Secreted Cytokines within the Urine of AKI Patients Modulate TP53 and SIRT1 Levels in a Human Podocyte Cell Model

Acute kidney injury (AKI) is a major kidney disease with a poor clinical outcome. It is a common complication, with an incidence of 10–15% of patients admitted to hospital. This rate even increases for patients who are admitted to the intensive care unit, with an incidence of >50%. AKI is characterized by a rapid increase in serum creatinine, decrease in urine output, or both. The associated symptoms include feeling sick or being sick, diarrhoea, dehydration, decreased urine output (although occasionally the urine output remains normal), fluid retention causing swelling in the legs or ankles, shortness of breath, fatigue and nausea. However, sometimes acute kidney injury causes no signs or symptoms and is detected by lab tests. Therefore, the identification of cytokines for the early detection and diagnosis of AKI is highly desirable, as their application might enable the prevention of the progression from AKI to chronic kidney disease (CKD). In this study, we analysed the secretome of the urine of an AKI patient cohort by employing a kidney-biomarker cytokine assay. Based on these results, we suggest ADIPOQ, EGF and SERPIN3A as potential cytokines that might be able to detect AKI as early as 24 h post-surgery. For the later stages, as common cytokines for the detection of AKI in both male and female patients, we suggest VEGF, SERPIN3A, TNFSF12, ANPEP, CXCL1, REN, CLU and PLAU. These cytokines in combination might present a robust strategy for identifying the development of AKI as early as 24 h or 72 h post-surgery. Furthermore, we evaluated the effect of patient and healthy urine on human podocyte cells. We conclude that cytokines abundant in the urine of AKI patients trigger processes that are needed to repair the damaged nephron and activate TP53 and SIRT1 to maintain the balance between proliferation, angiogenesis, and cell cycle arrest

Levosimendan in Acute and Advanced Heart Failure : An Appraisal of the Clinical Database and Evaluation of Its Therapeutic Applications

The use of inotropes for correcting hemodynamic dysfunction in patients with congestive heart failure has been described over many decades. However, negative or insufficient data have been collected regarding the effects of cardiac glycosides, catecholamines, and phosphodiesterase inhibitors on quality of life and survival. More recently, the calcium sensitizer and potassium channel-opener levosimendan has been proposed as a safer inodilator than traditional agents in some heart failure settings, such as advanced heart failure. At the 2017 annual congress of the Heart Failure Association of the European Society of Cardiology (Paris, April 30-May 2), a series of tutorials delivered by lecturers from 8 European countries examined how to use levosimendan safely and effectively in acute and advanced heart failure. The proceedings of those tutorials have been collated in this review to provide an expert perspective on the optimized use of levosimendan in those settings.Peer reviewe

Aktueller Stand der Durchführung von Nierenersatztherapien auf deutschen Intensivstationen

