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Background The Seraph®100 Microbind Affinity Blood Filter® is a hemoperfusion device that is licensed for the reduction of pathogens, including several viruses, in the blood. It received Emergency Use Authorization (EUA) for the treatment of severe coronavirus disease 2019 (COVID-19) by the FDA. Several studies have shown that the blood viral load of SARS-CoV-2 correlates with adverse outcomes and removal of the nucleocapsid of the SARS-CoV-2 virus by the Seraph®100 has been recently demonstrated. The aim of this registry was to evaluate safety and efficacy of Seraph®100 treatment for COVID-19 patients. Methods Twelve hospitals from six countries representing two continents documented patient and treatment characteristics as well as outcome parameters without reimbursement. Additionally, mortality and safety results of the device were reported. One hundred-and-two treatment sessions in 82 patients were documented in the registry. Four patients were excluded from mortality analysis due to incomplete outcome data, which were available in the other 78 patients. Results Overall, a 30-day mortality rate of 46.2% in the 78 patients with complete follow up was reported. Median treatment time was 5.00 [4.00–13.42] h. and 43.1% of the treatments were performed as hemoperfusion only. Adverse events of the Seraph®100 treatment were reported in 8.8% of the 102 treatments and represented premature end of treatment due to circuit failure. Patients that died were treated later in their ICU stay and onset of COVID symptoms. They also had higher ferritin levels. Multivariate Cox regression revealed that delayed Seraph®100 treatment after ICU admission (>60 hours) as well as bacterial superinfection were associated with mortality. While average predicted mortality rate according to SOFA score in ICU patients was 56.7% the observed mortality was 50.7%. In non-ICU patients 4C-Score average predicted a mortality rate of 38.0% while the observed mortality rate was 11.1% Conclusions The treatment of COVID-19 patients with Seraph®100 is well tolerated and the circuit failure rate was lower than previously reported for KRT in COVID-19 patients. Mortality corelated with late initiation of Seraph treatment after ICU admission and bacterial superinfection infection. Compared to predicted mortality according to 4C-Score and SOFA Score, mortality of Seraph®100 treated patients reported in the registry was lower., Graphical Abstract Graphical Abstract

Background Fosfomycin is used increasingly in the treatment of MDR bacteria. It is eliminated by renal excretion, but data regarding dosing recommendations for patients undergoing modern means of renal replacement therapies are scarce. Objectives Evaluation of the pharmacokinetics (PK) of fosfomycin in patients undergoing prolonged intermittent renal replacement therapy (PIRRT) to guide dosing recommendations. Methods Fosfomycin was given in 11 (7 female) patients with severe infections undergoing PIRRT. Plasma levels were measured at several timepoints on the first day of fosfomycin therapy, as well as 5–6 days into therapy, before and after the dialyser, to calculate its clearance. Fosfomycin was measured in the collected spent dialysate. Results The median (IQR) plasma dialyser clearance for fosfomycin was 183.4 (156.9–214.9) mL/min, eliminating a total amount of 8834 (4556–10 440) mg of fosfomycin, i.e. 73.9% (45.3%–93.5%) of the initial dose. During PIRRT, the fosfomycin half-life was 2.5 (2.2–3.4) h. Data from multiple-dose PK showed an increase in fosfomycin Cmax from 266.8 (166.3–438.1) to 926.1 (446.8–1168.0) mg/L and AUC0–14 from 2540.5 (1815.2–3644.3) to 6714 (4060.6–10612.6) mg·h/L. Dialysis intensity during the study was 1.5 L/h. T>MIC was 100% in all patients. Conclusions Patients undergoing PIRRT experience significant fosfomycin elimination, requiring a dose of 5 g/8 h to reach adequate plasma levels. However, drug accumulation may occur, depending on dialysis frequency and intensity.

