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.

Treatment of the First Acute Relapse Following Therapeutic Plasma Exchange in Formerly Glucocorticosteroid-Unresponsive Multiple Sclerosis Patients-A Multicenter Study to Evaluate Glucocorticosteroid Responsiveness.

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.

AB0 incompatible kidney transplantation using unspecific immunoadsorption.

BACKGROUND: A protocol for ABO-incompatible kidney transplantation with antigen specific immunoadsorption, rituximab and conventional immunosuppression has been successfully implemented in many European centers. We report an alternative method for the elimination of isoagglutinins with a number of advantages - large amount of treatable plasma, parallel removal of other rejection-inducing antibodies, long operating life, favorable cost-benefit ratio. METHOD: We report our first successfully treated case of an ABO-incompatible living donor kidney transplantation using Immunoadsorption with Ig-TheraSorb. We performed 5 sessions preoperatively and one after transplantation. Per treatment session twice the calculated plasma volume (4400 ml in this patient) was treated. RESULTS: Per treatment session the IgM- isoagglutinin-titers were reduced from 1:16 to 1:1 and the IgG- isoagglutinin-titers from 1:32 to 1:2. There were no side effects and the procedure was well tolerated with good renal function 500 days post transplantation. CONCLUSION: Ig-TheraSorb-Immunoadsorption is an alternative method of elimination of harmful antibodies and it enables successful integration of ABO-incompatible transplantation into regular transplantation programs.

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.

Albumin-binding capacity (ABiC) is reduced in patients with chronic kidney disease along with an accumulation of protein-bound uraemic toxins.

BACKGROUND: Albumin is an important transport protein for non-water-soluble protein-bound drugs and uraemic toxins. Its transport capacity is reduced in patients with advanced chronic kidney disease (CKD) and unbound fractions of uraemic toxins are related to complications of CKD. We investigated whether this reduction could be quantified and how it correlated with the stages of CKD. Albumin-binding capacity (ABiC) is a dye-based method that quantifies the remaining binding capacity of one major binding site (site II) of the albumin molecule. METHODS: Blood samples from 104 CKD patients were incubated with a binding site-specific fluorescent marker and the amount of unbound marker was determined by means of fluorescence detection after filtration. Measurements in a pooled human plasma were used for reference. Glomerular filtration rate and serum indoxyl sulphate (IS) levels were also determined. RESULTS: Impairment of renal function was associated with a reduction in ABiC (mean ± SD: 118 ± 12; 111 ± 11; 99 ± 8 and 79 ± 9% for Stages 1/2, 3, 4 and 5, respectively; P < 0.001) and an increase in IS (3.9 ± 1.1; 6.2 ± 3.2; 16.3 ± 14.9 and 56.1 ± 28.6 µmol/L for Stages 1/2, 3, 4 and 5, respectively; P < 0.001). In dialysis patients, ABiC was lower in those with urine outputs <500 mL/day than in those with preserved urine output (73.7 ± 6.0 versus 83.8 ± 8.5%; P < 0.001). CONCLUSION: Impaired albumin function in CKD patients can be quantified, is related to severity of kidney disease and is associated with an accumulation of uraemic albumin-bound retention solutes.

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.

Industrial stabilizers caprylate and N-acetyltryptophanate reduce the efficacy of albumin in liver patients.

Liver failure is associated with an accumulation of toxic molecules that exert an affinity to albumin. Some of them have vasoactive activity. So far, albumin has been used as a plasma expander to improve the available circulating blood volume. However, recent studies have suggested that albumin is more effective than starch for this indication. It has not been reported yet whether the industrial stabilizers octanoate and N-acetyltryptophanate, added to albumin, occupy binding sites for vasoactive substances. The aim of this study was to determine whether the presence of the industrial stabilizers octanoate and caprylate has an impact on the effect of the albumin-binding function or circulating blood volume in patients with cirrhosis, portal hypertension, and an indication for albumin. In 25 patients who received albumin via an inline infusion filter that depleted stabilizers, there was an improvement of albumin binding, and there was less deterioration of circulating blood volume and renal function in comparison with a control group. Further studies are needed to confirm the results and identify the potential socioeconomic side effects of industrial stabilizers in commercial albumin solutions.

Extracorporeal cell therapy of septic shock patients with donor granulocytes: a pilot study.

