The Utility of Miniaturized Adsorbers in Exploring the Cellular and Molecular Effects of Blood Purification: A Pilot Study with a Focus on Immunoadsorption in Multiple Sclerosis.

Immunoadsorption (IA) has proven to be clinically effective in the treatment of steroid-refractory multiple sclerosis (MS) relapses, but its mechanism of action remains unclear. We used miniaturized adsorber devices with a tryptophan-immobilized polyvinyl alcohol (PVA) gel sorbent to mimic the IA treatment of patients with MS in vitro. The plasma was screened before and after adsorption with regard to disease-specific mediators, and the effect of the IA treatment on the migration of neutrophils and the integrity of the endothelial cell barrier was tested in cell-based models. The in vitro IA treatment with miniaturized adsorbers resulted in reduced plasma levels of cytokines and chemokines. We also found a reduced migration of neutrophils towards patient plasma treated with the adsorbers. Furthermore, the IA-treated plasma had a positive effect on the endothelial cell barrier's integrity in the cell culture model. Our findings suggest that IA results in a reduced infiltration of cells into the central nervous system by reducing leukocyte transmigration and preventing blood-brain barrier breakdown. This novel approach of performing in vitro blood purification therapies on actual patient samples with miniaturized adsorbers and testing their effects in cell-based assays that investigate specific hypotheses of the pathophysiology provides a promising platform for elucidating the mechanisms of action of those therapies in various diseases.

Adjunctive Hemoadsorption Therapy with CytoSorb in Patients with Septic/Vasoplegic Shock: A Best Practice Consensus Statement.

A dysregulated host response is a common feature in critically ill patients due to both infectious and non-infectious origins that can lead to life-threatening organ dysfunction, which is still the primary cause of death in intensive care units worldwide. In its course, pathologic, unregulated levels of inflammatory mediators are often released into the circulation, a phenomenon also referred to as a "cytokine storm". To date, there are no approved therapies to modulate the excessive immune response and limit hyperinflammation with the goal of preventing related organ failure and death. In this context, extracorporeal blood purification therapies aiming at the alteration of the host inflammatory response through broad-spectrum, non-selective removal of inflammatory mediators have come into focus. A novel hemoadsorption device (CytoSorb®, CytoSorbents Inc., Princeton, NJ, USA) has shown promising results in patients with hyperinflammation from various origins. Although a significant body of literature exists, there is ongoing research to address many important remaining questions, including the optimal selection of patient groups who might benefit the most, optimal timing for therapy initiation, optimal schedule for adsorber exchanges and therapy duration, as well as an investigation into the potential removal of concomitant antibiotics and other medications. In this review, we discuss the existing evidence and provide a consensus-based best practice guidance for CytoSorb® hemoadsorption therapy in patients with vasoplegic shock.

Exploring Albumin Functionality Assays: A Pilot Study on Sepsis Evaluation in Intensive Care Medicine.

Human serum albumin (HSA) as the most abundant plasma protein carries multifunctional properties. A major determinant of the efficacy of albumin relies on its potent binding capacity for toxins and pharmaceutical agents. Albumin binding is impaired in pathological conditions, affecting its function as a molecular scavenger. Limited knowledge is available on the functional properties of albumin in critically ill patients with sepsis or septic shock. A prospective, non-interventional clinical trial assessed blood samples from 26 intensive care patients. Albumin-binding capacity (ABiC) was determined by quantifying the unbound fraction of the fluorescent marker, dansyl sarcosine. Electron paramagnetic resonance fatty acid spin-probe evaluated albumin's binding and detoxification efficiencies. Binding efficiency (BE) reflects the strength and amount of bound fatty acids, and detoxification efficiency (DTE) indicates the molecular flexibility of patient albumin. ABiC, BE, and DTE effectively differentiated control patients from those with sepsis or septic shock (AUROC > 0.8). The diagnostic performance of BE showed similarities to procalcitonin. Albumin functionality correlates with parameters for inflammation, hepatic, or renal insufficiency. Albumin-binding function was significantly reduced in critically ill patients with sepsis or septic shock. These findings may help develop patient-specific algorithms for new diagnostic and therapeutic approaches.

