Safety and efficacy of the Seraph® 100 Microbind® Affinity Blood Filter to remove bacteria from the blood stream: results of the first in human study.

BACKGROUND: Bacterial burden as well as duration of bacteremia influence the outcome of patients with bloodstream infections. Promptly decreasing bacterial load in the blood by using extracorporeal devices in addition to anti-infective therapy has recently been explored. Preclinical studies with the Seraph® 100 Microbind® Affinity Blood Filter (Seraph® 100), which consists of heparin that is covalently bound to polymer beads, have demonstrated an effective binding of bacteria and viruses. Pathogens adhere to the heparin coated polymer beads in the adsorber as they would normally do to heparan sulfate on cell surfaces. Using this biomimetic principle, the Seraph® 100 could help to decrease bacterial burden in vivo. METHODS: This first in human, prospective, multicenter, non-randomized interventional study included patients with blood culture positive bloodstream infection and the need for kidney replacement therapy as an adjunctive treatment for bloodstream infections. We performed a single four-hour hemoperfusion treatment with the Seraph® 100 in conjunction with a dialysis procedure. Post procedure follow up was 14 days. RESULTS: Fifteen hemodialysis patients (3F/12 M, age 74.0 [68.0-78.5] years, dialysis vintage 28.0 [11.0-45.0] months) were enrolled. Seraph® 100 treatment started 66.4 [45.7-80.6] hours after the initial positive blood culture was drawn. During the treatment with the Seraph® 100 with a median blood flow of 285 [225-300] ml/min no device or treatment related adverse events were reported. Blood pressure and heart rate remained stable while peripheral oxygen saturation improved during the treatment from 98.0 [92.5-98.0] to 99.0 [98.0-99.5] %; p = 0.0184. Four patients still had positive blood culture at the start of Seraph® 100 treatment. In one patient blood cultures turned negative during treatment. The time to positivity (TTP) was increased between inflow and outflow blood cultures by 36 [- 7.2 to 96.3] minutes. However, overall TTP increase was not statistical significant. CONCLUSIONS: Seraph® 100 treatment was well tolerated. Adding Seraph® 100 to antibiotics early in the course of bacteremia might result in a faster resolution of bloodstream infections, which has to be evaluated in further studies. TRAIL REGISTRATION: ClinicalTrials.gov Identifier: NCT02914132 , first posted September 26, 2016.

Fosfomycin single- and multiple-dose pharmacokinetics in patients undergoing prolonged intermittent renal replacement therapy.

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

[Standardized histomorphological processing of peritoneal biopsies as part of the German Peritoneal Biopsy Registry (GRIP, German registry in PD)]. / Standardisierte histomorphologische Aufarbeitung von Peritonealbiopsien im Rahmen des Deutschen Peritonealbiopsieregisters (GRIP, German Registry In PD).

The peritoneal lining of the abdominal cavity consists of a parietal and visceral sheet. The serosa is an interesting organ, which in medical practice is particularly important in the context of chronic peritoneal dialysis (PD). This method of renal replacement therapy utilizes the semipermeability of the peritoneal surface by applying PD solutions of differing osmolarity to eliminate toxic substances and regulate fluid and electrolyte equilibrium. This method is an ideal approach especially for younger patients and is very effective at least for some time. Pre-existing injury to the peritoneum, for example as a consequence of chronic renal insufficiency or associated comorbidities and inflammatory changes that develop during PD, results in a structural remodelling of the serosa. As a consequence, the filtering function of the serosa is lost and PD has to be replaced by another renal replacement therapy. Thorough knowledge of the morphology of peritoneal changes as well as of the risk factors is of paramount importance for therapeutic management and prognosis of PD patients. In order to take this into account, the German Registry In Peritoneal Dialysis (Deutsches Peritonealbiopsieregister, GRIP) was founded a few years ago, which now includes roughly 1700 biopsies, of which detailed clinical and histomorphological information was systematically acquired and collected.

D2A sequence of the urokinase receptor induces cell growth through αvß3 integrin and EGFR.