INTRODUCTION: Neutrophil granulocytes are the first defense line in bacterial infections. However, granulocytes are also responsible for severe local tissue impairment. In order to use donor granulocytes, but at the same time to avoid local side effects, we developed an extracorporeal immune support system. This first-in-man study investigated whether an extracorporeal plasma treatment with a granulocyte bioreactor is tolerable in patients with septic shock. A further intention was to find suitable efficacy end-points for subsequent controlled trials. METHODS: The trial was conducted as a prospective uncontrolled clinical phase I/II study with 28-day follow-up at three university hospital intensive care units. Ten consecutive patients (five men, five women, mean age 60.3 ± 13.9 standard deviation (SD) years) with septic shock with mean ICU entrance scores of Acute Physiology and Chronic Health Evaluation (APACHE) II of 29.9 ± 7.2 and of Simplified Acute Physiology Score (SAPS) II of 66.2 ± 19.5 were treated twice within 72 hours for a mean of 342 ± 64 minutes/treatment with an extracorporeal bioreactor containing 1.41 ± 0.43 × 10E10 granulocytes from healthy donors. On average, 9.8 ± 2.3 liters separated plasma were treated by the therapeutic donor cells. Patients were followed up for 28 days. RESULTS: Tolerance and technical safety during treatment, single organ functions pre/post treatment, and hospital survival were monitored. The extracorporeal treatments were well tolerated. During the treatments, the bacterial endotoxin concentration showed significant reduction. Furthermore, noradrenaline dosage could be significantly reduced while mean arterial pressure was stable. Also, C-reactive protein, procalcitonin, and human leukocyte antigen DR (HLA-DR) showed significant improvement. Four patients died in the hospital on days 6, 9, 18 and 40. Six patients could be discharged. CONCLUSIONS: The extracorporeal treatment with donor granulocytes appeared to be well tolerated and showed promising efficacy results, encouraging further studies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00818597.

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.

Treatment of thyrotoxic crisis with plasmapheresis and single pass albumin dialysis: a case report.

Thyrotoxic crisis (thyroid storm) is a life-threatening condition. Standard therapy is based on thiamazole, prednisolone, and nonselective beta-blockers. Extracorporeal plasmapheresis is an additional tool for removing circulating thyroxine in patients who do not respond quickly to conventional standard therapy. As thyroxine can be bound by albumin, the aims of the present therapy report were to investigate the potential of extracorporeal single-pass albumin dialysis (SPAD) to remove thyroid hormones and to compare it with plasmapheresis. A 68-year-old female with thyrotoxic crisis refractory to conventional therapy underwent two sessions of plasmapheresis without clinical response. For the treatment dose to be increased, the patient was then treated with a modified continuous veno-venous hemodialysis with a dialysate containing 4% of human serum albumin (SPAD) intended to bind and remove thyroxines continuously. In total, the patient received three sessions of plasmapheresis and four SPAD treatments. Thyroxine levels were detected in the patient and in exchanged plasma or albumin dialysate, respectively, to calculate the amount removed. The main finding was that SPAD treatments were tolerated well by the patient. Due to continuous approach, SPAD sessions removed more thyroid hormone than plasmapheresis did, resulting in the improvement of the clinical status of the patient (reduction of heart rate and catecholamine dosage), which enabled bridging the patient to thyroidectomy as the ultimate surgical treatment. This is the first clinical report of the use of albumin dialysis in thyroid storm. SPAD represents a safe and efficient alternative to plasmapheresis as it can be performed continuously in this critical condition.

Giant brachial artery aneurysm as a rare complication of a dialysis shunt.

Our patient exhibited a large tumor on his right upper arm where his former dialysis access site had been. X-ray, Doppler ultrasound, and magnetic resonance imaging scan could not fully reveal the nature of that tumor. Eventually, a surgical approach showed a giant aneurysm of the inflowing brachial artery to a partially obliterated arteriovenous fistula. This case highlights the importance of ongoing care for patients with arteriovenous shunts. Even arteriovenous fistulas, that are obliterated or no longer in use, can, especially when immunosuppressant therapy and other vascular risk factors are added to the overall cardiovascular risk, transform and endanger the health of our patients.

Biocompatibility assessment of peritoneal dialysis solutions with a new in vitro model of preconditioned human HL60 cells.

