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Immunologically mediated diseases can lead to severe courses that have to be treated in an intensive care unit. The use of extracorporeal organ support systems (ventilation, ECMO) is common. A therapeutic principle for these diseases is the removal of disease-causing antibodies. This can be done nonspecifically by plasmapheresis or specifically by immune adsorption. While most intensive care units have the facilities for plasmapheresis (membrane plasma filtration), immunoadsorption is much less common. Over a period of 10 years, the numbers of immunoadsorption and plasmapheresis treatments performed in a single center intensive care unit are shown according to their indication (IA: 18 Pts, 58 treatments. PA: 54 Pts, 148 treatments). A case study of a patient with granulomatosis with polyangiitis shows the successful treatment with immunoadsorption. The advantages of immunoadsorption in patients with complex coagulation disorders and a critical clinical picture in terms of SIRS and ARDS are shown.

Sepsis is a leading cause of morbidity and mortality worldwide. Dysregulated immune response to infection is a hallmark of sepsis, leading to life-threatening organ dysfunction or even death. Advancing knowledge of the complex pathophysiological mechanisms has been a strong impetus for the development of therapeutic strategies aimed at rebalancing the immune response by modulating the excess of both pro- and anti-inflammatory mediators. There is a wealth of preclinical data suggesting clinical benefits of various extracorporeal techniques in an attempt to modulate the exaggerated host inflammatory response. However, the evidence base is often weak. Owing to both an advancing comprehension of the pathophysiology and the increased quality of clinical trials, progress has been made in establishing extracorporeal therapies as part of the general therapeutic canon in sepsis. We aim for a comprehensive overview of the technical aspects and clinical applications in the context of the latest evidence concerning these techniques.

Purpose: This study aimed to analyze our data on delayed graft function (DGF) and to identify associated factors. Methods: This is a retrospective case-control study of all patients transplanted in our center over a period of 11 years (January 1, 2003, to December 31, 2014) comparing patients with immediate graft function (n = 332) to those with DGF (n = 165). DGF was defined as the need for hemodialysis within the first 7 days after transplantation. Donor and recipient characteristics as well as procedural factors were compared by univariate and multivariate logistic regression analyses. Results: Overall, 33% of patients had DGF. The rate of DGF declined from 2003 to 2011. In cases with DGF, donors and recipients were significantly older (p = 0.004 and p = 0.005, respectively), had longer cold ischemia times (p = 0.039), more revision surgeries (p < 0.001), and more HLA mismatches (p = 0.001), especially in the DR locus (p = 0.002). Neither donor nor recipient gender, waiting time, nor CMV status had any influence. In multivariable analysis, significant risk factors were ischemia time and mismatches at the HLA-DR loci. Conclusions: DGF is a common complication in renal transplantation which occurred in 33% of our cases. Important factors identified were donor and recipient age, ischemia time, HLA mismatching, and revision surgery.

BACKGROUND Use of donor granulocyte concentrate (GC) has been limited due to its short storage time of 6-24 h, which is partially due to residual red blood cells (RBCs) and platelets and the resulting lactate production leading to an acidotic milieu. To increase this storage time, we developed a closed system procedure compatible with standard blood bank technologies to remove RBC and platelets and to enrich the GC. METHODS Standard GCs (sGCs) were sedimented, washed twice with 0.9% sodium chloride (NaCl), and resuspended in blood group-identical fresh frozen plasma. The resulting purified GCs (pGCs) were then stored in platelet bags at a cell concentration of about 5 × 107 ± 1.8 × 107 leukocytes/ml without agitation at room temperature for up to 72 h. Cell count and viability, pH, blood gases, phagocytosis, and oxidative burst were monitored daily. RESULTS A significant reduction in RBC (98%) through sedimentation, and platelets (96%) by washing, purified the white blood cell (WBC) population and enriched the granulocytes to 96% of the WBC in the pGC. After 72 h of storage, over 90% of the initial WBC count of pGC remained, was viable (≥97%), and the granulocytes exhibited a high phagocytosis and oxidative burst functionality, comparable to sGC after 24 h. CONCLUSION Purification extends the maximum storage period of GC from 24 to 72 h and may therefore improve the availability of GC and its clinical use.

Acute liver failure (ALF) is a potentially life-threatening condition. Liver support therapies can be applied as a bridging-to-transplantation or bridging-to-recovery; however, results of clinical trials are controversial. Our aim was to compare liver support systems in acute and hyperacute liver failure with network meta-analysis. After systematic search, randomized controlled trials (RCT) comparing liver support therapies in adults with acute or hyperacute liver failure were included. In-hospital mortality was the primary outcome, the secondary outcomes were hepatic encephalopathy and mortality-by-aetiology. A Bayesian-method was used to perform network meta-analysis and calculate surface under the cumulative ranking curve (SUCRA) values to rank interventions. Eleven RCTs were included. BioLogic-DT and molecular adsorbent recirculating system (MARS) resulted in the lowest mortality (SUCRAs: 76% and 73%, respectively). In non-paracetamol-poisoned patients, BioLogic-DT, charcoal hemoperfusion and MARS may be equally efficient regarding mortality (SUCRAs: 53%, 52% and 52%, respectively). Considering hepatic encephalopathy, extracorporeal liver assist device (ELAD) may be the most effective option (SUCRA: 78%). However, in pairwise meta-analysis, there were no statistically significant differences between the interventions in the outcomes. In conclusion, MARS therapy seems to be the best available option in reducing mortality. Further research is needed on currently available and new therapeutic modalities. (CRD42020160133).