About 50% of all critically ill patients develop acute kidney injury (AKI) and approximately 15% receive renal replacement therapy (RRT). Although RRT is frequently used in intensive care units in Germany, it is currently unknown which RRT procedures are available, which qualification the involved staff has, which anticoagulation strategies are used and how RRT doses are prescribed. To investigate quality and structural characteristics of the performance of RRT in intensive care units throughout Germany, the German Interdisciplinary Society of Intensivists (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin [DIVI]) performed an inquiry among their members. A total of 897 members participated in the survey in which practical aspects were queried. In 69.1% of the cases, RRT was performed in hospitals with more than 400 beds and in 74.5% in university hospitals or other primary care hospitals. Furthermore, 93.3% of clinics are equipped with continuous and 75.8% with intermittent renal replacement devices. In 91.9%, indication for initiation of RRT was performed by trained physicians specialized in intensive care medicine or nephrologists. Intermittent as well as continuous modalities are both present in three-quarters of cases, which allows for individualized therapy. However, the documentation of dialysis dose needs to be improved.Eine akute Nierenschädigung (AKI) tritt heute bei 50 % aller kritisch kranken Patienten auf und etwa 15 % müssen mit einer Nierenersatztherapie (NET) behandelt werden. Obwohl eine NET ein häufiges und essenzielles Organersatzverfahren in der deutschen Intensivmedizin darstellt, ist es ist nicht bekannt, in welchem Umfang Nierenersatzverfahren zur Verfügung stehen, wer mit welcher Qualifikation eine NET durchführt, welche Formen der Antikoagulation verwendet werden und wie die Dosis der NET verschrieben wird. Die Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin (DIVI) hat deshalb Ende 2019 unter ihren Mitgliedern eine Umfrage zu den strukturellen Gegebenheiten der NET in ihrem Arbeitsumfeld durchgeführt. Es konnten 897 Datensätze erfasst werden (31,1 % der Befragten), anhand derer die aktuellen strukturellen und prozeduralen Gegebenheiten bei der Durchführung der NET auf deutschen Intensivstationen beschrieben werden können. Es waren Krankenhäuser aller Versorgungsstufen vertreten, allerdings waren Krankenhäuser mit einer Bettenzahl von > 400 Betten (69,1 %) und Krankenhäuser der Schwerpunkt- und Maximalversorgung und Unikliniken (74,5 %) verstärkt vertreten. Kontinuierliche Nierenersatzverfahren stehen auf 93,3 % und intermittierende Verfahren auf 75,8 % der Intensivstationen in Deutschland zur Verfügung. Die Indikation zur NET wird in 91,9 % durch eine/n Facharzt/Fachärztin oder einen Facharzt/Fachärztin mit Zusatzweiterbildung Intensivmedizin und/oder Nephrologie gestellt. In Fragen der Therapiedurchführung sind jedoch Aspekte der Dialysedosis besser zu implementieren und dokumentieren

Study protocol: The DOse REsponse Multicentre International collaborative initiative (DO-RE-MI)

INTRODUCTION: Current practices for renal replacement therapy in intensive care units (ICUs) remain poorly defined. The DOse REsponse Multicentre International collaborative initiative (DO-RE-MI) will address the issue of how the different modes of renal replacement therapy are currently chosen and performed. Here, we describe the study protocol, which was approved by the Scientific and Steering Committees. METHODS: DO-RE-MI is an observational, multicentre study conducted in ICUs. The primary end-point will be the delivered dose of dialysis, which will be compared with ICU mortality, 28-day mortality, hospital mortality, ICU length of stay and number of days of mechanical ventilation. The secondary end-point will be the haemodynamic response to renal replacement therapy, expressed as percentage reduction in noradrenaline (norepinephrine) requirement. Based on the the sample analysis calculation, at least 162 patients must be recruited. Anonymized patient data will be entered online in electronic case report forms and uploaded to an internet website. Each participating centre will have 2 months to become acquainted with the electronic case report forms. After this period official recruitment will begin. Patient data belong to the respective centre, which may use the database for its own needs. However, all centres have agreed to participate in a joint effort to achieve the sample size needed for statistical analysis. CONCLUSION: The study will hopefully help to collect useful information on the current practice of renal replacement therapy in ICUs. It will also provide a centre-based collection of data that will be useful for monitoring all aspects of extracorporeal support, such as incidence, frequency, and duration

Blood pH Analysis in Combination with Molecular Medical Tools in Relation to COVID-19 Symptoms †

