Extracorporeal removal of per- and polyfluoroalkyl substances (PFAS) by hemoadsorption: in vitro kinetic model.

INTRODUCTION: Per- and polyfluoroalkyl substances (PFAS) are known water pollutants leading to potential public health consequences. High blood levels of PFAS have been associated with several pathological conditions including testicular and kidney cancer. Classic extracorporeal therapies have demonstrated limited efficiency and new approaches should be explored. In this study we studied the possible role of hemoadsorption to achieve a fast, safe and effective removal of PFAS from blood in patients with high blood levels. METHODS: We developed an in vitro model of hemoadsorption to test the potential of PFAS removal by extracorporeal treatment. We recirculated a highly polluted batch of water (4 liters) through a sorbent cartridge (Jafron medical, Zuhai, China) for 120 minutes at a flow of 150 mL/min. We collected samples at different time points and analyzed 39 different PFAS compounds. RESULTS: For the PFAS compounds with concentrations significantly above normal, we observed a removal ratio close to 90% already within the first 60 minutes of circulation leading to almost complete elimination of all pollutants at 120 minutes. CONCLUSIONS: The in vitro model of hemoadsorption suggests the possible application in vivo of this technique to reduce/normalize the concentrations of PFAS in patients exposed to water or environmental pollution.

Adsorption Mass Transfer Zone of Vancomycin in Cartridges With Styrene-Divinylbenzene Sorbent.

Cartridges for hemoadsorption containing styrene-divinylbenzene sorbent are used for multiple conditions, such as intoxication. The mass transfer zone comprises the extension along the longitudinal span of the cartridge where adsorption occurs. The aim of this experiment is to evaluate the mass transfer zone for vancomycin in the HA380 cartridge. The experiment was carried out twice. A saline solution with vancomycin passed through a HA380-modified cartridge at 100 ml/min in a single-pass fashion. The cartridge had four openings along its longitudinal dimension, at 3, 6, 9, and 12 cm. In both experiments, the collection of aliquots occurred at minute 4, in the four openings and pre- and post-cartridge, and an additional sample from the effluent bag at the end of each experiment. In the second experiment, an additional sampling of the same six sites occurred at minute 14. The sigmoidal shape of the curve for the mass transfer zone of vancomycin was similar to the theoretical one. In experiment one, at minute 4, vancomycin clearance was 98.75 ml/min. In experiment two, vancomycin clearance at minutes 4 and 14 was 93.76 and 93.20 ml/min, respectively. This implies an adequate and optimal design of the HA380 cartridge.

EFFECT OF MECHANICAL VIBRATION ON KINETICS OF SOLUTE ADSORPTION.

INTRODUCTION Hemoadsorption with new sorbent cartridges is an emerging extracorporeal blood purification technique. Flow distribution inside the sorbent is one of the main issues concerning the device's performance and optimal sorbent utilization. In this experiment, we aimed to investigate the efficacy of vibration during adsorption by measuring the removal of Vancomycin. METHODS In this experimental study, 1,000 mL of saline with 10 g of Vancomycin was circulated in a closed circuit (set flow of 250 mL/min) simulating a hemoadsorption blood run using HA380 minimodule cartridge containing 75 g of wet resin. This vibration model was implemented with a damping head device installed in front of the adsorption cartridge during the experiment. The kinetics of the Vancomycin were assessed by removal ratio over 120 minutes. RESULTS We found no difference between the two models. Adsorption with and without vibration did not differ significantly for partial reduction ratios, overall amount of adsorbed molecule, or adsorption kinetics. CONCLUSION The current design and structure of the minimodule cartridge demonstrated no difference in small-middle solute removal. Further improvement with the addition of mechanical vibration to the device was not observed.

Neutrophil Gelatinase-Associated Lipocalin in Peritoneal Dialysis-Related Peritonitis: Correlation with White Blood Cells over Time and a Possible Role as the Outcome Predictor.