Das akute Nierenversagen bei Sepsis (septisches akutes Nierenversagen, sANV) ist mit etwa 50 % der Falle die am haufigsten auftretende ANV-Form auf Intensivstationen. Zumindest initial liegt ein uberwiegend funktionelles Versagen mit normalem oder erhohtem renalen Blutfluss, Gefasendothelschaden, mikrovaskularem Shunting und Tubuluszellstress durch glomerular filtrierte, proinflammatorische Substanzen (PAMP [„pathogen-associated molecular pattern“]/DAMP [„damage-associated molecular pattern“]) vor. Schockinduzierte Ischamie und direkte Effekte von Nephrotoxinen konnen verstarkend wirken. Die Diagnose des sANV beruht auf der Bestimmung von Serumkreatinin und Urinausscheidung, sie bildet die Schnittmenge der entsprechenden Konsensusdefinitionen nach Sepsis‑3 (The Third International Consensus Definitions for Sepsis and Septic Shock) und KDIGO (Kidney Disease: Improving Global Outcomes). Eine spezifische Therapie existiert bis heute nicht. Daher kommen der fruhen Risikostratifizierung und Pravention besondere Bedeutung zu. Bei manifestem sANV sind abgewogenes Flussigkeitsmanagement in Kombination mit Vasopressoren tragende Saulen der Therapie. Neben Noradrenalin werden derzeit Vasopressin und Angiotensin II klinisch untersucht. Nierenersatzverfahren werden bei fortgeschrittenem Funktionsverlust eingesetzt. Krankenhausuberlebende sANV-Patienten haben ein deutlich erhohtes Risiko fur chronisches Nierenversagen und Sterblichkeit. Dies gilt insbesondere fur Patienten, bei denen ein Nierenersatzverfahren eingesetzt wurde. Eine nephrologische Nachbetreuung ist empfehlenswert.

BACKGROUND AND AIMS Therapeutic plasma exchange (TPE) is an established therapy in the treatment of various immunologic kidney and neurological diseases. Humoral factors as antibodies, complement factors, cytokines and immune complexes, which all are assumed to play a role in demyelinating or inflammatory disorders as multiple sclerosis, can be eliminated. TPE has been implemented into therapeutic guidelines of a broad spectrum of neurological diseases [1–3]. Centrifugal (cTPE) and membrane-based (mTPE) are the methods of choice for TPE. Head to head studies comparing both methods are scarce and patients’ comfort has not yet been investigated [4–7]. Our aim was to compare cTPE (Spectra Optia™, TerumoBCT) with mTPE (multiFiltrate™, Fresenius Medical Care) with a focus not only on safety and efficacy parameters but also on patients’ comfort with the present monocentric, prospective and randomized crossover study. This is, to the best of our knowledge, the first study addressing patients’ comfort comparing both systems. METHODS The study was conducted as an open-label prospective trial with a cross-over design comparing cTPE using the Spectra Optia™ (Terumo BCT, Lakewood, CO, USA), and mTPE using the multiFiltrate™ with the plasmafilter plasmaFluxP2dry™ (Fresenius Medical Care, Bad Homburg, Germany). The first two treatments were performed within the study for each patient: one with the Spectra Optia and one with the multiFiltrate. Duration of set-up and priming of the devices, total procedure time, blood flow, total plasma volume exchanged, volume of the removal bag, volume of the anticoagulant and the type of vascular access were documented. Laboratory parameters such as IgG, IgA, IgM, fibrinogen, white blood cell, red blood count and thrombocytes were documented before and after treatment. Data from the first two treatments were documented. The differences of the parameters were compared using the Wilcoxon matched-pairs signed-rank or Mann-Whitney (U) test. RESULTS A total of 26 patients (17 women /9 mem) were included in the study and 52 treatments were documented. A median of 3000 mL of plasma was treated; the median duration of the procedure was 117 min (cTPE) versus 154 min (mTPE) (P = .03). Despite removal of fibrinogen (P = .04), no significant differences were found for the removal IgG (P = .09), IgM (P = .18) and IgA (P = .57). Both methods were equally effective. Erythrocyte loss was higher with mTPE (P = .003), platelet loss tended to be higher with mTPE, but without reaching a level of significance (P = .22; Table 1). The results of the patient questionnaire are shown in Figure 1. CONCLUSION Both procedures can be performed safely with comparable results regarding parameters of quality as fibrinogen, IgG, IgM and IgA with a trend to better elimination with cTPE. Comparing the duration of the procedure, cTPE was significantly superior to mTPE. An advantage regarding cell loss (RBC) was seen for cTPE, platelet loss tended to be higher with mTPA, but without statistical significance. Finally, as a result of shorter duration, patients’ comfort was significantly higher with cTPE.

The present narrative review on albumin dialysis provides evidence-based and expert opinion guidelines for clinicians caring for adult patients with different types of liver failure. The review was prepared by an expert panel of 13 members with liver and ntensive care expertise in extracorporeal liver support therapies for the management of patients with liver failure. The coordinating committee developed the questions according to their importance in the management of patients with liver failure. For each indication, experts conducted a comprehensive review of the literature aiming to identify the best available evidence and assessed the quality of evidence based on the literature and their experience. Summary statements and expert’s recommendations covered all indications of albumin dialysis therapy in patients with liver failure, timing and intensity of treatment, efficacy, technical issues related to the device and safety. The panel supports the data from the literature that albumin dialysis showed a beneficial effect on hepatic encephalopathy, refractory pruritus, renal function, reduction of cholestasis and jaundice. However, the trials lacked to show a clear beneficial effect on overall survival. A short-term survival benefit at 15 and 21 days respectively in acute and acute-on-chronic liver failure has been reported in recent studies. The technique should be limited to patients with a transplant project, to centers experienced in the management of advanced liver disease. The use of extracorporeal albumin dialysis could be beneficial in selected patients with advanced liver diseases listed for transplant or with a transplant project. Waiting future large randomized controlled trials, this panel experts’ statements may help careful patient selection and better treatment modalities.