Introduction Extracorporeal blood purification systems represent a promising alternative for treatment of blood stream infections with multiresistant bacteria. Objectives The aim of this study was to analyse the binding activity of S. aureus to Seraph affinity filters based on heparin coated beads and to identify effectors influencing this binding activity. Results To test the binding activity, we used gfp-expressing S. aureus Newman strains inoculated either in 0.9% NaCl or in blood plasma and determined the number of unbound bacteria by FACS analyses after passing through Seraph affinity filters. The binding activity of S. aureus was clearly impaired in human plasma: while a percent removal of 42% was observed in 0.9% NaCl (p-value 0.0472) using Seraph mini columns, a percent removal of only 10% was achieved in human plasma (p-value 0.0934). The different composition of surface proteins in S. aureus caused by the loss of SarA, SigB, Lgt, and SaeS had no significant influence on its binding activity. In a clinically relevant approach using the Seraph® 100 Microbind® Affinity Filter and 1000 ml of human blood plasma from four different donors, the duration of treatment was shown to have a critical effect on the rate of bacterial reduction. Within the first four hours, the number of bacteria decreased continuously and the reduction in bacteria reached statistical significance after two hours of treatment (percentage reduction 64%, p-value 0.01165). The final reduction after four hours of treatment was close to 90% and is dependent on donor. The capacity of Seraph® 100 for S. aureus in human plasma was approximately 5 x 108 cells. Conclusions The Seraph affinity filter, based on heparin-coated beads, is a highly efficient method for reducing S. aureus in human blood plasma, with efficiency dependent on blood plasma composition and treatment duration.

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.

BACKGROUND AND AIMS In-hospital AKI is associated with increased morbidity and mortality. AKI Alert systems are frequently used to allow time detection of AKI patients based on changes in creatinine. We aimed to examine the hydration status, medication errors and prior existing CKD in a series of AKI 3 patients in a tertiary care hospital. METHOD Prospective single centre cohort study. Study was approved by the local IRB. Hydration status was assessed by Bioimpedance using the body composition monitor (Fresenius Medical Care). Renal size and exclusion of postrenal failure were accomplished using a point of care ultrasound system (Butterfly Network Inc.). Pharmacotherapy was entered into the Federal Medication Plan of Germany (Bundesmedikationsplan). RESULTS A total of 101 patients with AKI 3 were identified based on changes in creatinine only. The median (IQR) age was 74.0 (64.7–82.0) years with a BMI of 27.8 (23.5–34.2) kg/m2. The baseline creatinine of the patients was 1.53 (0.92–2.85) mg/dL. At the time of AKI 3 diagnosis the median [IQR] 4.1 (1.9–5.9) L. Systolic blood pressure was 116 (100–140) mmHg (Fig. 1). Median (IQR) kidney length was 10.4 (9.2–11.7) cm. Polypharmacy (> 5 drugs) was seen in 89.7% of all patients. Almost half of the patients (48.3%) received 10 or more drugs. A total of 38% of patients receiving an antibiotic received an inadequately high dose, followed by 7.8% receiving an inadequate dosing of oral antidiabetic drugs. CONCLUSION Patients detected by an AKI alert in a tertiary care hospital did mostly neither exhibit low blood pressure nor volume depletion. Postrenal AKI was undetected in 1 out of 101 patients. Medication dosing errors were frequently seen, especially in the dosing of antibiotics. A joined nephron-pharmacological approach seems to be important in patients with hospital acquired AKI 3.

BACKGROUND AND AIMS Acute kidney injury (AKI) is a common complication in allogeneic stem cell transplantation (SCT). Although short-lived, i.e. METHOD Over a 17-year period, 1394 allogeneic stem cell transplants were performed at our tertiary center. Of those, 42 were second transplants. For 1387, a detailed history of creatinine (n = 142 563) and eGFR (n = 96 689) could be extracted from the Enterprise Clinical Research Data Warehouse. The classification of the respective AKI stages was based on the current KDIGO classification relying solely on the changes in serum creatinine. For AKI, an increase in serum creatinine of ≥ 0.3 mg/dL (26.5 µmol/L) within 48 h or an increase in serum creatinine to ≥ 1.5× baseline within 7 days was used. Persistence of impaired renal function beyond day 90 was defined as CKD. For the analysis of big data and classification of the AKI/CKD an algorithm was programmed. Validation of the results was performed using a colour-coded visualization of renal function (Fig. 1). RESULTS Between 1 January 2003 and 31 December 2020, 239 252 values for creatinine and eGFR were enriched for 1387 transplantations for a period between day –28 before today + 118 after allogeneic stem cell transplantation. The overall incidence of AKI was 86% (n = 1199). A total of 993 patients (83%) have shown an AKIN 1, 173 (14%) an AKIN 2 and 33 (3%) an AKIN 3. Of those, 122 (13%) patients died before day + 90 after allogeneic stem cell transplantation and were therefore excluded from CKD analysis. For 271 of 833 patients (33%), the transition to chronic kidney disease has been observed. Further information on patient characteristics, underlying disease, transplant coordinates and related complications and relapse mortality are shown in Table 1. CONCLUSION AKI after SCT is the rule and not the exception. As the vast majority of patients show AKIN 1, it might be often clinically overlooked. However, early intervention might mitigate the development of long-term renal impairment. Automated detection (AKI alert systems) as well as identification and subsequent avoidance of factors contributing or aggravating injury (e.g. conditioning, immunosuppression, perfusion, tissue edema, inappropriate dosing of drugs) might minimize long-term renal complications in allogeneic SCT.

