for pulmonary oedema like end stage kidney disease (ESKD) patients. Objective and methods We investigated the efect modifcation by systemic infammation (serum CRP) on the relationship between a surrogate of the flling pressure of the LV [left atrial volume indexed to the body surface area (LAVI)] and lung water in a series of 220 ESKD patients. Lung water was quantifed by the number of ultrasound B lines (US-B) on lung US. Six-hundred and three recordings were performed during a 2-year follow up. Longitudinal data analysis was made by the Mixed Linear Model. Results At baseline, 88 had absent, 101 had mild to moderate lung congestion and 31 severe congestion. The number of US B lines associated with LAVI (r=0.23, P

NLRP3-inflammasome-driven inflammation is involved in the pathogenesis of a variety of diseases. Identification of endogenous inflammasome activators is essential for the development of new anti-inflammatory treatment strategies. Here, we identified that apolipoprotein C3 (ApoC3) activates the NLRP3 inflammasome in human monocytes by inducing an alternative NLRP3 inflammasome via caspase-8 and dimerization of Toll-like receptors 2 and 4. Alternative inflammasome activation in human monocytes is mediated by the Toll-like receptor adapter protein SCIMP. This triggers Lyn/Syk-dependent calcium entry and the production of reactive oxygen species, leading to activation of caspase-8. In humanized mouse models, ApoC3 activated human monocytes in vivo to impede endothelial regeneration and promote kidney injury in an NLRP3- and caspase-8-dependent manner. These data provide new insights into the regulation of the NLRP3 inflammasome and the pathophysiological role of triglyceride-rich lipoproteins containing ApoC3. Targeting ApoC3 might prevent organ damage and provide an anti-inflammatory treatment for vascular and kidney diseases.

Background and aims Data of experimental rodent models suggest that hypoxia with subsequent increase in erythropoietin stimulates the expression of the phosphaturic hormone fibroblast growth factor 23 (FGF23). Methods and results To translate the findings of animal studies into human physiology, herein we exposed eight healthy volunteers to high altitude (2656 m above sea level) for four days. The volunteers were randomized on a low-phosphorous diet (n = 4) or a normal phosphorus diet (n = 4). Although high-altitude exposure caused a significant increase in plasma erythropoietin (EPO) (before high-altitude exposure: low phosphorus: median EPO 6.6 mIU/ml [interquartile range (IQR) 6.0; 8.2], normal phosphorus: median EPO 9.0 mIU/ml [IQR 7.9; 11.5]; at day 2: low phosphorus: median EPO 21.3 mIU/ml [IQR 19.5; 23.8], normal phosphorus: median EPO 19.4 mIU/ml [IQR 18.0; 20.8]), there was no consistent increase in plasma c-terminal FGF23 or plasma intact FGF23. We observed only a single, intermittent peak in c-terminal FGF23 levels after 5 h of maximal aerobic exercise. Conclusion These data do not support a substantial effect of moderate hypoxia alone on the expression of FGF23, but they suggest that combined exercise and high-altitude exposure may temporarily induce FGF23 expression.

Chronic kidney disease (CKD) is associated with substantial cardiovascular morbidity and mortality. This is mediated by the high prevalence of traditional cardiovascular risk factors in patients with CKD such as arterial hypertension and diabetes mellitus, but also by the presence of CKD-specific so-called nontraditional cardiovascular risk factors such as vascular calcification, uremic toxins, uremic dyslipidemia as well as inflammation and oxidative stress. Therefore, the primary and secondary prevention of cardiovascular disease represents an integral part of nephrology. This entails optimal control of blood pressure and diabetes, therapy of the uremic dyslipidemia as well as lifestyle-modifying factors such as weight reduction and smoking cessation.

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.