Background The progression of chronic kidney disease (CKD) is associated with an increasing risk of cardiovascular morbidity and mortality due to elevated serum phosphate levels. Besides low phosphate diets and hemodialysis, oral phosphate binders are prescribed to treat hyperphosphatemia in CKD patients. This study reports on a processed clay mineral as a novel and efficient phosphate sorbent with comparable efficacy of a clinically approved phosphate binder. Methods 5/6 nephrectomized rats, which develop chronic renal failure (CRF), received a high phosphate and calcium diet supplemented with either a processed Montmorillonite-Illite clay mineral (pClM) or lanthanum carbonate (LaC) for 12 weeks. Levels of plasma uremic toxins, glomerular filtration rates and microalbuminuria were determined and the histomorphology of blood vessels and smooth muscle cells was analyzed. Results 5/6 nephrectomy induced an increase in plasma uremic toxins levels and progressive proteinuria. Treatment of CRF rats with pClM decreased observed vascular pathologies such as vascular fibrosis, especially in coronary vessels. The transition of vascular smooth muscle cells from a contractile to a secretory phenotype was delayed. Moreover, pClM administration resulted in decreased blood creatinine and urea levels, and increased glomerular filtration rates, reduced microalbuminuria and eventually the mortality rate in CRF rats. Conclusion Our study reveals pClM as a potent phosphate binding agent with beneficial impacts on pathophysiological processes in an animal model of CKD. pClM effectively attenuates the progression of vascular damage and loss of renal function which are the most severe consequences of chronic renal failure.

The extracellular matrix (ECM) obtained by decellularization provides scaffolds with the natural complex architecture and biochemical composition of the target organ. Whole kidney decellularization by perfusion uses the vasculature to remove cells leaving a scaffold that can be recellularized with patient-specific cells. However, decellularization and recellularization are highly complex processes that require intensive optimization of various parameters. In pursuit of this, a huge number of animals must be sacrificed. Therefore, we used precision-cut kidney slices (PCKS) as a source of natural scaffolds, which were decellularized by immersion in chemical reagents allowing the examination of more parameters with less animals. However, chemical reagents have a damaging effect on the structure and components of the ECM. Therefore, this study aimed at investigating the effects of physical treatment methods on the effectiveness of PCKS decellularization by immersion in chemical reagents (CHEM). PCKS were treated physically before or during immersion in chemicals (CHEM) with high hydrostatic pressure (HHP), freezing–thawing cycles (FTC) or in an ultrasonic bath system (UBS). Biochemical and DNA quantification as well as structural evaluation with conventional histology and scanning electron microscopy (SEM) were performed. Compared to decellularization by CHEM alone, FTC treatment prior to CHEM was the most effective in reducing DNA while also preserving glycosaminoglycan (GAG) content. Moreover, while UBS resulted in a comparable reduction of DNA, it was the least effective in retaining GAGs. In contrast, despite the pretreatment with HHP with pressures up to 200 MPa, it was the least effective in DNA removal. Histological scoring showed that HHP scaffolds received the best score followed by UBS, FTC and CHEM scaffolds. However further analysis with SEM demonstrated a higher deterioration of the ultrastructure in UBS scaffolds. Altogether, pretreatment with FTC prior to CHEM resulted in a better balance between DNA removal and structural preservation.

Background The CAMI-1 study dealt with the depletion of CRP by apheresis in patients with acute myocardial infarction (AMI). CRP, the prototype human acute phase protein, has been known as a marker of poor prognosis in AMI and independently predicts 30-day mortality. Methods 66 STEMI patients were enrolled following complete coronary revascularization (2–12 h after AMI). 32 patients received CRP apheresis, whereas 34 patients treated by standard protocols served as controls. CRP apheresis started 24±12 h and 48±12 h after onset of symptoms. A specific CRP adsorber removed ≤79% of the original CRP. 6000 ml of plasma was treated via peripheral venous access. Primary endpoint was myocardial infarction size as determined by Cardiac Magnetic Resonance Imaging (CMR) 3–9 days after STEMI. Results Aphereses sessions were well tolerated with no relevant side effects. The expected peak CRP level after AMI can be calculated precisely with 2–3 CRP quantifications during the first 24h after the onset of symptoms (CRP gradient). The regression coefficient for this analysis is 0.91. This mathematical step allows for the comparison of the CRP-apheresis group and the controls on the basis of their individual CRP gradients. The mean CRP gradient does not differ between both groups, whereas the mean area under the curve (AUC) of CRP within the first 72 h after AMI does. Thus, there was no bias in CRP kinetics between the two groups. The AUC of CRP is a significant indicator for infarct size (p=0.002), LVEF (p Conclusions For the first time we find an unequivocal association between myocardial infarct size and the AUC of CRP. The results show a significant beneficial effect of CRP apheresis on myocardial infarction size and wall motion. Selective CRP apheresis is now being further evaluated as a therapeutic approach in the treatment of acute myocardial infarction in a registry (CAMI registry). Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Pentracor GmbH

Hemophagocytic lymphohistiocytosis is a life-threatening clinical syndrome caused by severe hypercytokinemia brought on by a highly stimulated but ineffective immune response. Animal studies and case series have demonstrated that a reduction in blood cytokine levels achieved with an extracorporeal adsorption cartridge that contains blood-compatible porous polymer beads (CytoSorb®) can effectively attenuate the inflammatory response during sepsis and possibly improve outcomes. We report a case series of two patients in which three episodes of severe hemophagocytic lymphohistiocytosis triggered by infections with herpesviridae were treated successfully with cytokine adsorption. A marked decrease in interleukin-6 plasma levels and a stable or decreasing need of vasopressor therapy were the most significant results of this treatment. Importantly, treatment was safe and well-tolerated, without any adverse events.