BACKGROUND AND AIMS The long-term use of peritoneal dialysis is limited due to changes of the peritoneum. Those can be attributed to both, uremia and the effect of the peritoneal dialysis solution on the peritoneum. Although the effect of peritoneal dialysis on the peritoneal histology has been investigated for more than 40 years, most studies fail to report intraindividual changes of the peritoneum but report cross-sectional data from different patients at different timepoints of their dialysis career. The aim of our study was to investigate the intraindividual changes over time associated with peritoneal dialysis as part of the GRiP (German Registry in PD). METHOD Among patients documented by the GRiP study group 37 patients were identified in which two peritoneal samples were collected at least 2 months apart. The median [IQR] patient age was 63.6 [52.8–70.5] years with a median [IQR] BMI of 27.8 [22.4–31.8] kg/m2. The time between the two biopsies was 20.0 [7.2–27.6] months. Removal or change of the PD catheter was due to infection in 20 of the 37 patients (54%). Samples from the parietal peritoneum were collected at prespecified locations. Routine histology using hematoxylin–eosin was performed. The thickness of the submesothelial compacta was analysed with AxioVision SE64 Rel.4.9. software. GraphPad Prism 9 (San Diego, CA, USA) was used for statistical analysis. Comparison between histological parameters at implantation and explantation was done by using a paired t-test using a significance level of P RESULTS Comparing the intraindividual thickness of the compacta at the time of implantation and explantation of the peritoneal dialysis catheter we saw a significant increase of the median [IQR] ‘minimum thickness’ from 50.0 [20.5–89.5] µm to 130.0 [42.5–195.5] µm, the ‘average thickness’ from 102.0 [77.75–162.5.5] µm to 181.5 [123.3–265.5] as well as the ‘maximum thickness’ from 148.0 [107.0–208.0] µm to 240 [182.0–381.0] (Fig. 1). Further, the degree of peritoneal fibrosis increased significantly (Fig. 2). CONCLUSION The longitudinal, intraindividual assessment of peritoneal biopsies in a sizeable cohort of patients confirms previous cross-sectional data showing an increase in the thickness of the sumesothelial compacta over time.

During the last century, there has been an increasing prevalence of hyperuricaemia noted in many populations. While uric acid is usually discussed in the context of gout, hyperuricaemia is also associated with hypertension, chronic kidney disease, hypertriglyceridaemia, obesity, atherosclerotic heart disease, metabolic syndrome, and type 2 diabetes. Here we review the connection between hyperuricaemia and cardiovascular, kidney and metabolic diseases. Contrary to the popular view that uric acid is an inert metabolite of purine metabolism, recent studies suggest serum uric acid may have a variety of pro-inflammatory, pro-oxidative and vasoconstrictive actions that may contribute to cardiometabolic diseases. Hyperuricaemia is a predictive factor for the development of hypertension, metabolic syndrome, type 2 diabetes, coronary artery disease, left ventricular hypertrophy, atrial fibrillation, myocardial infarction, stroke, heart failure and chronic kidney disease. Treatment with uric acid-lowering therapies has also been found to improve outcomes in patients with hypertension and kidney disease, in some but not all studies. In conclusion, uric acid is emerging as a potentially treatable risk factor for cardiometabolic diseases, and more clinical trials investigating the potential benefit of lowering serum uric acid are recommended in individuals with hyperuricaemia with and without deposition and concomitant hypertension, metabolic syndrome or chronic kidney disease.