The purposes of this study were to test the human promyelocytic cell line HL60 for its usability as a new cell model for the immune barrier of the peritoneum, and to investigate the impact of different peritoneal dialysis (PD) solutions in the model. HL60 cells were stimulated by retinoic acid and recombinant human granulocyte and macrophage colony-stimulating factor to differentiate into neutrophilic granulocytes. Cells were incubated in different commercially available PD solutions. After a 4-h incubation, functional (chemiluminescence phagocytosis) and viability tests (Live-Dead, XTT) were performed. High glucose concentrations (>1.36%) and low pH values (<7.0) appeared to be detrimental for neutrophil functions and for neutrophil viability. There is a quantitative correlation between glucose concentration and the cytotoxicity of standard PD solutions (PD 1.36% glucose shows 42.6% higher chemiluminescence than PD 3.86% glucose [P < 0.05]). PD solution containing icodextrin shows 74.3% higher chemiluminescence than PD 3.86% glucose, and PD solution with amino acids shows 52.4% higher chemiluminescence than PD 3.86% glucose which is a sign for better biocompatibility in these tests (P < 0.05). The test system is useful for biocompatibility investigations of PD solutions and their effect on immune cells, for example, neutrophil granulocytes. It does not depend on donor variability and availability in comparison to models based on primary isolated leukocytes.

Cytokine adsorption is a promising tool in the therapy of hemophagocytic lymphohistiocytosis.

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.

High Pneumocystis jirovecii colonization rate among haemodialysis patients.

Haemodialysis patients have been found to have an increased risk of developing Pneumocystis pneumonia (PcP) compared to the control population. To the best of our knowledge, no data are available on pulmonary colonization with Pneumocystis jirovecii in haemodialysis patients; therefore, the aim of this study was to determine the prevalence of pulmonary colonization with P. jirovecii in haemodialysis patients, and to find the related risk factors. Induced sputa of 62 haemodialysis patients were investigated using quantitative polymerase chain reaction for the presence of P. jirovecii. 20.9% of the patients were colonized with P. jirovecii and 46.2% of whom had CD4 cell counts below 400/µl. There was no significant correlation between colonization and time on dialysis treatment. As haemodialysis patients seem to be at higher risk of PcP than the general population, doctors should be aware of the high rate of P. jirovecii colonization amongst them. Furthermore, colonized patients remain a potential source of transmission of P. jirovecii to other patients or to health care workers.

Response to Therapeutic Plasma Exchange as a Rescue Treatment in Clinically Isolated Syndromes and Acute Worsening of Multiple Sclerosis: A Retrospective Analysis of 90 Patients.

OBJECTIVES: Experience with therapeutic plasma exchange (TPE) for acute relapses in clinically isolated syndrome (CIS) or multiple sclerosis (MS) patients has been derived from small and inhomogeneous patient populations so far. In the present study, we retrospectively evaluated features associated with TPE response in a larger cohort of CIS and MS patients with acute worsening of disease. PARTICIPANTS: Ninety CIS and MS patients with acute relapses or acute worsening of symptoms were firstly treated with TPE. The population consisted of 62 women and 28 men with a median age of 38 years (range 18-69 years). OUTCOME MEASURES: Primary endpoint was the clinical response to TPE, focused on the functional improvement of the target neurologic deficit. Secondary endpoint was an improvement in expanded disability status scale (EDSS) scoring. RESULTS: A clinical response to TPE was observed in 65 out of 90 patients (72.2%), with marked improvement in 18 (20.0%) and moderate improvement in 47 out of 90 patients (52.2%). The median EDSS was reduced from 3.75 before to 3.0 after TPE (p = 0.001). Response to TPE was significantly more frequent in patients with relapsing courses of disease (CIS, RR-MS, p = 0.001), no disease modifying drugs (p = 0.017), gadolinium-positive (Gd+) MRI lesions (p = 0.001) and EDSS ≤ 5.0 before TPE (p = 0.014). In the multiple logistic regression analysis only the detection of Gd+ MRI lesions was significantly altered (p = 0.004). CONCLUSION: Clinical response to TPE was achieved in the majority of our patients. We identified clinical and diagnostic features in CIS and MS relapses that might be helpful to identify patients responding to TPE. Gd+ MRI lesions before treatment were the best predictor of the response to TPE in our cohort.

Therapeutic plasma exchange in glucocorticosteroid-unresponsive patients with Clinically Isolated Syndrome.

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.