Natural smectites have demonstrated efficacy in the treatment of diarrhea. The present study evaluated the prophylactic effect of a diosmectite (FI5pp) on the clinical course, colon damage, expression of tight junction (TJ) proteins and the composition of the gut microbiota in dextran sulfate sodium (DSS) colitis. Diosmectite was administered daily to Balb/c mice from day 1 to 7 by oral gavage, followed by induction of acute DSS-colitis from day 8 to 14 (“Control”, n = 6, “DSS”, n = 10, “FI5pp + DSS”, n = 11). Mice were sacrificed on day 21. Clinical symptoms (body weight, stool consistency and occult blood) were checked daily after colitis induction. Colon tissue was collected for histological damage scoring and quantification of tight junction protein expression. Stool samples were collected for microbiome analysis. Our study revealed prophylactic diosmectite treatment attenuated the severity of DSS colitis, which was apparent by significantly reduced weight loss (p = 0.022 vs. DSS), disease activity index (p = 0.0025 vs. DSS) and histological damage score (p = 0.023 vs. DSS). No significant effects were obtained for the expression of TJ proteins (claudin-2 and claudin-3) after diosmectite treatment. Characterization of the microbial composition by 16S amplicon NGS showed that diosmectite treatment modified the DSS-associated dysbiosis. Thus, diosmectites are promising candidates for therapeutic approaches to target intestinal inflammation and to identify possible underlying mechanisms of diosmectites in further studies.

Background and Aims Dialysis therapy of patients at increased risk of bleeding is a well-known clinical problem. Systemic anticoagulation with heparin increases the risk of severe hemorrhage. Alternative strategies include the use of heparin-coated dialysis membranes, regional citrate anticoagulation, airless dialysis tubing, flushing the dialyzer with saline and earlier regional heparin anticoagulation with protamine reversal. However, either special devices (e.g. airless or heparin coated tubing) are needed, or the procedures are complex and require additional time and personnel resources for administration and monitoring. Current data on heparin-free dialysis are rare. After a pilot study from 282 dialysis sessions we reviewed 949 dialysis protocols from 2.5 years of 480 hospitalized and outpatient dialysis patients who were treated without systemic anticoagulation due to an increased risk of bleeding or a manifest hemorrhage. The duration of each dialysis session and the number of dialyses with or without clotting were evaluated. Method A total of 949 dialysis sessions of 480 patients were reviewed from October 2017 to January 2021. Dialysis were performed with Fresenius 4008/5008 (FX80,FX50, KF-210) and Gambro Artis (Poly170H, Theranova). All dialysis sessions were performed via AV-fistula with double-needle puncture or via single- or double-lumen central venous catheters (CVC). No additional technical devices or procedures were used beside standard hemodialysis or hemodiafiltration. Some of the patients had coagulopathies (sepsis, liver cirrhosis), thrombocytopenia or were on systemic anticoagulant therapy (vitamin K antagonists, DOAKs, heparin independent from dialysis therapy). The primary outcome was the need to interrupt the dialysis session because of clotting events due to a complete coagulation of the circuit, a partial coagulation of the circuit or a significant rise in the venous pressure. Results In 81 procedures (8.5%) systemic clotting made a discontinuation of the dialysis session necessary. In only 10 sessions (1%), the dialysis treatment had to be continued with new tubing and filter. More than one change of a system was never necessary. In the other 71 sessions, dialysis had to be stopped with retransfusion 5 minutes until 1.5 hours before the scheduled end of therapy, and therapy was considered as clinically sufficient. The frequency of clotting did not correlate with dialysis time (Fig.1.). Regarding the venous access clotting happened in 14.6% of acute CVC, in 12.6% of tunneled CVCs and in 9.4 % of AV-fistulas or -grafts, (Fig 2). Conclusion Dialysis without anticoagulation can be performed routinely with modern synthetic filters and dialysis concentrates. Patients at high risk of bleeding, with manifest hemorrhage or before surgery can undergo dialysis treatment for up to five hours without complications. In the present study clotting did not correlate with dialysis time. Patient-specific factors, as the venous access seem to play a more important role. In summary additional cost intensive devices, personnel intensive procedures and complex treatment protocols are only rarely needed to perform heparin-free dialysis for patients at risk.

Background: Albumin is important for the transport of protein-bound substances (PBS). Albumin binding capacity (ABiC) is reduced in dialysis patients. This can contribute to worsening of uremic symptoms. It is presumed that open-porous middle cut off filters that is, HDx (Baxter-Theranova) remove high molecular substances more efficiently than conventional treatment. To evaluate HDx for the improvement of ABiC and removal of PBS, HDx was compared to hemodiafiltration (Fresenius-FX80, HDF). Methods: We included 32 chronic patients on HDF. After inclusion patients were treated with HDx for 14 days. Blood samples were drawn before/after treatments at study entry, first HDx and sixth HDx, to determine ABiC and other study parameters. Results: ABiC improved in HDx (68.4% vs 72.4%) and HDF (69.9% vs 72.4%) without differences between both therapies. No reduction of albumin concentration during HDx treatment was observed. Conclusion: HDx is accepted as a safe and equally efficient therapy for removing albumin bound uremic toxins compared to HDF with high flux dialyzers.