ZusammenfassungDas Peritoneum stellt als seröse Haut, die mit ihrem viszeralen und parietalen Anteil den Bauchraum auskleidet, ein interessantes Organ dar, welches bei der sog. Peritoneal- oder Bauchfelldialyse (PD) klinische Beachtung findet. Bei diesem Nierenersatzverfahren wird die Semipermeabilität des Peritoneums genutzt, um mittels unterschiedlich osmolarer Dialyseflüssigkeiten die sog. harnpflichtigen Substanzen aus dem Körper zu eliminieren. Dies ist insbesondere bei jungen Patienten eine ideales Nierenersatzverfahren und funktioniert in der Regel zumindest einige Zeit sehr gut. Vorschäden des Peritoneums durch die Grunderkrankung der chronischen Niereninsuffizienz oder assoziierte Komorbiditäten sowie v. a. entzündliche Veränderungen während der PD führen zu einem morphologischen Umbau des Peritoneums mit der Konsequenz des Verlusts der Filtereigenschaften, sodass die PD beendet und auf ein anderes Nierenersatzverfahren gewechselt werden muss. Die Kenntnis des morphologischen Umbaus des Peritoneums sowie möglicher begünstigender Faktoren, zu denen es derzeit noch zu wenige Daten gibt, ist wichtig für die Therapie und Prognose der Patienten, die mit PD behandelt werden. Aus diesem Grund wurde vor einigen Jahren das Deutsche Peritonealbiopsieregister (GRIP, German Registry In PD) gegründet, das mittlerweile knapp 1700 Biopsate umfasst und an diesen standardisiert klinische und histomorphologische Parameter erhebt und dokumentiert.

Vor 10 Jahren hat die EXtracorporeal Treatments In Poisoning (EXTRIP) Workgroup – ein internationaler Zusammenschluss von Pharmakologen, Toxikologen, Nephrologen und Intensivmedizinern – begonnen, durch standardisierte Bewertung der existierenden Literatur Empfehlungen zur extrakorporalen Therapie von Vergiftungen zu erarbeiten. Im Mittelpunkt der aktuellen Empfehlungen steht unter anderem Ethylenglykol. Der geschilderte Fall zeigt die erfolgreiche Behandlung eines 60-jahrigen, 65 kg wiegenden Mannes, der ca. eine halbe Flasche (500 ml) des Frostschutzmittels Aral Antifreeze in suizidaler Absicht getrunken hatte. Der somnolente Patient wurde ca. 12 h nach der oralen Aufnahme des Frostschutzmittels mit schwerer metabolischer Azidose (venose Blutgasanalyse: pH 7,13; Laktat 30 mmol/l, Anionenlucke 23,3 mmol/l) aufgenommen. Zunachst erfolgten eine Ethanolinfusion und eine intermittierende Dialysetherapie, da Fomepizol nicht sofort verfugbar war. Die erste verfugbare Ethylenglykolkonzentration betrug 1230 mg/l, wurde jedoch erst spater im Speziallabor gemessen. Die wahrend der intermittierenden Dialyse und der nachfolgend verlangert intermittierenden Dialyse eliminierte Menge an Ethylenglykol wurde erfasst (102 und 65 g). Anhand dieses Falls werden die neuen Therapieempfehlungen der EXTRIP Workgroup zur Therapie von Ethylenglykolvergiftungen besprochen.

Synopsis On April 17th 2020 the US Food and Drug Administration granted Coronavirus Disease 2019 (COVID‐19) emergency use authorizations for the Seraph® 100 Microbind® Affinity Blood Filter. The medical device is aimed to treat critically ill COVID‐19 patients with confirmed or imminent respiratory failure. The aim of this life size in vitro pharmacokinetic study was to investigate the in‐vitro adsorption of chloroquine and hydroxychloroquine from human plasma using equipment that is also used at the bedside. After start of the hemoperfusion Pre (Cpre) Seraph® plasma levels were obtained at 5 (C5), 10 (C10), 15 (C15), 30 (C30), 60 (C60) and 120 (C120) minutes into the procedure. At two timepoints (5 min and 120 min) post (Cpost) Seraph® plasma levels were determined that were used to calculate the plasma clearance. Both drugs were determined using a validated HPLC method Median [IQR] plasma clearance of the Seraph for chloroquine / hydroxychloroquine was 1.71 [0.51‐4.38] ml/min / 1.79 [0.21‐3.68] ml/min respectively. The lack of elimination was also confirmed by the fact that plasma levels did not change over the 120 min treatment. As neither chloroquine nor hydroxychloroquine were removed by the treatment with the Seraph dose adjustments in COVID‐19 patients undergoing this treatment are not necessary. This article is protected by copyright. All rights reserved.