The urokinase receptor (uPAR) stimulates cell proliferation by forming a macromolecular complex with αvß3 integrin and the epidermal growth factor receptor (EGFR, ErbB1 or HER1) that we name the uPAR proliferasome. uPAR transactivates EGFR, which in turn mediates uPAR-initiated mitogenic signal to the cell. EGFR activation and EGFR-dependent cell growth are blocked in the absence of uPAR expression or when uPAR activity is inhibited by antibodies against either uPAR or EGFR. The mitogenic sequence of uPAR corresponds to the D2A motif present in domain 2. NMR analysis revealed that D2A synthetic peptide has a particular three-dimensional structure, which is atypical for short peptides. D2A peptide is as effective as EGF in promoting EGFR phosphorylation and cell proliferation that were inhibited by AG1478, a specific inhibitor of the tyrosine kinase activity of EGFR. Both D2A and EGF failed to induce proliferation of NR6-EGFR-K721A cells expressing a kinase-defective mutant of EGFR. Moreover, D2A peptide and EGF phosphorylate ERK demonstrating the involvement of the MAP kinase signalling pathway. Altogether, this study reveals the importance of sequence D2A of uPAR, and the interdependence of uPAR and EGFR.

Therapeutic plasma exchange in a tertiary care center: 185 patients undergoing 912 treatments - a one-year retrospective analysis.

BACKGROUND: Therapeutic plasma exchange (TPE) is increasingly used throughout the world. Although the procedure itself is fairly standardized, it is yet unknown how the underlying disease entities influence the key coordinates of the treatment. METHODS: Retrospective chart review. The treatment indications were clustered into four categories. Data are presented as median and interquartile (25-75%) range [IQR]. RESULTS: Within 1 year, 912 TPE treatments were performed in 185 patients (90 female, 48.6%). The distribution of the treatment numbers to the pre-specified disease categories were as follows: transplantation (35.7%), neurology (31.9%), vasculitis and immunological disease (17.3%), and others including thrombotic microangiopathy (8.1%), critical care related diseases (5.4%), hematology [multiple myeloma] (1.1%), and endocrine disorders (0.5%). The calculated plasma volume was significantly higher in patients with vasculitis and immunological diseases (3984 [3433-4439] ml) as compared to patients treated for transplant related indications (3194 [2545-3658] ml; p = 0.0003) and neurological diseases (3058 [2533-3359] ml; p < 0.0001). This was mainly due to the differences in the hematocrit which was 30.5 [27.0-33.6] % in the vasculitis/immunological disease patients and 40.2 [37.5-42.9] % in the neurological patients; p < 0.0001. Interestingly, treatment time using a membrane based technology was significantly longer than TPE using a centrifugal device 135.0 [125.0-140.0] min vs. 120.0 [112.5-135.0] min. Furthermore, the relative exchanged plasma volume was significantly lower in the treatment of vasculitis and immunological diseases as compared to treatments of transplant related indications and neurological diseases. CONCLUSION: Patients with low hematocrit and high body weight do not receive the minimum recommended dose of exchange volume. Centrifugal TPE allowed faster plasma exchange than membrane TPE.

Removal of methadone by extended dialysis using a high cut-off dialyzer: implications for the treatment of overdose and for pain management in patients undergoing light chain removal.

The synthetic opioid methadone hydrochloride has a low molecular weight of 346 D, a high volume of distribution (4 - 7 L/kg), and is lipophilic. It is used as an analgesic and for the maintenance treatment of opiate dependence. In drug addicts, methadone is frequently involved in mixed intoxications that can lead to death. Here we present the case of a drug addict in whom a high cut-off dialysis membrane together with extended dialysis was used in the setting of suspected overdose and acute kidney injury. Although the observed dialyzer plasma clearance (31.5 mL/min) and reduction ratio (38%) were higher than previously reported for standard hemodialysis, the total amount of methadone in the spent dialysate after 1 extended dialysis session was quite low. Hence, even extended dialysis with a high cut-off membrane does not seem to offer a clinically relevant benefit in the setting of overdose for enhanced methadone removal. On the other hand, in patients undergoing high cut-off dialysis for the removal of light chains, methadone could still be used as an analgesic without an additional dose after high cut-off hemodialysis.

More Drug Monitoring and Less CT Scans of the Brain: Gabapentin Overdose in Two Peritoneal Dialysis Patients.