Introduction: Continuous renal replacement therapies (CRRTs) are essential in the treatment of critically ill patients with acute kidney injury and are also discussed as a supporting sepsis therapy. CRRT can affect antibiotics plasma concentrations. Objective: The effect of continuous venovenous hemofiltration (CVVH) with an asymmetric triacetate (ATA) membrane hemofilter on concentrations of antibiotics with low (meropenem), medium (vancomycin), and high (daptomycin) protein binding (PB) was investigated. Methods: 1 L human whole blood supplemented with antibiotics was recirculated and filtrated for 6 h in vitro. Clearances and sieving coefficients (SC) were determined from antibiotics concentrations measured at filter inlet, outlet, and filtrate side. Reservoir concentration data were fitted using a first-order kinetic model. Results: Meropenem and vancomycin concentrations decreased to 5–10% of the initial plasma level, while only 50% of daptomycin were removed. Clearances and SCs were (10.8 [10.8–17.4] mL/min, SC = 0.72 [0.72–1.16]) for meropenem, (13.4 [12.3–13.7] mL/min, 0.89 [0.82–0.92]) for vancomycin, and (2.1 [1.8–2.1] mL/min, 0.14 [0.12–0.14]) for daptomycin. Removal by adsorption was negligible. Conclusions: The clearances and SCs presented are comparable with findings of other authors. Meropenem and vancomycin, which exhibit low and medium PB, respectively, were strongly removed, while considerably less daptomycin was removed because of its high PB. Our results suggest that in clinical use of the tested antibiotics during CRRT with the ATA hemofilter, the same factors have to be considered for determining the dosing strategy as with filters with other commonly applied membrane materials.

Background The role of artificial and bioartificial liver support systems in acute-on-chronic liver failure (ACLF) is still controversial. We aimed to perform the first network meta-analysis comparing and ranking different liver support systems and standard medical therapy (SMT) in patients with ACLF. Methods The study protocol was registered with PROSPERO (CRD42020155850). A systematic search was conducted in five databases. We conducted a Bayesian network meta-analysis of randomized controlled trials assessing the effect of artificial or bioartificial liver support systems on survival in patients with ACLF. Ranking was performed by calculating the surface under cumulative ranking (SUCRA) curve values. The RoB2 tool and a modified GRADE approach were used for the assessment of the risk of bias and quality of evidence (QE). Results In the quantitative synthesis 16 trials were included, using MARS®, Prometheus®, ELAD®, plasma exchange (PE) and BioLogic-DT®. Overall (OS) and transplant-free (TFS) survival were assessed at 1 and 3 months. PE significantly improved 3-month OS compared to SMT (RR 0.74, CrI: 0.6–0.94) and ranked first on the cumulative ranking curves for both OS outcomes (SUCRA: 86% at 3 months; 77% at 1 month) and 3-month TFS (SUCRA: 87%) and second after ELAD for 1-month TFS (SUCRA: 76%). Other comparisons did not reach statistical significance. QE was moderate for PE concerning 1-month OS and both TFS outcomes. Other results were of very low certainty. Conclusion PE seems to be the best currently available liver support therapy in ACLF regarding 3-month OS. Based on the low QE, randomized trials are needed to confirm our findings for already existing options and to introduce new devices.

Background The CAMI-1 study dealt with the depletion of CRP by apheresis in patients with acute myocardial infarction (AMI). CRP, the prototype human acute phase protein, has been known as a marker of poor prognosis in AMI and independently predicts 30-day mortality. Methods 66 STEMI patients were enrolled in the study following complete coronary revascularization (2–12 h after the onset of symptoms). 32 patients received CRP apheresis, whereas 34 patients treated by standard protocols served as controls. CRP apheresis started 24±12 h and 48±12 h after onset of symptoms. In case of a rapid increase in CRP plasma levels following the 2nd session, a 3rd session was carried out another 24 h later. A specific CRP adsorber removed up to 79% of the original CRP. In each apheresis session, 6000 ml of plasma was treated via peripheral venous access. Primary study endpoint was myocardial infarction size as determined by Cardiac Magnetic Resonance Imaging (CMR) 2–9 days after STEMI. Results Aphereses sessions were well tolerated with no relevant side effects. Peak CRP plasma levels after STEMI ranged from 9 to 279 mg/l. The expected peak CRP level after AMI can be calculated precisely with 2–3 CRP quantifications during the first 24 h after the onset of symptoms. The regression coefficient for this analysis is 0.91. This mathematical step allows for the comparison of the CRP-apheresis group and the controls on the basis of their individual CRP peak levels. The statistical evaluation shows that the CRP concentration is significantly associated with the damage (infarct size, LVEF, circumferential strain) in the controls. This association was lost in the aphereses patients: they performed significantly better at all endpoints (infarct size, LVEF, circumferential strain) than the controls. The CRP apheresis significantly reduced myocardial damage. To our surprise, two apheresis patients had an infarct size of 0%. Conclusions For the first time we find an unequivocal association between myocardial infarct size and the CRP concentration. This is in some respects a surprise, since the basic assumption in AMI is that the vascular occlusion leads to primary damage and the reperfusion to secondary damage, which would not have led one to expect such a clear dose-response relationship as that observed here. In addition, our results show a significant beneficial effect of CRP apheresis on myocardial infarction size and wall motion. Selective CRP apheresis is now being further evaluated as a therapeutic approach in the treatment of acute myocardial infarction in a registry (CAMI registry). Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Pentracor GmbH