ZUSAMMENFASSUNGDie akute Nierenschädigung tritt heute vor allem bei Intensivpatienten nach großen operativen Eingriffen, mit Sepsis oder im Rahmen des Versagens eines oder mehrerer anderer Organe auf. Intensivpatienten, die einer Nierenersatztherapie bedürfen, haben eine Krankenhausmortalität von ca. 60 %. Der Zeitpunkt des Beginns der Nierenersatztherapie ist Gegenstand zahlreicher Studien gewesen. Zu den hartnäckigsten Legenden in der Medizin zählt jene zum Harnstoff-Schwellenwert, der die Notwendigkeit einer Nierenersatztherapie anzeigen soll. Zwei rezente Arbeiten zeigen, dass allein ein durch den Laborwert getriggerter Dialysebeginn, z. B. Erfüllung der AKIN-3-Kriterien, dazu führt, dass knapp die Hälfte der Patienten eine Dialysetherapie bekommen, die sie nicht benötigt. Bezüglich der Dosis der Nierenersatztherapie konnte eine Meta-Analyse belegen, dass neben einem fehlenden Vorteil einer hohen Intensität der Nierenersatztherapie auf die Mortalität sogar die Wiederaufnahme der Nierenfunktion verzögert wird. Unter der hohen Dosis der heutzutage eingesetzten Nierenersatzverfahren kommt es auch zur vermehrten Elimination von Elektrolyten, Nährstoffen und Antibiotika, denn die Anpassung von Antibiotika an die Intensität der Nierenersatztherapie ist schwierig. Für die Behandlung der akuten Nierenschädigung stehen mehrere Nierenersatzverfahren zur Verfügung: die klassische intermittierende Hämodialyse, die kontinuierliche Nierenersatztherapie (CVVH), die verlängerte tägliche Dialyse (PIRRT/SLED/GENIUS-Dialyse) und die Peritonealdialyse. Trotz intensiver Forschungsbemühungen in diesem Gebiet gibt es bisher keine Studie, die die Überlegenheit eines dieser Verfahren in Bezug auf die Mortalität oder renale Endpunkte wie z. B. die Wiederaufnahme der Nierenfunktion belegen. Gegenwärtig gibt es auch keinen Konsens bezüglich der Kriterien für die Beendigung der Nierenersatztherapie. Die Menge des Urins scheint jedoch ein guter Parameter zu sein, auch die Höhe des Kreatininanstieges in der RRT-Pause (RRT: renal replacement therapy) oder die 6-h-Kreatininclearance eignen sich als Prädiktor für den erfolgreichen Auslass der Nierenersatztherapie.

Placement of central venous catheters (CVC) into the internal jugular vein represents a routine clinical intervention. The periprocedural complication rate ranges from 5 to 20% and can be reduced by ultrasound guidance, training of residents and other measures. We aimed to proof that the average Seldinger needle is too long, increasing the risk of periprocedural injury, best epitomized in the stellate ganglion injury/irritation. The first part of the study was an online market analysis to investigate the standard needle length currently offered as part of the CVC placement sets. The second part of the study involved 35 hospitalized patients (14 female; median age 74.5 years). In those the distance between the skin and the internal jugular vein as well as the diameter of the internal jugular vein was measured by ultrasound in both, supine position as well as 45° semi-sitting position. In the third part of the study 80 body donors (45 female; median age 83.0 years) preserved by the ethanol/formaldehyde method were studied. In those the distance and angle between the typical landmark for insertion of the Seldinger needle for internal jugular vein catheter placement to the stellate ganglion was measured. The median [interquartile range] Seldinger needle length was 7 [4.0–10.0] cm. In the examined patients the maximum distance between the skin and the internal jugular vein was 1.87 cm. The minimum distance was 0.46 cm and the median distance averaging supine and 45° position was 1.14 [0.94–1.31] cm. Regarding the body donors the median distance from the insertion point of the internal jugular vein to the stellate ganglion was longer in men 5.5 [4.95–6.35] cm than in women 5.2 [4.7–5.9] (p = 0.031 unpaired t-test). With 7 cm average length the Seldinger needle currently sold as part of CVC sets is long enough to physically reach the stellate ganglion, not to mention more proximal structures. A shorter needle length would be sufficient to reach the internal jugular vein even in obese patients and with a small insertion angle while minimizing the possibility to cause severe injury as structures like the pleura and the stellate ganglion could not be reached by shorter needles.