INTRODUCTION: The present study aimed to monitor peritoneal neutrophil gelatinase-associated lipocalin (pNGAL) during peritonitis episodes and to enhance its diagnostic value by evaluating pNGAL at scheduled times in parallel with white blood cell (WBC) count. In addition, we investigated possible correlations between pNGAL and the etiology of peritonitis, evaluating it as a possible marker of the clinical outcome. METHODS: Twenty-two patients with peritoneal dialysis (PD)-related peritonitis were enrolled. Peritonitis was divided into Gram-positive, Gram-negative, polymicrobial, and sterile. WBC count and neutrophil gelatinase-associated lipocalin (NGAL) in PD effluent were measured at different times (days 0, 1, 5, 10, 15, and/or 20 and 10 days after antibiotic therapy discontinuation). NGAL was measured by standard quantitative laboratory-based immunoassay and by colorimetric NGAL dipstick (NGALds) (dipstick test). RESULTS: We found strong correlations between peritoneal WBC, laboratory-based NGAL, and NGALds values, both overall and separated at each time point. On day 1, we observed no significant difference in WBC, both NGALds (p = 0.3, 0.9, and 0.2) between Gram-positive, Gram-negative, polymicrobial, and sterile peritonitis. No significant difference has been found between de novo versus relapsing peritonitis for all markers (p > 0.05). We observed a parallel decrease of WBC and both NGAL in patients with favorable outcomes. WBC count and both pNGAL resulted higher in patients with negative outcomes (defined as relapsing peritonitis, peritonitis-associated catheter removal, peritonitis-associated hemodialysis transfer, peritonitis-associated death) at day 10 (p = 0.04, p = 0.03, and p = 0.05, respectively) and day 15 (p = 0.01, p = 0.04, and tendency for p = 0.005). There was a tendency toward higher levels of WBC and NGAL in patients with a negative outcome at day 5. No significant difference in all parameters was proven at day 1 (p = 0.3, p = 0.9, p = 0.2) between groups. CONCLUSION: This study confirms pNGAL as a valid and reliable biomarker for the diagnosis of PD-peritonitis and its monitoring. Its trend is parallel to WBC count during peritonitis episodes, in particular, patients with unfavorable outcomes.

Sorbent functionalization with vancomycin enhances bacteria killing in extracorporeal hemoadsorption.

BACKGROUND: The level of bacteremia in patients with sepsis and septic shock is a predictor of complications and mortality, regardless of the type of bacteria. Devices for bacteria, endotoxin and cytokines removal by adsorption have been recently developed. Thus, extracorporeal blood purification therapies have been proposed as adjunctive therapy in sepsis in combination with drugs. Some potentially useful drugs, however, are precluded due to their organ or metabolic toxicity. The present study represents a preliminary report on the in vitro effect of a sorbent device (minimodule with HA380 beads, Jafron medical, Zhuhai, China) in which the particles have been functionalized with vancomycin on the surface. The impact of the surface-modified beads on circulating bacteria (Staphylococcus aureus) has been tested in a simulated in vitro circulation. METHODS: In vitro experiments were carried out with 800 mL of blood enriched with S. aureus species. Blood was circulated in the vancomycin-functionalized and non-functionalized mini-module cartridges in hemoadsorption setup (300 mL each) and the bactericidal effect was assessed. Also, 200 mL of blood was used as a control. RESULTS: A significant increase in the time to positivity of blood cultures was observed after 60 min and also after 120 min of therapy with the mini-module functionalized with vancomycin as opposed to the non-functionalized cartridge. CONCLUSIONS: These results suggest a possible way of treating sepsis by using drug- or antibiotic-functionalized cartridges without worrying about pharmacological toxicity. The prolongation of the time to bacterial culture positivity to S. aureus after a passage through a column packed with beads functionalized with vancomycin represents a proof of concept.

Endotoxin removal therapy with Polymyxin B immobilized fiber column: a single center experience from EUPHAS2 registry.