Imaging Predictors of Left Ventricular Functional Recovery after Reperfusion Therapy of ST-Elevation Myocardial Infarction Assessed by Cardiac Magnetic Resonance.

BACKGROUND: Left ventricular global longitudinal strain (LV GLS) is a superior predictor of adverse cardiac events in patients with myocardial infarction and heart failure. We investigated the ability of morphological features of infarcted myocardium to detect acute left ventricular (LV) dysfunction and predict LV functional recovery after three months in patients with acute ST-segment elevation myocardial infarction (STEMI). METHODS: Sixty-six STEMI patients were included in the C-reactive protein (CRP) apheresis in Acute Myocardial Infarction Study (CAMI-1). LV ejection fraction (LVEF), LV GLS, LV global circumferential strain (LV GCS), infarct size (IS), area-at-risk (AAR), and myocardial salvage index (MSI) were assessed by CMR 5 ± 3 days (baseline) and 12 ± 2 weeks after (follow-up) the diagnosis of first acute STEMI. RESULTS: Significant changes in myocardial injury parameters were identified after 12 weeks of STEMI diagnosis. IS decreased from 23.59 ± 11.69% at baseline to 18.29 ± 8.32% at follow-up (p < 0.001). AAR and MVO also significantly reduced after 12 weeks. At baseline, there were reasonably moderate correlations between IS and LVEF (r = -0.479, p < 0.001), LV GLS (r = 0.441, p < 0.001) and LV GCS (r = 0.396, p = 0.001) as well as between AAR and LVEF (r = -0.430, p = 0.003), LV GLS (r = 0.501, p < 0.001) and weak with LV GCS (r = 0.342, p = 0.020). At follow-up, only MSI and change in LV GCS over time showed a weak but significant correlation (r = -0.347, p = 0.021). Patients with larger AAR at baseline improved more in LVEF (p = 0.019) and LV GLS (p = 0.020) but not in LV GCS. CONCLUSION: The CMR tissue characteristics of myocardial injury correlate with the magnitude of LV dysfunction during the acute stage of STEMI. AAR predicts improvement in LVEF and LV GLS, while MSI is a sensitive marker of LV GCS recovery at three months follow-up after STEMI.

Randomized, controlled clinical trial of the DIALIVE liver dialysis device versus standard of care in patients with acute-on- chronic liver failure.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation, multi-organ failure and high mortality rates. Its treatment is an urgent unmet need. DIALIVE is a novel liver dialysis device that aims to exchange dysfunctional albumin and remove damage- and pathogen-associated molecular patterns. This first-in-man randomized-controlled trial was performed with the primary aim of assessing the safety of DIALIVE in patients with ACLF, with secondary aims of evaluating its clinical effects, device performance and effect on pathophysiologically relevant biomarkers. METHODS: Thirty-two patients with alcohol-related ACLF were included. Patients were treated with DIALIVE for up to 5 days and end points were assessed at Day 10. Safety was assessed in all patients (n = 32). The secondary aims were assessed in a pre-specified subgroup that had at least three treatment sessions with DIALIVE (n = 30). RESULTS: There were no significant differences in 28-day mortality or occurrence of serious adverse events between the groups. Significant reduction in the severity of endotoxemia and improvement in albumin function was observed in the DIALIVE group, which translated into a significant reduction in the CLIF-C (Chronic Liver Failure consortium) organ failure (p = 0.018) and CLIF-C ACLF scores (p = 0.042) at Day 10. Time to resolution of ACLF was significantly faster in DIALIVE group (p = 0.036). Biomarkers of systemic inflammation such as IL-8 (p = 0.006), cell death [cytokeratin-18: M30 (p = 0.005) and M65 (p = 0.029)], endothelial function [asymmetric dimethylarginine (p = 0.002)] and, ligands for Toll-like receptor 4 (p = 0.030) and inflammasome (p = 0.002) improved significantly in the DIALIVE group. CONCLUSIONS: These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy. IMPACT AND IMPLICATIONS: This is the first-in-man clinical trial which tested DIALIVE, a novel liver dialysis device for the treatment of cirrhosis and acute-on-chronic liver failure, a condition associated with severe inflammation, organ failures and a high risk of death. The study met the primary endpoint, confirming the safety of the DIALIVE system. Additionally, DIALIVE reduced inflammation and improved clinical parameters. However, it did not reduce mortality in this small study and further larger clinical trials are required to re-confirm its safety and to evaluate efficacy. CLINICAL TRIAL NUMBER: NCT03065699.