Background: C-reactive protein (CRP) is a well-known marker of inflammation. It is less known that CRP mediates tissue damage in acute myocardial infarction (AMI) thus potentially worsening prognosis. A newly developed specific CRP adsorber allows efficient lowering of CRP levels and may improve survival.Objectives: Aim of this multi-center, controlled, non-randomized first-in-man CRP apheresis in Acute Myocardial Infarction study (CAMI-1) was to investigate the relationship between CRP levels (CRP gradient), myocardial infarct size and function as well as safety and efficacy of CRP apheresis in the setting of acute ST-segment Elevation Myocardial Infarction (STEMI) in humans.Methods: Eighty-three patients (45 apheresis, 38 controls) were recruited. CRP apheresis was performed 24 ± 12, 48 ± 12, and optionally 72 ± 12 h after onset of symptoms. First aphereses were performed at a median CRP concentration of 23.0 mg/L (range 9–279). In each apheresis session, 5,900 ± 400 mL plasma was processed via peripheral venous access. Primary study endpoint was a reduction in myocardial infarct size after STEMI as determined by cardiovascular magnetic resonance (CMR).Results: In controls, the CRP concentration significantly correlated with infarct size (p = 0.002) and decreased myocardial function (p ≤ 0.001). The CRP concentration in apheresis patients did not correlate with infarct size (p = 0.66) or left ventricular (LV) function (p = 0.79) and global strains and therefore significantly differed from controls (p = 0.03 and p = 0.002). Three major adverse cardiac events occurred in the control group after 12 months, none occurred in the apheresis group. Mean CRP depletion achieved over all apheresis procedures was 53.0 ± 15.1%. Apheresis sessions were well-tolerated. Reduced infarct size in the apheresis group compared to the control group (primary endpoint) was not achieved according to the original statistical analysis plan. Taking into account the individual CRP levels, however, revealed significant results. Modifications of the analysis plan were introduced in order to recruit a sufficient number of patients.Conclusions: This pilot study in humans reveals a correlation between CRP concentration and myocardial infarct size. CRP concentrations in STEMI can effectively be reduced by CRP apheresis without relevant side effects. CRP apheresis has the potential to interfere with deleterious aspects of STEMI. By lowering CRP levels, it resulted in the loss of correlation of CRP concentrations with myocardial infarct sizes as well as LV function. These results encourage a larger, randomized clinical trial.Clinical Trial Registration:https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00008988, DRKS00008988.

Background and Aims The removal of inflammatory mediators and cytokines is of great importance in the treatment of patients with acute or chronic renal failure. In patients with acute renal failure and sepsis, an attempt is made to achieve removal through the use of high-volume treatments or adsorbers in order to achieve better circulatory stability. In chronic dialysis patients, this has so far not been sufficiently addressed, but is important for mortality and cardiovascular events (MIA syndrome). Some studies show a superiority of HDF over conventional HD. By using new MCO filters in HD mode such as the Baxter Theranova (HDx), an improvement of cytokine status seems to be possible in both areas (chronic and acute). The effectiveness of MCO filters (HDx) compared to high flux hemodiafiltration in the removal of interleukins (interleukin 6, interleukin 10 and TNF (tumor necrosis factor) alpha will be assessed. Method The efficacy of HDx was compared with that of conventional high-flux dialysis filters (Fresenius FX80, HDF) in HDF mode. Based on real world conditions the ultrafiltration/substitution rate was set to 50 ml/min. (blood flow 200 ml/min., dialysate flow 500 ml/min.) No effective ultrafiltration was used. The measurements were performed in vitro in a 3l pool of fresh frozen plasma (citrate anticoagulated, with additional heparin during dialysis treatment). IL6 (24.5 kDa) IL10 (18.6 kDa, dimer)) and TNFalpha (17.4 kDa, trimer) were added to the plasma pool in concentrations of 1.5 μg/l each. This results in very high cytokine levels, as for example in severe sepsis. Samples were taken before and after the dialyzer for 180 minutes (after 5, 15, 30, 60, 120 and 180 minutes).For HDF the measured cytokine concentration was corrected for ultrafiltration rates. In addition to cytokines, albumin and total protein concentration were measured (ELISA Kit LEGEND MAX Human IL-6 / IL-10 / TNF-α; Biolegend and Cobas Mira Plus; Roche Kit LT-AB 0103 and LT-TP 0253). Every test was repeat 5 times. Results Theranova HDx showed higher removal rates of all tested cytokines over a period of 180 minutes. A comparison of the concentrations at the beginning and end of the measurements showed: IL-6 reduction - HDx about 77% / HDF about 63%. IL-10 reduction - HDx about 53% and HDF about 22%. TNF-α Reduction - HDx about 26%; HDF about 18% The concentration of albumin and total serum protein was not significant different during the treatments in both groups. Conclusion Hemodialysis therapy with Theranova HDx appears to be a superior or equal therapy option for the removal of cytokines. This opens up new treatment options for both acute renal failure and chronic dialysis patients, especially if citrate anticoagulation is necessary. The ultrafiltration rate in HDF was lower than recommended for high volume diafiltration,but as high as in our real world experience. Therefore the effect of HDF could be underestimated. Clinical studies with clinically relevant blood flow and ultrafiltration rates are still necessary.