Background: The Seraph®100 Microbind Affinity Blood Filter® is a hemofiltration device that is licensed for pathogen reduction in the blood. This includes several viruses. Removal of the nucleocapsid of the SARS-CoV-2 virus by the Seraph®100 has been recently demonstrated. As viral load has repeatedly been shown to correlate with adverse outcome in severe coronavirus disease 2019 (COVID-19), the aim of this registry was to evaluate safety and efficacy of Seraph®100 treatment for COVID-19.Methods: An online registry in which main patient charcteristics, treatment coordinates and outcome parameters was documented without reimbursement. So far 12 hospitals in 4 countries on 2 continents took part in the registry. 75 treatment sessions in 60 patients were documented in the registry. Results: Adverse effects of the Seraph® 100 treatment were reported in 2 (2.6 %) of the 75 treatments. Eight (10.6 %) of all the procedures ended prematurely due to circuit failure / clotting. Half of the treatments (47.6 %) were performed as hemoperfusion only. 21.6 % of the treatments were performed in conjuction with intermittent hemodialysis. Median treatment time was 4.21 [4.00 - 8.06] h. Anticoagulation was performed using citrate in 20.6 % of treatments. Patients that died despite treatment with the Seraph® 100 filter had a higher rate of bacterial superinfection, higher level of inflammatory laboratory markers (procalcitonin and ferritin) and higher d-dimer levels. While predicted survival rate in ICU patients was >80 %, the observed survival rate was 47.6 %. In non-ICU patients, 4 C score predicted a survival rate of 31.4-34.9 % while the observed survival rate was 22.2 %.Conclusion: Seraph® 100 treatment was well tolerated and circuit failure rate was significantly lower than reported for KRT in COVID-19 patients. All patients that died despite of Seraph® 100 treatment had serious pre-existing medical conditions, coexisting bacterial infections and more pronounced systemic signs of inflammation. Compared to the calculated mortality using established scores, the observed mortality in the Seraph® 100 treated patients was lower.Trial registration:ClinicalTrials.gov Identifier: NCT04361500

Although intravenous thrombolysis (IVT) with recombinant tissue-plasminogen-activator represents a highly effective treatment in acute ischemic stroke patients, not every patient benefits. We hypothesized that pretreatment levels of mediators of hemostasis (VWF and ADAMTS13) and dimethylarginines (ADMA and SDMA) are associated with early neurological improvement and outcome after IVT in ischemic stroke. Moreover we aimed to investigate the link between ADAMTS13 and markers of inflammation (CRP, IL-6, MMP-9 and MCP-1). In 43 patients with acute ischemic stroke treated with IVT blood samples for determination of the different markers were strictly taken before treatment, as well as at 24 h, 3, 7 and 90 days after symptom onset. Early neurological improvement was assessed using the shift between National Institutes of Health Stroke Scale (NIHSS) at baseline and at 24 h. Outcome at 90 days was assessed using the modified Rankin Scale. The lowest quartile of ADAMTS13 activity was independently associated with less improvement in NIHSS (baseline-24 h) (OR 1.298, p = 0.050). No independent association of ADMA or SDMA levels at baseline with outcome could be shown. Furthermore, IL-6, MCP-1 and CRP levels at 90 days significantly differed between patients with low and high ADAMTS13 activity. Thus, ADAMTS13 might indicate or even influence efficacy of IVT.

Clinical kidney journal : CKJ 12(5), 663-672 (2019). doi:10.1093/ckj/sfz046, Published by Oxford Univ. Press, Oxford

BACKGROUND Owing to the emerging problem of MDR bacteria, interest in 'old' antibiotics such as colistin has re-emerged. However, research on the dosing of colistin in patients undergoing renal replacement therapy (RRT), such as prolonged intermittent renal replacement therapy (PIRRT), is scarce. OBJECTIVES The aim of this study was to evaluate single- and multiple-dose pharmacokinetics of colistin and its prodrug colistin methanesulfonate in ICU patients with acute kidney injury (AKI) undergoing PIRRT. METHODS We performed a prospective clinical pharmacokinetic single- and multiple-dose study. Eight ICU patients with AKI undergoing treatment with PIRRT and receiving intravenous colistin were studied on day 1 and days 5-9 of treatment, depending on the timing of dialysis. Six million IU (MIU) of colistin methanesulfonate was administered 8 h prior to the PIRRT session followed by 3 MIU every 8 h. The study was registered under clinicaltrails.gov (NCT02556190). RESULTS PIRRT removed a considerable amount of colistin and colistin methanesulfonate with a median dialyser plasma CL of 70.1 mL/min (IQR 36.6-96.2) for colistin and 69.3 mL/min (IQR 56.3-318.7) for colistin methanesulfonate. The median amount of colistin in the total collected dialysate was 154 mg (IQR 105-175), corresponding to about 50% of the daily dose. Median colistin peak concentrations accumulated from 5.79 mg/L (IQR 4.14-8.79) on day 1 to 9.49 mg/L (IQR 8.39-10.41) on days 5-9. Cmax was significantly and inversely correlated with body weight. CONCLUSIONS PIRRT eliminates about half of the daily administered colistin dose. Even a 6 MIU loading dose of colistin methanesulfonate may not ensure immediate sufficient colistin plasma levels in all critically ill patients. However, we measured significant colistin accumulation, suggesting that the dose of colistin methanesulfonate should be adjusted according to body weight and RRT intensity.