Although the precise clinical indication for initiation of PMX-HA is widely debated in the literature, a proper patient selection and timing of treatment delivery might play a critical role in the clinical course of a specific subphenotype of septic shock (endotoxic shock). In light of this view, since 2019, we have introduced in our clinical practice a diagnostic-therapeutic flowchart to select patients that can benefit the most from the treatment proposed. In addition, we reported in this study our experience of PMX-HA in a cohort of critically ill patients admitted to our intensive care unit (ICU). We analyzed a single centre, retrospective, observational web-based database (extracted from the EUPHAS2 registry) of critically ill patients admitted to the ICU between January 2016 and May 2021 who were affected by endotoxic shock. Patients were divided according to the diagnostic-therapeutic flowchart in two groups: Pre-Flowchart (Pre-F) and Post-Flowchart (Post-F). From January 2016 to May 2021, 61 patients were treated with PMX-HA out of 531 patients diagnosed with septic shock and of these, fifty patients (82%) developed AKI during their ICU stay. The most common source of infection was secondary peritonitis (36%), followed by community-acquired pneumonia (29%). Fifty-five (90%) out of 61 patients received a second PMX-HA treatment, with a statistically significant difference between the two groups (78% of the Pre-F vs. 100% of the Post-F group, p = 0.005). In both groups, between T0 and T120, the Endotoxin Activity Assay (EAA) decreased, while the SOFA score, mean arterial pressure (MAP), and Vasoactive Inotropic Score (VIS) improved with no statistically significant difference. Furthermore, when performing a propensity score matching analysis to compare mortality between the two groups, statistically significant lower ICU and 90-day mortalities were observed in the Post-F group [p = 0.016]. Although in this experienced centre data registry, PMX-HA was associated with organ function recovery, hemodynamic improvement, and current EAA level reduction in critically ill patients with endotoxic shock. Following propensity score-matched analysis, ICU mortality and 90-day mortalities were lower in the diagnostic-therapeutic flowchart group when considering two temporal groups based on strict patient selection criteria and timing to achieve PMX. Further Randomised Control Trials focused on centre selection, adequate training and a flowchart of action when assessing extracorporeal blood purification use should be performed.

The Cytotoxic Effect of Septic Plasma on Healthy RBCs: Is Eryptosis a New Mechanism for Sepsis?

Sepsis is a life-threatening multiple-organ dysfunction induced by infection and is one of the leading causes of mortality and critical illness worldwide. The pathogenesis of sepsis involves the alteration of several biochemical pathways such as immune response, coagulation, dysfunction of endothelium and tissue damage through cellular death and/or apoptosis. Recently, in vitro and in vivo studies reported changes in the morphology and in the shape of human red blood cells (RBCs) causing erythrocyte death (eryptosis) during sepsis. Characteristics of eryptosis include cell shrinkage, membrane blebbing, and surface exposure to phosphatidylserine (PS), which attract macrophages. The aim of this study was to evaluate the in vitro induction of eryptosis on healthy RBCs exposed to septic plasma at different time points. Furthermore, we preliminary investigated the in vivo levels of eryptosis in septic patients and its relationship with Endotoxin Activity Assay (EAA), mortality and other biological markers of inflammation and oxidative stress. We enrolled 16 septic patients and 16 healthy subjects (no systemic inflammation in the last 3 months) as a control group. At diagnosis, we measured Interleukin-6 (IL-6) and Myeloperoxidase (MPO). For in vitro study, healthy RBCs were exposed to the plasma of septic patients and CTR for 15 min, 1, 2, 4 and 24 h. Morphological markers of death and eryptosis were evaluated by flow cytometric analyses. The cytotoxic effect of septic plasma on RBCs was studied in vitro at 15 min, 1, 2, 4 and 24 h. Healthy RBCs incubated with plasma from septic patients went through significant morphological changes and eryptosis compared to those exposed to plasma from the control group at all time points (all, p < 0.001). IL-6 and MPO levels were significantly higher in septic patients than in controls (both, p < 0.001). The percentage of AnnexinV-binding RBCs was significantly higher in septic patients with EAA level ≥0.60 (positive EAA: 32.4%, IQR 27.6-36.2) compared to septic patients with EAA level <0.60 (negative EAA: 14.7%, IQR 5.7-30.7) (p = 0.04). Significant correlations were observed between eryptosis and EAA levels (Spearman rho2 = 0.50, p < 0.05), IL-6 (Spearman rho2 = 0.61, p < 0.05) and MPO (Spearman rho2 = 0.70, p < 0.05). In conclusion, we observed a quick and great cytotoxic effect of septic plasma on healthy RBCs and a strong correlation with other biomarkers of severity of sepsis. Based on these results, we confirmed the pathological role of eryptosis in sepsis and we hypothesized its use as a biomarker of sepsis, potentially helping physicians to face important treatment decisions.