The global outbreak of SARS-CoV-2/COVID-19 provided the stage to accumulate an enormous biomedical data set and an opportunity as well as a challenge to test new concepts and strategies to combat the pandemic. New research and molecular medical protocols may be deployed in different scientific fields, e.g., glycobiology, nanopharmacology, or nanomedicine. We correlated clinical biomedical data derived from patients in intensive care units with structural biology and biophysical data from NMR and/or CAMM (computer-aided molecular modeling). Consequently, new diagnostic and therapeutic approaches against SARS-CoV-2 were evaluated. Specifically, we tested the suitability of incretin mimetics with one or two pH-sensitive amino acid residues as potential drugs to prevent or cure long-COVID symptoms. Blood pH values in correlation with temperature alterations in patient bodies were of clinical importance. The effects of biophysical parameters such as temperature and pH value variation in relation to physical-chemical membrane properties (e.g., glycosylation state, affinity of certain amino acid sequences to sialic acids as well as other carbohydrate residues and lipid structures) provided helpful hints in identifying a potential Achilles heel against long COVID. In silico CAMM methods and in vitro NMR experiments (including 31P NMR measurements) were applied to analyze the structural behavior of incretin mimetics and SARS-CoV fusion peptides interacting with dodecylphosphocholine (DPC) micelles. These supramolecular complexes were analyzed under physiological conditions by 1H and 31P NMR techniques. We were able to observe characteristic interaction states of incretin mimetics, SARS-CoV fusion peptides and DPC membranes. Novel interaction profiles (indicated, e.g., by 31P NMR signal splitting) were detected. Furthermore, we evaluated GM1 gangliosides and sialic acid-coated silica nanoparticles in complex with DPC micelles in order to create a simple virus host cell membrane model. This is a first step in exploring the structure–function relationship between the SARS-CoV-2 spike protein and incretin mimetics with conserved pH-sensitive histidine residues in their carbohydrate recognition domains as found in galectins. The applied methods were effective in identifying peptide sequences as well as certain carbohydrate moieties with the potential to protect the blood–brain barrier (BBB). These clinically relevant observations on low blood pH values in fatal COVID-19 cases open routes for new therapeutic approaches, especially against long-COVID symptoms

Personalized medicine with IgGAM compared with standard of care for treatment of peritonitis after infectious source control (the PEPPER trial): study protocol for a randomized controlled trial

Background: Peritonitis is responsible for thousands of deaths annually in Germany alone. Even source control (SC) and antibiotic treatment often fail to prevent severe sepsis or septic shock, and this situation has hardly improved in the past two decades. Most experimental immunomodulatory therapeutics for sepsis have been aimed at blocking or dampening a specific pro-inflammatory immunological mediator. However, the patient collective is large and heterogeneous. There are therefore grounds for investigating the possibility of developing personalized therapies by classifying patients into groups according to biomarkers. This study aims to combine an assessment of the efficacy of treatment with a preparation of human immunoglobulins G, A, and M (IgGAM) with individual status of various biomarkers (immunoglobulin level, procalcitonin, interleukin 6, antigen D-related human leucocyte antigen (HLA-DR), transcription factor NF-κB1, adrenomedullin, and pathogen spectrum). Methods/design: A total of 200 patients with sepsis or septic shock will receive standard-of-care treatment (SoC). Of these, 133 patients (selected by 1:2 randomization) will in addition receive infusions of IgGAM for 5 days. All patients will be followed for approximately 90 days and assessed by the multiple-organ failure (MOF) score, by the EQ QLQ 5D quality-of-life scale, and by measurement of vital signs, biomarkers (as above), and survival. Discussion: This study is intended to provide further information on the efficacy and safety of treatment with IgGAM and to offer the possibility of correlating these with the biomarkers to be studied. Specifically, it will test (at a descriptive level) the hypothesis that patients receiving IgGAM who have higher inflammation status (IL-6) and poorer immune status (low HLA-DR, low immunoglobulin levels) have a better outcome than patients who do not receive IgGAM. It is expected to provide information that will help to close the knowledge gap concerning the association between the effect of IgGAM and the presence of various biomarkers, thus possibly opening the way to a personalized medicine. Trial registration: EudraCT, 2016–001788-34; ClinicalTrials.gov, NCT03334006. Registered on 17 Nov 2017. Trial sponsor: RWTH Aachen University, represented by the Center for Translational & Clinical Research Aachen (contact Dr. S. Isfort)

Prevalence and prognostic value of neurological affections in hospitalized patients with moderate to severe COVID-19 based on objective assessments.