Background and Aims The COVID-19 pandemic has serious impact on health and economics worldwide. Despite the recent advent of SARS-Cov-2 vaccines, treatment options are needed, yet pharmacologic interventions remain limited. Several extracorporeal treatments are currently explored concerning their potential to improve the clinical course and outcome of critically ill patients with COVID-19. The Seraph® 100 Microbind® Affinity adsorber (Exthera Medical, CA, USA) has recently been introduced for the elimination of several pathogens from the blood and an emergency authorization in patients with COVID-19 was granted by the FDA. Bacteria, viruses (including the SARS-CoV-2 spike glycoprotein), fungi and toxins have been shown to bind to the immobilized heparin on the ultra-high molecular weight polyethylene beads of the device in a similar way to the interaction with heparan sulfate on the cell-surface and are thereby removed from the bloodstream. Here we report the interim analysis of the COVID-19 patients treated with the Seraph® 100 Microbind® Affinity filter (COSA) registry. The goal of the registry is to gather data regarding the safety and efficacy of the Seraph® 100 in the treatment of COVID-19 patients. Method Participating sites were advised to insert patient data of COVID-19 patients, treated with the Seraph® 100, during their hospital stay into the COSA registry (ClinicalTrials.gov Identifier: NCT04361500). A total of 66 items were asked in a web-based platform. Results Until January 2021, 33 patients with 39 treatment sessions form six different hospitals were reported to the register (seven female, median age 61 years, Table 1). The patients were treated between March and December 2020. Eleven patients with a hospital admission between March and August and 22 between September and December 2020. The Seraph® 100 treatment was initiated 9 days after symptom onset, without any difference between survivors and non-survivors. Overall, a mortality of 27% was reported. Serious comorbidities (as preadmission immunosuppressive therapy, lung fibrosis or CKD5T) were reported in all of the non-survivors. Invasive ventilation was needed in 67% of these patients when Seraph treatment was initiated. A non-significant trend towards higher Ferritin levels in non-survivors (2000 (1963 – 8326) vs. 989 (644 – 2000), p=0.09) was reported. All treatments were well tolerated, three clotting events were reported. Conclusion Viral SARS-CoV-2 RNA is frequently (up to 78%) seen in the blood of critically ill COVID-19 patients and correlates with the severity of the disease. The Seraph® 100 can bind to viral spike protein, proinflammatory cytokines may be reduced by the device and hemodynamic stabilization has been reported during the Seraph®100 treatment of COVID-19 patients. Platelets can be hyperactivated in association with SARS-CoV-2 proteins and thus presumably trigger the hypercoagulation and thrombosis. In this context, the removal of SARS-CoV-2 proteins to prevent hyperactivated platelets appears to be a sensible approach. All reported deaths were associated with serious preexisting comorbidities, immunosuppression, dialysis dependent renal failure, or a combination of these factors. Hence, Seraph® 100 treatment may be most beneficial in COVID-19 courses of patients without multi organ failure. More clinical data is needed to describe possible benefits of the Seraph®100 in the treatment of COVID-19 patients.