In parallel with the decline of renal excretory function, drug dosing of many drugs becomes more challenging. Finding the right dose is even more difficult if kidney replacement therapy is instituted. This is further aggravated by the fact that even for substances with a narrow therapeutic range, drug monitoring is only rarely offered, let alone advocated. This holds also true for gabapentin, an anticonvulsant drug that is increasingly prescribed for indications such as cancer-related pain, restless legs syndrome, migraine, or uremic pruritus. The drug is excreted unchanged in urine, so plasma clearance of gabapentin is directly proportional to creatinine clearance. Hence, renal impairment reduces gabapentin excretion and increases plasma gabapentin concentrations in a linear fashion. Therefore, the elimination half-life of gabapentin is between 5 and 9 h, in patients with normal renal function but increases to 132 h in patients on dialysis. Epidemiological data from the USRDS underline this problem. About 19% of the 140,899 adult USA patients enrolled in Medicare coverage received gabapentin in 2011. Its use was associated with an increased risk of altered mental status, fall, and fracture. We report 2 patients in which overdose of gabapentin occurred. In 1 patient, severe neurological symptoms prompted an extensive diagnostic work up, while the underlying cause of the clinical presentation was a supra-therapeutic drug level of gabapentin. Consequently, symptoms subsided with the discontinuation of the drug. Indication and drug dose of gabapentin in dialysis patients should be tightly controlled, and drug monitoring used to avoid unintended overdose.

Clearance of chloroquine and hydroxychloroquine by the Seraph® 100 Microbinda Affinity Blood Filter -a device approved for the treatment of COVID-19 patients.

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

Barriers and opportunities to increase PD incidence and prevalence: Lessons from a European Survey.

INTRODUCTION: Peritoneal dialysis (PD) remains underutilised and unplanned start of dialysis further diminishes the likelihood of patients starting on PD, although outcomes are equal to haemodialysis (HD). METHODS: A survey was sent to members of EuroPD and regional societies presenting a case vignette of a 48-year-old woman not previously known to the nephrology department and who arrives at the emergency department with established end-stage kidney disease (unplanned start), asking which dialysis modality would most likely be chosen at their respective centre. We assessed associations between the modality choices for this case vignette and centre characteristics and PD-related practices. RESULTS: Of 575 respondents, 32.8%, 32.2% and 35.0% indicated they would start unplanned PD, unplanned HD or unplanned HD with intention to educate patient on PD later, respectively. Likelihood for unplanned start of PD was only associated with quality of structure of the pre-dialysis program. Structure of pre-dialysis education program, PD program in general, likelihood to provide education on PD to unplanned starters, good collaboration with the PD access team and taking initiatives to enhance home-based therapies increased the likelihood unplanned patients would end up on PD. CONCLUSIONS: Well-structured pre-dialysis education on PD as a modality, good connections to dedicated PD catheter placement teams and additional initiatives to enhance home-based therapies are key to grow PD programs. Centres motivated to grow their PD programs seem to find solutions to do so.

Assisted peritoneal dialysis across Europe: Practice variation and factors associated with availability.

BACKGROUND: In Europe, the number of elderly end-stage kidney disease patients is increasing. Few of those patients receive peritoneal dialysis (PD), as many cannot perform PD autonomously. Assisted PD programmes are available in most European countries, but the percentage of patients receiving assisted PD varies considerably. Hence, we assessed which factors are associated with the availability of an assisted PD programme at a centre level and whether the availability of this programme is associated with proportion of home dialysis patients. METHODS: An online survey was sent to healthcare professionals of European nephrology units. After selecting one respondent per centre, the associations were explored by χ2 tests and (ordinal) logistic regression. RESULTS: In total, 609 respondents completed the survey. Subsequently, 288 respondents from individual centres were identified; 58% worked in a centre with an assisted PD programme. Factors associated with availability of an assisted PD programme were Western European and Scandinavian countries (OR: 5.73; 95% CI: 3.07-10.68), non-academic centres (OR: 2.01; 95% CI: 1.09-3.72) and centres with a dedicated team for education (OR: 2.87; 95% CI: 1.35-6.11). Most Eastern & Central European respondents reported that the proportion of incident and prevalent home dialysis patients was <10% (72% and 63%), while 27% of Scandinavian respondents reported a proportion of >30% for both incident and prevalent home dialysis patients. Availability of an assisted PD programme was associated with a higher incidence (cumulative OR: 1.91; 95% CI: 1.21-3.01) and prevalence (cumulative OR: 2.81; 95% CI: 1.76-4.47) of patients on home dialysis. CONCLUSIONS: Assisted PD was more commonly offered among non-academic centres with a dedicated team for education across Europe, especially among Western European and Scandinavian countries where higher incidence and prevalence of home dialysis patients was reported.

Elimination of Staphylococcus aureus from the bloodstream using a novel biomimetic sorbent haemoperfusion device.