Background Inflammation is increasingly recognized as an important pathogenic feature in cardiovascular disease. In patients with STEMI, C-reactive protein (CRP), the prototype human acute phase protein, is a marker of poor prognosis and independently predicts 30-day mortality. In STEMI, CRP may indeed be intimately involved in myocardial damage by activating the complement system in the ischemic tissue. In animal experiments, CRP removal after STEMI reduces infarct size and results in a significantly better left ventricular ejection fraction (LVEF). Recently, in the multi-center matched-control pilot study on CRP apheresis in Acute Myocardial Infarction (CAMI1), a newly designed CRP adsorber has been demonstrated to efficiently and selectively lower CRP plasma levels in humans. Here, we present preliminary data of the ongoing trial. Methods Up to the present day, 67 STEMI patients were enrolled in the study following complete coronary revascularization. 32 patients received CRP apheresis, whereas 35 patients treated by standard protocols served as controls. CRP apheresis started 24±12 h and 48±12 h after onset of symptoms. In case of a rapid increase in CRP plasma levels following the 2nd session, a 3rd session was carried out another 24 h later. In each apheresis session, 6000 ml plasma was treated via peripheral venous access. Primary study endpoint was myocardial infarction size as determined by Cardiac Magnetic Resonance Imaging (MRI) 5±3 days after STEMI. Results Apheresis sessions were well tolerated with no relevant side effects. Peak CRP plasma levels after STEMI ranged from 12 mg/l to 279 mg/l. The peak CRP level after AMI can be calculated precisely with at 2–3 CRP quantifications during the first 24 h after the onset of symptoms. The regression coefficient for this analysis is 0.95. This mathematical step allows for the comparison of the CRP-apheresis group and the controls on the basis of their individual CRP peak levels. The statistical evaluation shows that the apheresis patients no longer correlate with the control with regard to the endpoints infarct size, LVEF, longitudinal strain and circumferential strain. They perform significantly better at all endpoints. The CRP apheresis reduced the development of myocardial damage. Conclusions Here, an unequivocal association between infarct size and CRP is demonstrated for the first time. CRP apheresis following STEMI is feasible and safe. Our preliminary results in a small cohort show a significant beneficial effect of CRP apheresis on myocardial infarction size and wall motion. Selective CRP apheresis may emerge as a new therapeutic approach in the treatment of acute myocardial infarction.

Background Data are lacking on the relative incidence of thrombotic thrombocytopenic purpura (TTP), haemolytic uraemic syndrome (HUS) caused by Shiga toxin–producing Escherichia coli (STEC) and atypical HUS (aHUS) in patients presenting with thrombotic microangiopathies (TMAs). Methods This was a prospective, cross-sectional, multicentre and non-interventional epidemiological study. Patients fulfilling criteria for TMAs (platelet consumption, microangiopathic haemolytic anaemia and organ dysfunction) were included in the study. The primary objective was to assess the relative incidence of TTP, STEC-HUS, aHUS and ‘other’ physician-defined diagnoses. The secondary objective was to develop an algorithm to predict a severe deficiency in ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity (≤10%) using routine laboratory parameters. A post hoc classification using the recent Kidney Disease: Improving Global Outcomes diagnostic criteria was then undertaken to further classify patient groups. Results aHUS was diagnosed with a relative incidence of 61%, whereas TTP, STEC-HUS and ‘other’ were diagnosed in 13, 6 and 20% of patients, respectively. In the post hoc analysis, 27% of patients with a TMA were classified as ‘primary aHUS’ and 53% as ‘secondary aHUS’. Multivariate analysis revealed that severe deficiency in ADAMTS13 activity (≤10%) was unlikely to underlie TMA if platelet and serum creatinine were above threshold values of 30 × 109/L and 1.8 mg/dL, respectively (negative predictive value of 92.3 and 98.1, respectively, if one or both values were above the threshold). Conclusions In this study, aHUS was the most common single diagnosis among patients presenting with a TMA. In the absence of an ADAMTS13 activity result, platelet count and serum creatinine may aid in the differential diagnosis.

Hemofilters applied in continuous renal replacement therapies (CRRTs) for the treatment of acute kidney injury must meet high standards in biocompatibility and permeability for middle and large molecules over extended treatment times. In general, cellulose-based membranes exhibit good biocompatibility and low fouling, and thus appear to be beneficial for CRRT. In this in vitro study, we compared a novel asymmetric cellulose triacetate (ATA) membrane with three synthetic membranes [polysulfone (PS), polyethersulfone (PES), and polyethylenimine-treated acrylonitrile/sodium methallyl sulfonate copolymer (AN69 ST)] regarding thrombogenicity and cytokine removal. For thrombogenicity assessment, we analyzed the thrombin-antithrombin complex (TAT) generation in human whole blood during 5 h recirculation and filtration. Sieving coefficients of interleukin-6 (IL-6), IL-8, IL-10, and tumor necrosis factor-alpha (TNF-a) were determined using human plasma as test fluid. ATA and AN69 ST membrane permeability were determined also during long-term experiments (48.5 h). ATA exhibited the lowest TAT generation (6.3 µg/L at 5 h), while AN69 ST induced a pronounced concentration increase (152.1 µg/L) and filter clogging during 4 out of 5 experiments. ATA (IL-8: 1.053; IL-6: 1.079; IL-10: 0.898; TNF-a: 0.493) and PES (0.973; 0.846; 0.468; 0.303) had the highest sieving coefficients, while PS (0.697; 0.100; 0.014; 0.012) and AN69 ST (N/A; 0.717; 0; 0.063) exhibited lower permeability. Long-term experiments revealed stronger fouling of the AN69 ST compared to the ATA membrane. We observed the highest permeability for the tested cytokines, the lowest thrombogenicity, and the lowest fouling with the ATA membrane. In CRRT, these factors may lead to increased therapy efficacy and lower incidence of coagulation-associated events.