Hemoperfusion with CytoSorb®: Current Knowledge on Patient Selection, Timing, and Dosing.

Direct hemoperfusion with the CytoSorb® adsorbent has experienced widespread use in several critical care settings including sepsis and multiorgan failure. The reported conditions of clinical usage and resulting outcomes vary considerably. The aim of the study was to provide an overview on current treatment recommendations based on the available clinical evidence. We performed a literature analysis using PubMed/MEDLINE and ClinicalTrials.gov to identify clinical data describing parameters of clinical usage of CytoSorb® in patients with septic shock (inclusion and exclusion criteria, starting, and dosing of treatment) and their impact on outcome. The literature search terms yielded 146 entries in September 2022, including clinical case reports, case series, and controlled and uncontrolled clinical trials. Five recommendations were identified linking usage parameters with improved outcome. These were (a) early start of treatment within 12-24 h after onset of septic shock, (b) individualized patient selection (preferably with higher severity scores, procalcitonin >3 ng/mL, serum interleukin 6 >500 pg/mL), (c) exclusion of patients with lactate ≥6 mmol/L or platelets <100 GPT/L, (d) intense treatment (>6 L of blood/kg body weight), and (e) early change of the adsorbent (e.g., every 12 h). Moreover, there is a rationale suggesting therapeutic drug monitoring when possible, avoidance of drug application at the beginning of treatment, and/or usage of increased dosages of antibiotics. However, for the later recommendations, no links to clinical outcome were reported yet. All recommendations are based on the best available knowledge. They need confirmation in future clinical investigations. Currently available clinical data on the use of CytoSorb® in septic patients suggest that early and intense treatment in carefully chosen patients increases the chance of survival. The analysis can inform current clinical practice and future clinical trials.

Extracorporeal therapy of sepsis by purified granulocyte concentrates: ex vivo circulation model.

BACKGROUND: Immune cell dysfunction is a central part of immune paralysis in sepsis. Granulocyte concentrate (GC) transfusions can induce tissue damage via local effects of neutrophils. The hypothesis of an extracorporeal plasma treatment with granulocytes is to show beneficial effects with fewer side effects. Clinical trials with standard GC have supported this approach. This ex vivo study investigated the functional properties of purified granulocyte preparations during the extracorporeal plasma treatment. METHODS: Purified GC were stored for up to 3 days and compared with standard GC in an immune cell perfusion therapy model. The therapy consists of a plasma separation device and an extracorporeal circuit. Plasma is perfused through the tubing system with donor immune cells of the GC, and only the treated plasma is filtered for re-transfusion. The donor immune cells are retained in the extracorporeal system and discarded after treatment. Efficacy of granulocytes regarding phagocytosis, oxidative burst as well as cell viability and metabolic parameters were assessed. RESULTS: In pGC, the metabolic surrogate parameters of cell functionality showed comparable courses even after a storage period of 72 h. In particular, glucose and oxygen consumption were lower after extended storage. The course of lactate dehydrogenase concentration yields no indication of cell impairment in the extracorporeal circulation. The cells were viable throughout the entire study period and exhibited preserved phagocytosis and oxidative burst functionality. CONCLUSION: The granulocytes demonstrated full functionality in the 6 h extracorporeal circuits after 3 days storage and in septic shock plasma. This is demonstrating the functionality of the system and encourages further clinical studies.

Decellularization of precision-cut kidney slices-application of physical and chemical methods.

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.

Impact of Albumin Binding Function on Pharmacokinetics and Pharmacodynamics of Furosemide.