Plasma Cell-Free DNA and Caspase-3 Levels in Patients with Chronic Kidney Disease.

BACKGROUND: Cell-free plasma DNA (cfDNA) is circulating extracellular DNA arising from cell death mechanisms (apoptosis, necrosis, etc.). It is commonly existent in healthy individuals, but its ranks increase in diverse clinical circumstances, such as kidney disease, sepsis, myocardial infarction, trauma and cancer. In patients with advanced chronic kidney disease, cfDNA is connected to inflammation, and it has been associated with higher mortality. Caspase-3 plays a dominant role in apoptosis, a mechanism of programmed cell death involved in the pathogenesis and progression of chronic kidney disease (CKD). The aim of this pilot study was the evaluation of cfDNA levels and caspase-3 concentrations in patients with chronic kidney disease, in order to investigate the potential role of these molecules, deriving from inflammatory and apoptotic mechanisms, in the progression of renal damage. METHODS: We compared cfDNA and caspase-3 levels in 25 CKD patients and in 10 healthy subjects, evaluating their levels based on CKD stage. We also explored correlations between cfDNA and caspase-3 levels in CKD patients and between cfDNA and caspase-3 levels and serum creatinine and urea in this population. RESULTS: We observed that cfDNA and caspase-3 levels were higher in patients with CKD compared to healthy subjects, in particular in patients with advanced renal disease (CKD stage 5). A positive correlation between cfDNA and caspase-3 levels and between cfDNA and caspase-3 and creatinine and urea were also noticed. CONCLUSIONS: Patients with chronic kidney disease show higher levels of cfDNA and caspase-3 levels compared to the control group. Based on these preliminary results, we speculated that the worsening of renal damage and the increase in uremic toxin concentration could be associated with higher levels of cfDNA and caspase-3 levels, thus reflecting the potential role of inflammation and apoptosis in the progression of CKD. Future studies should focus on the validation of these promising preliminary results.

Extracorporeal therapy in the treatment of sepsis: In vitro assessment of the effect of an absorbent cartridge on the circulating bacterial concentration and its interaction with the antibiotic therapy.

Sepsis is one of the major causes of death worldwide. In its physiopathological process, a broad spectrum of pro and antiinflammatory mediators plays a strategic role, leading to a sepsis induced state of immunoparalysis. The rationale behind the employment of extracorporeal purification techniques as a complement to therapy for sepsis is based on their ability to remove the mediators involved. Until now, attention was focused on the immunomodulation allowed by purification therapies. However, the focus of studies on the application possibilities that these techniques offer as a supplement to antimicrobial therapy and resuscitation of critically ill patients must be extended. In this study, the possible removal by adsorption that the Jafron® HA330 cartridge operates against bacteria (S. aureus) was evaluated in vitro. Subsequently, it was evaluated whether the adsorptive capabilities toward bacteria were maintained by using a cartridge functionalized with Vancomycin and whether the latter maintains its bactericidal activity. This study showed that HA330 reduces the circulating bacterial load, even in the presence of pre-adsorbed Vancomycin. Vancomycin, once adsorbed by the cartridge, does not guarantee its bactericidal activity during the 2-h of hemoperfusion treatment.

Bilirubin Removal by Plasmafiltration-Adsorption: Ex vivo Adsorption Kinetics Model and Single Case Report.