Therapeutic options to treat multiple sclerosis (MS) relapses comprise glucocorticosteroids (GCS) as first-line and therapeutic plasma exchange (TPE) as second-line treatments in GCS-unresponsive patients. No guidelines exist for the treatment of another relapse following TPE. We retrospectively analyzed the responsiveness to GCS in a subsequent relapse following TPE in previously GCS-unresponsive MS patients. Thirty-seven patients with GCS-unresponsive MS relapses received TPE (relapse A). All patients developed another relapse after the completion of TPE and received GCS again (relapse B). The primary study endpoint was the clinical response to GCS and TPE. Marked improvement was defined as clinically significant improvement in function, moderate improvement as a definite change of symptoms without significant impact on function, no effect comprised unchanged symptoms, and deterioration a worsening of symptoms or new deficits. The secondary endpoint was an improvement in expanded disability status scale (EDSS) scoring. All patients were GCS-unresponsive during relapse A and received TPE. During GCS treatment of relapse B, marked improvement was observed in 10, moderate improvement in 24, and no effect in three patients. The EDSS decreased in 15 patients. GCS might remain the first-line relapse treatment following TPE in formerly GCS-unresponsive MS patients.

Because of its efficacy, ease of dosing, and safety, the direct oral anticoagulant rivaroxaban is increasingly applied in a number of indications, for example, prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and treatment of deep vein thrombosis and pulmonary embolism. Median therapeutic peak plasma concentrations range from 46 to 270 µg/L, depending on the respective indication. However, there are concerns regarding the accumulation of the drug in patients with impaired renal clearance or in case of overdosing, potentially leading to an increased risk of bleeding. With its high degree of protein binding of 92-95%, rivaroxaban is regarded as non-dialyzable, as also suggested by results from a clinical study conducted by Dias et al.. Since protein binding is regarded as not a limiting factor in hemoperfusion, the removal of rivaroxaban, as for example by commonly available coated charcoal cartridges, has been deemed possible, but experimental evidence is still lacking. While Andexanet alfa may offer a promising approach to reverse the FXa inhibitor-mediated anticoagulation of rivaroxaban, it has not yet been approved. In case of rivaroxaban-related major bleeding events or emergency interventions with a high bleeding risk, therefore, a fast and effective countermeasure is urgently needed. Here, we present experimental work to remove rivaroxaban from the blood by means of hemoperfusion using an approved adsorption device (CytoSorb®; Cyto¬Sorbents Europe, Germany). Currently, CytoSorb is used mainly in patients with severe infections and sepsis (cytokine storm). We applied a model device containing 60 mL of the adsorbent polyvinylpyrrolidone-coated polystyrene-divinylbenzene copolymer in an in vitro recirculation system to remove high plasma concentrations of rivaroxaban (571 ± 20 µg/L) from citrate-anticoagulated human whole blood (1,000 mL, flow rate 40 mL/min) during 120 min of hemoperfusion (Fig. 1a). Molecules are captured on the internal pore surface of polystyrene-divinylbenzene by nonspecific hydrophobic interactions, whereby solutes with molecular weights equal to and larger than that of albumin, particularly clotting factors, are excluded from adsorption by adjustment of the pore size distribution.

Therapeutic options to treat multiple sclerosis (MS) relapses comprise glucocorticosteroids (GCS) as first-line and therapeutic plasma exchange (TPE) as second-line treatments in GCS-unresponsive patients. No guidelines exist for the treatment of another relapse following TPE. We retrospectively analyzed the responsiveness to GCS in a subsequent relapse following TPE in previously GCS-unresponsive MS patients. Thirty-seven patients with GCS-unresponsive MS relapses received TPE (relapse A). All patients developed another relapse after the completion of TPE and received GCS again (relapse B). The primary study endpoint was the clinical response to GCS and TPE. Marked improvement was defined as clinically significant improvement in function, moderate improvement as a definite change of symptoms without significant impact on function, no effect comprised unchanged symptoms, and deterioration a worsening of symptoms or new deficits. The secondary endpoint was an improvement in expanded disability status scale (EDSS) scoring. All patients were GCS-unresponsive during relapse A and received TPE. During GCS treatment of relapse B, marked improvement was observed in 10, moderate improvement in 24, and no effect in three patients. The EDSS decreased in 15 patients. GCS might remain the first-line relapse treatment following TPE in formerly GCS-unresponsive MS patients.

Reduction of platelets is a common finding in patients with liver disease and can be aggravated by extracorporeal therapies, e.g. artificial liver support. The impact of extracorporeal albumin dialysis on the time count and time course of platelets in liver failure patients was evaluated in a randomized controlled clinical trial. Mean thrombocyte reduction during a single extracorporeal liver support therapy was -15.1% [95%CI: -17.7; -12.5]. No differences were found between treatments of patients with a more reduced platelet count (

Clinically Isolated Syndromes (CIS) summarize clinical features of possible multiple sclerosis (MS) as a first clinical event of the disease. Escalation therapy in CIS episodes comprises high dose glucocorticosteroid (GCS) treatment followed by therapeutic plasma exchange (TPE) in patients unresponsive to GCS. The aim of our study was to analyze TPE effects in CIS patients. Eleven GCS-unresponsive patients exhibiting CIS were treated with TPE. A median of 5.0 (range 3-8) treatments were performed with a median exchange volume of 3.0 L (range 2.2-3.5 L). Standard diagnostic results in CIS patients were collected. In 10 out of 11 patients clinical improvement was observed. In Expanded Disability Status Scale (EDSS) Scoring, a commonly used score to assess disability in MS and CIS patients, significant improvement was shown as well. One patient was a non-responder to TPE. Apheresis treatments were well tolerated in all patients. In the medical control of GCS-unresponsive CIS episodes, TPE appears to be an effective and well-tolerated treatment option. TPE response in CIS patients is comparable to TPE results in GCS-unresponsive MS relapses. Further prospective studies are indicated.

Inflammation is increasingly recognized as an important pathogenic feature in cardiovascular disease. In patients with ST-segment elevation myocardial infarction (STEMI), C-reactive protein (CRP), the prototype human acute phase protein, is a marker of poor prognosis and independently predicts 30