Removal of bacteria from the blood by means of extracorporeal techniques has been attempted for decades. In late 2019, the European Union licensed the first ever haemoperfusion device for removal of bacteria from the blood. The active ingredient of Seraph 100 Microbind Affinity Blood Filter is ultrahigh molecular weight polyethylene beads with endpoint-attached heparin. Bacteria have been shown to bind to heparin as they would usually do to the heparan sulfate on the cell surface, thereby being removed from the blood stream. We describe the first case of a female chronic haemodialysis patient in which this device was clinically used for a Staphylococcus aureus infection that persisted for 4 days despite antibiotic therapy. After a single treatment, the bacterial load decreased and the blood cultures at the end of a 4 hour haemoperfusion exhibited no bacterial growth.

In vitro elimination of anti-infective drugs by the Seraph® 100 Microbind® affinity blood filter.

BACKGROUND: In August 2019, the European Union licensed the first ever haemoperfusion device aimed to reduce pathogens in the blood. The core of the adsorber consists of ultra-high molecular weight polyethylene beads with endpoint-attached heparin. These beads utilize pathogen inherent adhesion mechanisms to reduce pathogen load. So far, it is unknown whether the device has an effect on anti-infective drug concentrations. The aim of this study was to investigate the in vitro adsorption of multiple anti-infective drugs from human plasma. METHODS: In this in vitro study, 18 anti-infective drugs were administered to human donor plasma and pumped through the heparin-coated pathogen adsorber (Seraph® 100 Microbind®Affinity Blood Filter; ExThera Medical Corp., Martinez, CA, USA) at a plasma flow rate of 250 mL/min for 60 min. Pre- and post-adsorber plasma samples were quantified after 5, 15, 30 and 60 min. RESULTS: We found a reduction ratio (RR) in anti-infective plasma levels between -1% and 62%. This decrease occurred mainly in the first 5 min of the experiment (RR0-5 -4 to 62%). Mean plasma clearance rates ranged between -11.93 mL/min (fluconazole) and 4.86 mL/min (clindamycin). The highest RRs were measured for aminoglycosides (tobramycin 62% and gentamycin 59%). CONCLUSIONS: The elimination of anti-infective drugs by the Seraph is neglectable in all but 2 of 18 of the investigated substances. Aminoglycosides may be adsorbed by the device during their first pass.

Data on the inhibition of cell proliferation and invasion by the D2A-Ala peptide derived from the urokinase receptor.

The data presented in this article are connected to our research article entitled "D2A-Ala peptide derived from the urokinase receptor exerts anti-tumoural effects in vitro and in vivo" (Furlan et al., 2018). These data further extend our understanding of the inhibitory effects of D2A-Ala peptide. Dose-response curve using a wide range of concentrations of D2A-Ala shows that this peptide has no effects per se on proliferation of rat smooth muscle cells (RSMC). However, D2A-Ala dose-dependently inhibits epidermal growth factor (EGF)-induced RSMC proliferation. Kinetics lasting up to seven days revealed that D2A-Ala peptide completely blocked EGF-promoted RSMC proliferation. Moreover, D2A-Ala peptide inhibited invasion of HT 1080 cells towards RSMC.

Patient Perspectives on Renal Replacement Therapy Modality Choice: A Multicenter Questionnaire Study on Bioethical Dimensions.

Background:Peritoneal dialysis (PD) incidence and prevalence in Germany are low compared with hemodialysis (HD), an underachievement with multifactorial causes. Patient perspectives on renal replacement therapy (RRT) choice play a growing role in research. To date, and to the best of our knowledge, the importance of bioethical dimensions in the context of RRT choice has not been analyzed. The aim of this multicenter questionnaire study was to delineate differences in patient perspectives of PD vs HD in terms of bioethical dimensions, thus helping nephrologists target potential PD candidates more efficiently.Methods:A total of 121 stable outpatients from 2 tertiary care hospitals and 4 dialysis clinics were surveyed for bioethical dimensions ("autonomy," "beneficence," "non-maleficence," "justice," and "trust") with ranking and Likert scale items. Inclusion criteria were RRT > 3 months, age ≥ 18 years, and sufficient cognitive and language skills.Results:A surprisingly high percentage of patients felt excluded from the RRT choice process. Peritoneal dialysis patients were more critical of RRT. They used more versatile information sources on RRT, whereas HD patients were mainly informed by their nephrologist. Peritoneal dialysis patients felt more often dissatisfied with RRT than HD patients and had less trust in their co-patients. However, PD patients felt less autonomy impairment regarding body integrity, fluid balance, and dialysis in general.Conclusions:Our study demonstrates that PD patients showed more scrutiny of their situation as patients, especially their co-patients. Their treatment empowered them toward feeling more autonomous than HD patients. These new insights into patient perspectives on RRT choice might facilitate modality choice for nephrologists.