BACKGROUND: Extracorporeal removal of bilirubin in patients with severe liver dysfunction is a key blood purification strategy. We conducted an ex vivo study to assess the quantitative capacity to remove bilirubin from plasma of a novel adsorptive cartridge. METHODS: We studied a downscaled module of the BS330 Plasma Bilirubin Adsorption Column Cartridge (Jafron Biomedical, Zhuhai City, China) to minimize the plasma requirement in an ex vivo circulation using a solution of hyperbilirubinemic plasma. We measured the bilirubin concentration gap (ΔC) between inlet (Cpin) and outlet (Cpout) of the unit and we calculated the removal ratio (RR) as mass adsorbed at different time points. Moreover, we compared the ex vivo model with the bilirubin adsorption kinetics in a patient with acute on chronic liver failure treated with the BS330 cartridge. RESULTS: Bilirubin concentration change across the cartridge at 30 min was 16.5%, and cartridge saturation was reached at 750 min. We used a minimodule downscaled to 1:3 and containing approximately 131 g of BS330 sorbent beads: the device retained 759 mg of bilirubin with a RR of 78.1% and a RR of 42.6% at 120 min. Thus, the adsorption capacity was 5.76 mg of bilirubin per gram of sorbent. Bilirubin adsorption kinetics in our clinical case with a full-scale unit shows a coherent trend with a total bilirubin mass adsorbed after 180 min of 470 mg. DISCUSSION: Our findings provide the first assessment of bilirubin adsorption in an ex vivo model of plasma perfusion and can be used to design interventional studies in humans, providing guidance for an adequate prescription of treatment frequency and duration.

Vancomycin Adsorption during in vitro Model of Hemoperfusion with Mini-Module of HA380 Cartridge.

INTRODUCTION: Sepsis is a frequent complication in critically ill patients. Patients may require control of the source of infection, removal of pathogens and damaged cells, and organ support. Often, these targets can be achieved through the utilization of extracorporeal therapies including hemoperfusion for the adsorption of cytokines and other circulating mediators. On extracorporeal organ support, patients are generally treated with antibiotic therapy, and vancomycin is one of the most commonly used antibiotics. Because of the aspecific nature of adsorption, antibiotics can be removed from the circulation, leading to altered plasma levels and requiring prescription adjustment. The aim was to define the amount of vancomycin adsorbed by a sorbent cartridge (HA380, Jafron, China) during hemoperfusion and to establish possible strategies to maintain an effective plasma level in critically ill patients undergoing extracorporeal therapies. METHODS: In vitro experiments with incremental concentrations of vancomycin in the test solution (500 and 1,000 mL) were carried out in a recirculation circuit until sorbent saturation was observed. A maximum of 10 g of vancomycin were injected and mini-modules containing 25 g of dry resin were utilized. RESULTS: In different experiments with various concentration of vancomycin, a maximum amount of 244 mg/g of sorbent was adsorbed reaching saturation between 60 and 80 min from the beginning of the experiments. The kinetics of adsorption appears to be governed by a Langmuir-like isotherm with maximal removal speed in the early minutes and a plateau after 60 min. DISCUSSION/CONCLUSION: HA380 adsorbs significant amounts of vancomycin. Adjusting the achieved results with the experimental mini-module to a full-scale cartridge, a total of 25 g of antibiotic can be removed. This might have affected outcome results in clinical trials. This suggests prescribing administration to critically ill patients requiring hemoperfusion, immediately after or in the inter-session time window. In case of administration during hemoperfusion, adequate adjustment and plasma level monitoring is strongly recommended.

Incidence of Acute Kidney Injury in Polytrauma Patients and Predictive Performance of TIMP2 × IGFBP7 Biomarkers for Early Identification of Acute Kidney Injury.