Background and Objectives: Albumin binding of the loop diuretic furosemide forms the basis for its transport to the kidney and subsequent tubular secretion, which is a prerequisite for its therapeutic effects. Accordingly, high albumin concentrations should result in higher efficacy of furosemide. However, study results on the combination of furosemide in conjunction with albumin, and on the efficacy of furosemide in hypoalbuminemia, did not confirm this hypothesis. The aim of this study was to determine the efficacy of furosemide not only in relation to albumin concentration, but also taking albumin function into account. Materials and Methods: In a prospective and non-interventional clinical observational trial, blood and urine samples from 50 intensive care patients receiving continuous intravenous furosemide therapy were evaluated. Albumin binding capacity (ABiC) determination allowed conclusions to be drawn about the binding site-specific loading state of albumin, by quantifying the unbound fraction of the fluorescent marker dansylsarcosine. In addition, assessment of the total concentration of furosemide in plasma and urine, as well as the concentration of free furosemide fraction in plasma, was performed by HPLC−MS. The efficacy of furosemide was evaluated by the ratio of urine excretion to fluid intake. Results: In patients with an ABiC ≥ 60% free furosemide fraction was significantly lower compared to patients with a lower ABiC (p < 0.001), urinary furosemide concentration was higher (p = 0.136), and a significantly higher proportion of infused furosemide was excreted renally (p = 0.010). ABiC was positively correlated (r = 0.908, p = 0.017) with increase in the urine excretion to fluid input ratio after initiation of furosemide therapy. Conclusions: ABiC could serve as a marker for individual response to furosemide and could be used to generate patient-specific therapeutic regimens. In view of the relatively low number of patients in this study, the relationship between furosemide efficacy and albumin function should be investigated in larger studies in the future.

Therapeutic apheresis in sepsis.

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.

Immunoadsorption and plasmapheresis at the ICU - A description of the frequencies and indications in a single center experience and a case report.

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.

Artificial liver support in patients with liver failure: a modified DELPHI consensus of international experts.

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.

Extracorporeal immune cell therapy of sepsis: ex vivo results.

BACKGROUND: Immune cell dysfunction plays a central role in sepsis-associated immune paralysis. The transfusion of healthy donor immune cells, i.e., granulocyte concentrates (GC) potentially induces tissue damage via local effects of neutrophils. Initial clinical trials using standard donor GC in a strictly extracorporeal bioreactor system for treatment of septic shock patients already provided evidence for beneficial effects with fewer side effects, by separating patient and donor immune cells using plasma filters. In this ex vivo study, we demonstrate the functional characteristics of a simplified extracorporeal therapy system using purified granulocyte preparations. METHODS: Purified GC were used in an immune cell perfusion model prefilled with human donor plasma simulating a 6-h treatment. The extracorporeal circuit consisted of a blood circuit and a plasma circuit with 3 plasma filters (PF). PF1 is separating the plasma from the patient's blood. Plasma is then perfused through PF2 containing donor immune cells and used in a dead-end mode. The filtrated plasma is finally retransfused to the blood circuit. PF3 is included in the plasma backflow as a redundant safety measure. The donor immune cells are retained in the extracorporeal system and discarded after treatment. Phagocytosis activity, oxidative burst and cell viability as well as cytokine release and metabolic parameters of purified GCs were assessed. RESULTS: Cells were viable throughout the study period and exhibited well-preserved functionality and efficient metabolic activity. Course of lactate dehydrogenase and free hemoglobin concentration yielded no indication of cell impairment. The capability of the cells to secret various cytokines was preserved. Of particular interest is equivalence in performance of the cells on day 1 and day 3, demonstrating the sustained shelf life and performance of the immune cells in the purified GCs. CONCLUSION: Results demonstrate the suitability of a simplified extracorporeal system. Furthermore, granulocytes remain viable and highly active during a 6-h treatment even after storage for 3 days supporting the treatment of septic patients with this system in advanced clinical trials.

Phosphate restriction using a processed clay mineral reduces vascular pathologies and microalbuminuria in rats with chronic renal failure.

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.

Predictors of Delayed Graft Function in Renal Transplantation.

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.

Prolonged storage of purified granulocyte concentrates: Introduction of a new purification method.

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.

Smectite as a Preventive Oral Treatment to Reduce Clinical Symptoms of DSS Induced Colitis in Balb/c Mice.

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.

Comparison of changes in albumin binding capacity during hemodiafiltration or hemodialysis with middle cut off membranes.

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.

C-Reactive Protein Apheresis as Anti-inflammatory Therapy in Acute Myocardial Infarction: Results of the CAMI-1 Study.

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.