Background and Aims Macrophages and monocytes are main players in innate immunity. In renal diseases, their role is poorly understood. Our multicentric cross-sectional study aimed to study the prevalence of macrophages and monocytes in various human native kidney diseases. For this, we used precise pixel-based digital quantification of their densities in renal biopsies and correlated our findings with clinical data. Method We included 324 patients, who underwent a diagnostic renal biopsy. Additional normal kidney samples from 16 tumour nephrectomies were used as controls. According to the diagnosed diseases, we established 17 patient groups. Biopsies were stained for CD68+-macrophages using automated immunohistochemistry (Ventana Ultra) and selected groups were further subtyped for CD14+-monocytes and CD163+-M2-macrophages (67 cases, pauci-immune glomerulonephritis (PIGN), IgA-nephropathy (IgAN) and control samples). Digitized sections (Leica) were analysed using the open-source software QuPath to quantify cell densities (positively stained areas displayed as percentages of ROI) in renal cortex, medulla and extrarenal tissue, respectively. Detailed clinical and laboratory data at timepoint of biopsy were available for all patients. Additional data for follow-up were achievable in 158 cases. Results Renal disease samples presented higher mean macrophage densities compared to control cases (CD68: cortex 1.2 vs. 0.2%, p64 years) showed a higher medullary M2-infiltration (1.81% vs. 4.34%, p Conclusion Macrophages may promote progression of human renal diseases, whereas monocytes do not correlate with eGFR-decline. Especially, in cANCA- vasculitis CD163+- infiltration is associated with renal outcome. Additional studies are needed to investigate, whether macrophages can serve as predictive markers or therapeutical targets in native renal diseases.

The coronavirus disease 2019 (COVID-19) pandemic has a serious impact on health and economics worldwide. Even though the majority of patients present with moderate and mild symptoms, yet a considerable portion of patients need to be treated in the intensive care unit. Aside from dexamethasone, there is no established pharmacological therapy. Moreover, some of the currently tested drugs are contraindicated for special patient populations like remdesivir for patients with severely impaired renal function. On this background, several extracorporeal treatments are currently explored concerning their potential to improve the clinical course and outcome of critically ill patients with COVID-19. Here, we report the use of the Seraph 100 Microbind Affinity filter, which is licensed in the European Union for the removal of pathogens. Authorization for emergency use in patients with COVID-19 admitted to the intensive care unit with confirmed or imminent respiratory failure was granted by the U.S. Food and Drug Administration on April 17, 2020.A 53-year-old Caucasian male with a severe COVID-19 infection was treated with a Seraph Microbind Affinity filter hemoperfusion after clinical deterioration and commencement of mechanical ventilation. The 70-minute treatment at a blood flow of 200 mL/minute was well tolerated, and the patient was hemodynamically stable. The hemoperfusion reduced D-dimers dramatically.This case report suggests that the use of Seraph 100 Microbind Affinity filter hemoperfusion might have positive effects on the clinical course of critically ill patients with COVID-19. However, future prospective collection of data ideally in randomized trials will have to confirm whether the use of Seraph 100 Microbind Affinity filter hemoperfusion is an option of the treatment for COVID-19.

Baclofen toxicity results from intentional self-poisoning (acute baclofen poisoning) or accumulation of therapeutic dose in the setting of impaired kidney function. Standard care includes baclofen discontinuation, respiratory support and seizure treatment. Use of extracorporeal treatments (ECTRs) is controversial. To clarify this, a comprehensive review of the literature on the effect of ECTRs in baclofen toxicity was performed and recommendations following EXTRIP methods were formulated based on 43 studies (1 comparative cohort, 1 aggregate results cohort, 1 pharmacokinetic modeling, and 40 patient reports or series). Toxicokinetic data were available for 20 patients. Baclofen's dialyzability is limited by a high endogenous clearance and a short half-life in patients with normal kidney function. The workgroup assessed baclofen as "Moderately dialyzable" by intermittent hemodialysis for patients with normal kidney function (quality of evidence C) and "Dialyzable" for patients with impaired kidney function (quality of evidence C). Clinical data were available for 25 patients with acute baclofen poisoning and 46 patients with toxicity from therapeutic baclofen in kidney impairment. No deaths or sequelae were reported. Mortality in historical controls was rare. No benefit of ECTR was identified in patients with acute baclofen poisoning. Indirect evidence suggests a benefit of ECTR in reducing the duration of toxic encephalopathy from therapeutic baclofen in kidney impairment. These potential benefits were balanced against added costs and harms related to the insertion of a catheter, the procedure itself, and the potential of baclofen withdrawal. Thus, the EXTRIP workgroup suggests against performing ECTR in addition to standard care for acute baclofen poisoning and suggests performing ECTR in toxicity from therapeutic baclofen in kidney impairment, especially in the presence of coma requiring mechanical ventilation.