Background: Acute kidney injury (AKI) is a common cause of organ failure in trauma patients who survive their initial injuries. It is independently associated with increased morbidity and mortality and prolongs the length of hospital stays. The objectives of this study were to describe the incidence of early AKI and influence of risk factors in polytrauma patients and evaluate the predictive potential of TIMP2 × IGFBP7 biomarkers in this patient cohort. Methods: We conducted a retrospective cohort study of severely injured adult patients who were consecutively admitted to a multidisciplinary ICU from May 2017 to May 2019. Detailed patient data was retrieved from ICU medical records. Fluid balance, urinary output, and sCr values up to 72 h were collected. Urine samples for measuring TIMP2 × IGFBP7 concentrations were obtained and analyzed from ICU admission to 72 h. Results: Among the 153 patients eligible for analysis, 45 were included in the AKI, and 108 in the no AKI cohorts. The incidence of AKI within 72 h, based on KDIGO criteria, was 28.8%. There were no differences in ISS, type and mechanism of injury, heart rate, and systolic BP at admission between groups. Patients with early AKI were older (68 vs. 49 years, p < 0.001), obese (BMI 26.2 vs. 24.7, p < 0.048), and more likely to have previous cardiac disease (27% vs. 5.6%, p < 0.001). TIMP2 × IGFBP7 values on ICU admission were associated with subsequent AKI in patients without evidence of AKI at the time of ICU admission. They were also higher in the AKI cohort and significantly correlated with renal replacement therapy (RRT) and episodes of hypotension. Multivariable analysis confirmed age, previous cardiac disease, and NephroCheck as the variables mostly associated with AKI, with AUC 0.792. Conclusions: TIMP2 × IGFBP7 may help identify trauma patients with tubular damage that may evolve into a clinically manifested syndrome. Prospective studies of TIMP2 × IGFBP7, as a trigger for early AKI bundle care, are warranted.

Clinical Assessment of Continuous Hemodialysis with the Medium Cutoff EMiC®2 Membrane in Patients with Septic Shock.

INTRODUCTION: At the time of renal replacement therapy, approximately 20% of critically ill patients have septic shock. In this study, medium cutoff (MCO) continuous venovenous hemodialysis (CVVHD) was compared to high-flux membrane continuous venovenous hemodiafiltration (CVVHDF) in terms of hemodynamic improvement, efficiency, middle molecule removal, and inflammatory system activation. METHODS: This is a monocenter crossover randomized study. Between December 31, 2017, and December 31, 2019, 20 patients with septic shock and stage 3 acute kidney injury (AKI) admitted to 2 Italian ICUs were enrolled. All patients underwent CVVHD with Ultraflux® EMiC®2 and CVVHDF with AV1000S® without washout. Each treatment lasted 24 h. RESULTS: Compared to AV1000S®-CVVHDF, EMIC®2-CVVHD normalized cardiac index (ß = -0.64; p = 0.02) and heart rate (ß = 5.72; p = 0.01). Interleukin-8 and myeloperoxidase removal were greater with AV1000S®-CVVHDF than with EMiC®2-CVVHD (ß = 0.35; p < 0.001; ß = 0.43; p = 0.03, respectively). Leukocytosis improved over 24 h in EMiC®2-CVVHD-treated patients (ß = 4.13; p = 0.03), whereas procalcitonin levels decreased regardless of the modality (ß = 0.89; p = 0.01) over a 48-h treatment period. Reduction rates, instantaneous plasmatic clearance of urea, creatinine, and ß2-microglobulin were similar across modalities. ß2-Microglobulin removal efficacy was greater in the EMiC®2 group (ß = 0-2.88; p = 0.002), while albumin levels did not differ. Albumin was undetectable in the effluent in both treatments. DISCUSSION: In patients with septic shock and severe AKI, the efficacy of uremic toxin removal was comparable between MCO-CVVHD and CVVHDF. Further, MCO-CVVHD was associated with improved hemodynamics. Fraction of filtration and transmembrane pressure reduction and the maintenance of equal efficacy might be the key features of CVVHD with MCO membranes in critically ill patients.

Electrospun Chitosan Functionalized with C12, C14 or C16 Tails for Blood-Contacting Medical Devices.