Enhanced elimination of cyclophosphamide by high cut-off haemodialysis: single-dose pharmacokinetics in a patient with cast nephropathy.

High cut-off (HCO) haemodialysis removes free light chains in patients with multiple myeloma. This is possible as HCO dialysers allow clearance of molecules up to a molecular weight of 65 kDa. In contrast, high-flux dialysers, which are used in routine haemodialysis, only remove molecules up to a molecular weight of 20 kDa. Even though patients with advanced myeloma frequently need dialysis and alkylating agents, drug dosing recommendations in this patient population are scarce at best or absent as for cyclophosphamide dosing in patients with myeloma undergoing HCO dialysis. Therefore, we aimed to determine pharmacokinetics of cyclophosphamide in a 52-year-old man (height 172 cm, weight 80 kg) with cast nephropathy. Intermittent 4-hour haemodialysis was started ~6 hours after the end of a 70 min cyclophosphamide infusion containing 1700 mg of this drug. Blood/dialysate flow rates were 300/500 mL/hour, respectively. Peak concentration of cyclophosphamide was 24.7 mg/L. Using HCO dialysis, plasma concentration of cyclophosphamide decreased from 10.8 mg/L to 3.7 mg/L during the treatment. The calculated whole blood dialyser clearance was 166 mL/min. HCO dialysis led to a marked decrease of cyclophosphamide resulting in a a 50% reduction in half-life as compared with the half-life before dialysis. This removal has to be accounted for in dosing cyclophosphamide.

D2A-Ala peptide derived from the urokinase receptor exerts anti-tumoural effects in vitro and in vivo.

D2A-Ala is a synthetic peptide that has been created by introducing mutations in the original D2A sequence, 130IQEGEEGRPKDDR142 of human urokinase receptor (uPAR). In vitro, D2A-Ala peptide displays strong anti-tumoural properties inhibiting EGF-induced chemotaxis, invasion and proliferation of a human fibrosarcoma cell line, HT 1080, and a human colorectal adenocarcinoma cell line, HT 29. D2A-Ala exerts its effects by preventing EGF receptor (EGFR) phosphorylation. To test D2A-Ala in vivo, this peptide was PEGylated generating polyethyleneglycol (PEG)-D2A-Ala peptide. PEGylation did not alter the inhibitory properties of D2A-Ala. Human tumour xenografts in the immunodeficient nude mice using HT 1080 and HT 29 cell lines showed that PEG-D2A-Ala significantly prevents tumour growth decreasing size, weight and density of tumours. The most efficient doses of the peptide were 5 and 10 mg/kg, thereby relevant for possible development of the peptide into a drug against cancer in particular tumours expressing EGFR.

Membrane versus centrifuge-based therapeutic plasma exchange: a randomized prospective crossover study.

BACKGROUND: Therapeutic plasma exchange (TPE) is either performed using a highly permeable filter with standard multifunctional renal replacement equipment (mTPE) or a centrifugation device (cTPE). Although both techniques are well established in clinical practice, performance of these two modes of TPE was never compared in a prospective randomized fashion. Thus we aimed to compare two commercially available therapeutic apheresis systems: mTPE (Octonova with Plasmaflo filter) and cTPE (Spectra Optia apheresis system). METHODS: Twenty-one patients (age 51.6 ± 13.5 years; 10 F/11 M; BMI 25.1 ± 5.0 kg/m(2)) were enrolled in this randomized, prospective, paired, crossover study performed in the Hannover Medical School, Germany. First treatment (either mTPE or cTPE) was chosen by an online randomization list. The primary endpoints were plasma removal efficiency with 1.2× of the total plasma volume exchanged. Secondary endpoints were total amount of plasma substances removed, such as IgG and fibrinogen. Further, the treatment effect on platelet count and complications were evaluated. RESULTS: Despite a comparable volume of the processed plasma, mTPE treatment time was 10.5 % longer than cTPE treatment time (p < 0.05), resulting in a 10 % lower plasma removal rate of the mTPE treatment. Both treatments were comparable in terms of decrease in median (IQR) IgG [pre-mTPE 5.34 (3.48-8.37), post-mTPE 1.96 (1.43-2.84) g/L; pre-cTPE 5.88 (3.42-8.84), post-cTPE 1.89 (1.21-3.52) g/L]. Also the median (IQR) amount of IgG removed in mTPE [13.14 (7.42-16.10) g] was not different from the cTPE treatment [9.30 (6.26-15.69) g]. This was also true for IgM removal. Platelet loss during mTPE was nearly twice as much as with cTPE (15 ± 9 versus 7 ± 9 %, p < 0.05). CONCLUSION: Although the centrifugal procedures were conducted using flow rates that could easily be obtained using peripheral access, plasma removal efficiency was significantly higher and treatment time was significantly lower in cTPE as compared to mTPE. Despite this lower treatment time, the decline in markers of procedure efficacy was comparable. Especially in centers performing many procedures per year, cTPE in contrast to mTPE can reduce treatment time without compromising treatment efficacy.