Neurological manifestations of coronavirus disease 2019 (COVID-19) have been frequently described. In this prospective study of hospitalized COVID-19 patients without a history of neurological conditions, we aimed to analyze their prevalence and prognostic value based on established, standardized and objective methods. Patients were investigated using a multimodal electrophysiological approach, accompanied by neuropsychological and neurological examinations. Prevalence rates of central (CNS) and peripheral (PNS) nervous system affections were calculated and the relationship between neurological affections and mortality was analyzed using Firth logistic regression models. 184 patients without a history of neurological diseases could be enrolled. High rates of PNS affections were observed (66% of 138 patients receiving electrophysiological PNS examination). CNS affections were less common but still highly prevalent (33% of 139 examined patients). 63% of patients who underwent neuropsychological testing (n = 155) presented cognitive impairment. Logistic regression models revealed pathology in somatosensory evoked potentials as an independent risk factor of mortality (Odds Ratio: 6.10 [1.01-65.13], p = 0.049). We conclude that hospitalized patients with moderate to severe COVID-19 display high rates of PNS and CNS affection, which can be objectively assessed by electrophysiological examination. Electrophysiological assessment may have a prognostic value and could thus be helpful to identify patients at risk for deterioration

Association of chronic heart failure with mortality in old intensive care patients suffering from Covid-19

Funding: This study was endorsed by the ESICM. Free support for running the electronic database was granted from the Department of Epidemiology, Aarhus University, Denmark. The support of the study in France by a grant from ‘Fondation Assistance Publique-Hôpitaux de Paris pour la recherche’ is greatly appreciated. In Norway, the study was supported by a grant from the Health Region West. In addition, the study was supported by a grant from the European Open Science Cloud (EOSC). EOSCsecretariat.eu has received funding from the European Union’s Horizon 2020 Framework Programme called H2020-INFRAEOSC-05-2018-2019, Grant Agreement Number 831644. This work was supported by the Forschungskommission of the Medical Faculty of the Heinrich Heine University Düsseldorf, No. 2018-32 to G.W. and No. 2020-21 to R.R.B. for a Clinician Scientist Track. Open access funding was enabled and organized by Projekt DEAL. No (industry) sponsorship has been received for this investigator-initiated study.AIMS: Chronic heart failure (CHF) is a major risk factor for mortality in coronavirus disease 2019 (COVID-19). This prospective international multicentre study investigates the role of pre-existing CHF on clinical outcomes of critically ill old (≥70 years) intensive care patients with COVID-19. METHODS AND RESULTS: Patients with pre-existing CHF were subclassified as having ischaemic or non-ischaemic cardiac disease; patients with a documented ejection fraction (EF) were subclassified according to heart failure EF: reduced (HFrEF, n = 132), mild (HFmrEF, n = 91), or preserved (HFpEF, n = 103). Associations of heart failure characteristics with the 30 day mortality were analysed in univariate and multivariate logistic regression analyses. Pre-existing CHF was reported in 566 of 3917 patients (14%). Patients with CHF were older, frailer, and had significantly higher SOFA scores on admission. CHF patients showed significantly higher crude 30 day mortality [60% vs. 48%, P < 0.001; odds ratio 1.87, 95% confidence interval (CI) 1.5-2.3] and 3 month mortality (69% vs. 56%, P < 0.001). After multivariate adjustment for confounders (SOFA, age, sex, and frailty), no independent association of CHF with mortality remained [adjusted odds ratio (aOR) 1.2, 95% CI 0.5-1.5; P = 0.137]. More patients suffered from pre-existing ischaemic than from non-ischaemic disease [233 vs. 328 patients (n = 5 unknown aetiology)]. There were no differences in baseline characteristics between ischaemic and non-ischaemic disease or between HFrEF, HFmrEF, and HFpEF. Crude 30 day mortality was significantly higher in HFrEF compared with HFpEF (64% vs. 48%, P = 0.042). EF as a continuous variable was not independently associated with 30 day mortality (aOR 0.98, 95% CI 0.9-1.0; P = 0.128). CONCLUSIONS: In critically ill older COVID-19 patients, pre-existing CHF was not independently associated with 30 day mortality. TRIAL REGISTRATION NUMBER: NCT04321265.publishersversionepub_ahead_of_prin