Medical applications stimulate the need for materials with broad potential. Chitosan, the partially deacetylated derivative of chitin, offers many interesting characteristics, such as biocompatibility and chemical derivatization possibility. In the present study, porous scaffolds composed of electrospun interwoven nanometric fibers are produced using chitosan or chitosan functionalized with aliphatic chains of twelve, fourteen or sixteen methylene groups. The scaffolds were thoroughly characterized by SEM and XPS. The length of the aliphatic tail influenced the physico-chemical and dynamic mechanical properties of the functionalized chitosan. The electrospun membranes revealed no interaction of Gram+ or Gram- bacteria, resulting in neither antibacterial nor bactericidal, but constitutively sterile. The electrospun scaffolds demonstrated the absence of cytotoxicity, inflammation response, and eryptosis. These results open the door to their application for blood purification devices, hemodialysis membranes, and vascular grafts.

Endotoxin in Sepsis: Methods for LPS Detection and the Use of Omics Techniques.

Lipopolysaccharide (LPS) or endotoxin, the major cell wall component of Gram-negative bacteria, plays a pivotal role in the pathogenesis of sepsis. It is able to activate the host defense system through interaction with Toll-like receptor 4, thus triggering pro-inflammatory mechanisms. A large amount of LPS induces inappropriate activation of the immune system, triggering an exaggerated inflammatory response and consequent extensive organ injury, providing the basis of sepsis damage. In this review, we will briefly describe endotoxin's molecular structure and its main pathogenetic action during sepsis. In addition, we will summarize the main different available methods for endotoxin detection with a special focus on the wider spectrum offered by omics technologies (genomics, transcriptomics, proteomics, and metabolomics) and promising applications of these in the identification of specific biomarkers for sepsis.

Flow Dynamic Analysis by Contrast-Enhanced Imaging Techniques of Medium Cutoff Membrane Hemodialyzer.

INTRODUCTION: Medium cutoff (MCO) membranes represent an interesting innovation in the field of hemodialysis. Given the correlation between large (PM >25 kDa) middle molecules (LMM) and clinical outcomes, the possibility to broaden the spectrum of solutes removed in hemodialysis with MCO membranes introduces a new perspective for end-stage kidney disease patients. Due to low diffusion coefficients of LMM, the use of convection is required to maximize extracorporeal clearance. High convective rates are achieved with high-flux membranes in hemodiafiltration, a technique not available in the US. In case of the MCO membrane, remarkable clearances of LMM are achieved combining the permeability of the membrane with a significant amount of internal convection. The mechanism of filtration-backfiltration inside the dialyzer enables effective removal of LMM in a technique called expanded hemodialysis (HDx). Given such theoretical explanation, it is important to demonstrate the blood and ultrafiltration rheology inside the MCO dialyzer. METHOD: This study for the first time describes flow dynamic parameters and internal cross-filtration, thanks to specific radiology and nuclear imaging techniques. RESULTS: Flow dynamic analysis of the blood and dialysate compartment confirms excellent distribution of velocities and an excellent matching of blood and dialysate. Average blood flow velocity allows for wall shear rates adequate to avoid protein stagnation at the blood membrane interface and increase in blood viscosity. Cross-filtration analysis demonstrates a remarkable filtration/backfiltration flux reaching values >30 mL/min at a blood flow of 300 mL/min and zero net filtration. CONCLUSION: The MCO dialyzer Theranova 400 appears to have a design optimized to perform expanded hemodialysis (HDx).

Ultrasonographic Intraparenchymal Renal Resistive Index Variation for Assessing Renal Functional Reserve in Patients Scheduled for Cardiac Surgery: A Pilot Study.