Daptomycin for a complicated urinary tract infection with vancomycin-resistant Enterococcus faecium in a renal transplant recipient.

There is an increasing prevalence of urinary tract infection (UTI) caused by multiresistant gram-negative enteric bacilli such as extended-spectrum beta-lactamase as well as Gram-positive enterococci whose vancomycin-resistance can be as high as 25%. We report on a 68-year-old Caucasian female with a UTI caused by a vancomycin-resistant Enterococcus faecium, only tested to be susceptible to gentamycin, linezolid and daptomycin. Within a day after administration of the bactericidal daptomycin clinical and laboratory signs of infection regressed and graft function recovered. Our case suggests that daptomycin might be an effective alternative for UTI caused by vancomycin-resistant enterococci.

The urokinase receptor in the central nervous system.

The urokinase receptor (uPAR) is a multifunctional glycosylphosphatidylinositol-anchored protein that regulates important processes such as gene expression, cell proliferation, adhesion, migration, invasion, and metastasis. uPAR is an essential component of the plasminogen activation cascade, a protease receptor that binds the urokinase-type plasminogen activator. uPAR is also an adhesion-modulating receptor, and a signalling receptor transmitting signals to the cell through lateral interactions with a wide array of membrane receptors. Altogether, the external ligands and membrane-bound partners of uPAR constitute a rich uPAR interactome. Recently, a new ligand of uPAR has been identified as the SRPX2 protein which is essential in language and cognitive development. SRPX2 is the second identified gene involved in language disorders. However, previous studies revealed cognitive disorders and defects in the development of the GABAergic interneurons in uPAR null mice. In addition, the expression of uPAR correlates with important human diseases such as epilepsy, autism, multiple sclerosis, Alzheimer's, AIDS dementia, cerebral malaria, and brain tumours. Therefore, uPAR has unexpectedly become a significant receptor in the central nervous system and made a few steps into philosophy. Language is indeed intimately linked to human culture. This in-depth review presents the structure and the sequences of uPAR that are essential for drug design and the generation of new inhibitors. In addition, we summarize all the inhibitors of uPAR that have been created so far. Finally, we discuss the functions of uPAR in the development, functioning, and pathology of the central nervous system.

The urokinase receptor interactome.

The urokinase receptor (uPAR) was originally identified as the membrane receptor of the serine protease urokinase (uPA), thereby implicated in the plasminogen activation cascade and regulation of pericellular proteolysis. Later on, vitronectin was showed to be another major ligand providing uPAR with a role in cell adhesion. Other unrelated ligands have been subsequently reported including for example factor XII and SRPX2 expanding the functions of uPAR to unexpected biological areas such as the initiation of the coagulation cascade or the regulation of language development. Due to its glycosylphosphatidylinositol (GPI) anchor, uPAR has no intracellular domain and thus exerts its signaling capacity through lateral interactions with other components of the plasma membrane that actually mediate uPAR-induced signals. As yet, a total 42 proteins interacting directly with uPAR can be numbered comprising 9 soluble ligands and 33 lateral partners. The fact that uPAR interacts with members of three major families of membrane receptors i.e. G protein-coupled receptors, receptor tyrosine kinases, and integrins implies that the actual number of components constituting the uPAR interacome is extremely high. For example, 156 factors belong to the integrin adhesome. Moreover, in the light of the wide diversity of the components of the uPAR interactome, uPAR appears to be an essential player of major biological systems including the blood coagulation, complement and plasma kallikrein-kinin cascades. This review describes the soluble ligands and lateral partners of the uPAR interactome, the mechanisms regulating uPAR interactions and their proved and/or potential biological functions.