INTRODUCTION: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common complication in patients undergoing cardiac surgery. Preoperative renal functional reserve (RFR) has been demonstrated to be highly predictive of CSA-AKI. We have previously demonstrated that intraparenchymal renal resistive index variation (IRRIV) measured by ultrasound (US) can identify the presence of RFR in healthy individuals. This study aimed (1) to examine the correlation between the US IRRIV test and RFR measured through the protein loading test in patients undergoing elective cardiac surgery and (2) to determine the value of the 2 methods for predicting occurrence of AKI or subclinical AKI after cardiac surgery. METHODS: Consecutive patients scheduled for cardiac surgery were enrolled for this pilot study. The protein loading test and the IRRIV test were performed in all patients 2 days before cardiac surgery. Correlation between IRRIV and RFR was tested using Pearson correlation analysis. Association between presence of RFR and positive IRRIV test, presence of RFR and AKI and subclinical AKI, and positive IRRIV test and AKI and subclinical AKI was evaluated using logistic regression analysis. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the values of IRRIV for predicting RFR, RFR for predicting AKI and subclinical AKI, and IRRIV for predicting AKI and subclinical AKI. RESULTS: Among the 31 patients enrolled, significant association was found between IRRIV and RFR (r = 0.81; 95% CI: 0.63-0.90; p < 0.01). The association between RFR and IRRIV was described in 27/31 (87.1%) patients. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the IRRIV test were 100, 84, 60, and 100%, respectively. In ROC curve analysis, the area under the curve (AUC) was 0.80 (95% CI: 0.64-0.96). After cardiac surgery, 1/31 (3.2%) patient had AKI and 12/31 (38.7%) had subclinical AKI. RFR predicted subclinical AKI (odds ratio [OR] = 0.93; 95% CI: 0.87-0.98; p = 0.02). The sensitivity, specificity, PPV, and NPV of the RFR were 61, 88.8, 80, and 76%, respectively; the AUC was 0.75 (95% CI: 0.59-0.91). IRRIV predicts subclinical AKI (OR = 0.79; 95% CI: 0.67-0.93; p = 0.005). The sensitivity, specificity, PPV, and NPV of the IRRIV test were 46.1, 100, 100, and 72%, respectively; the AUC was 0.73 (95% CI: 0.58-0.87). CONCLUSION: This pilot study suggests that a positive IRRIV test can significantly predict the presence of RFR in patients scheduled for cardiac surgery. RFR measured by the protein loading test or by the US IRRIV test can predict the occurrence of subclinical postoperative AKI. The findings of this study need to be confirmed in large patient cohorts.

PMMA-Based Continuous Hemofiltration Modulated Complement Activation and Renal Dysfunction in LPS-Induced Acute Kidney Injury.

Sepsis-induced acute kidney injury (AKI) is a frequent complication in critically ill patients, refractory to conventional treatments. Aberrant activation of innate immune system may affect organ damage with poor prognosis for septic patients. Here, we investigated the efficacy of polymethyl methacrylate membrane (PMMA)-based continuous hemofiltration (CVVH) in modulating systemic and tissue immune activation in a swine model of LPS-induced AKI. After 3 h from LPS infusion, animals underwent to PMMA-CVVH or polysulfone (PS)-CVVH. Renal deposition of terminal complement mediator C5b-9 and of Pentraxin-3 (PTX3) deposits were evaluated on biopsies whereas systemic Complement activation was assessed by ELISA assay. Gene expression profile was performed from isolated peripheral blood mononuclear cells (PBMC) by microarrays and the results validated by Real-time PCR. Endotoxemic pigs presented oliguric AKI with increased tubulo-interstitial infiltrate, extensive collagen deposition, and glomerular thrombi; local PTX-3 and C5b-9 renal deposits and increased serum activation of classical and alternative Complement pathways were found in endotoxemic animals. PMMA-CVVH treatment significantly reduced tissue and systemic Complement activation limiting renal damage and fibrosis. By microarray analysis, we identified 711 and 913 differentially expressed genes with a fold change >2 and a false discovery rate <0.05 in endotoxemic pigs and PMMA-CVVH treated-animals, respectively. The most modulated genes were Granzyme B, Complement Factor B, Complement Component 4 Binding Protein Alpha, IL-12, and SERPINB-1 that were closely related to sepsis-induced immunological process. Our data suggest that PMMA-based CVVH can efficiently modulate immunological dysfunction in LPS-induced AKI.