Effects of Medium Cutoff Membranes on Pro-Inflammatory Cytokine and Oxidative Marker Levels in Patients with Sepsis Who Developed Acute Kidney Injury

<b><i>Introduction:</i></b> There is insufficient data on the role of the medium cutoff (MCO) membranes in the clearance of pro-inflammatory cytokines and oxidant radicals in patients with sepsis requiring hemodialysis. <b><i>Methods:</i></b> The study consisted of 38 septic patients who developed acute kidney injury (AKI) and who were scheduled to undergo 2 sessions of hemodialysis. Nineteen patients underwent their first dialysis session with the MCO membrane and 19 patients with the high-flux (HF) membrane. In the second session, the membranes were switched. Pro-inflammatory cytokine and oxidative marker levels were measured in blood samples obtained before and after both dialysis sessions. Reduction ratios were compared for the 2 types of hemodialysis membranes. <b><i>Results:</i></b> After the first session, there was a greater reduction in tumor necrosis factor (TNF)-α with the MCO membrane (28.2 ± 21.1 vs. 8.0 ± 6.6, <i>p</i> = 0.001). After the second session, there was a greater reduction in interleukin (IL)-6 (27.8 ± 26.5 vs. 5.9 ± 13.3, <i>p</i> = 0.003) and IL-1β (20.5 ± 21.1 vs. 4.0 ± 6.5, <i>p</i> = 0.004) with the MCO membrane. When the first and second sessions of all 38 patients were compared, the reductions in TNF-α, IL-6, and IL-1β were consistently greater for MCO than HF (<i>p</i> = 0.001, <i>p</i> = 0.006, <i>p</i> &#x3c; 0.001, respectively). The reductions in total antioxidant status, total oxidant status, and myeloperoxidase were not statistically different for the 2 types of dialysis membranes. <b><i>Conclusions:</i></b> MCO membrane was superior to HF membrane in the removal of cytokines in septic patients with AKI. However, a similar effect was not observed for oxidative stress markers.

Expanded Haemodialysis as a Current Strategy to Remove Uremic Toxins

Chronic kidney disease (CKD) is characterized by the retention of solutes named uremic toxins, which strongly associate with high morbidity and mortality. Mounting evidence suggests that targeting uremic toxins and/or their pathways may decrease the risk of cardiovascular disease in CKD patients. Dialysis therapies have been developed to improve removal of uremic toxins. Advances in our understanding of uremic retention solutes as well as improvements in dialysis membranes and techniques (HDx, Expanded Hemodialysis) will offer the opportunity to ameliorate clinical symptoms and outcomes, facilitate personalized and targeted dialysis treatment, and improve quality of life, morbidity and mortality.

MO658POLYVINYLPYRROLIDONE IN HEMODIALYSIS MEMBRANES: IMPACT ON PLATELET LOSS DURING HEMODIALYSIS

Background and Aims Hydrophilic modification with polyvinylpyrrolidone (PVP) increases the biocompatibility profile of synthetic dialysis membranes. However, PVP may be eluted into patient’s blood, which has been discussed as a possible cause for adverse reactions rarely occurring with synthetic membranes. We now investigated the content of PVP and its elution from the blood-side surface from commercially available dialyzers, including the novel FX CorAL with α-tocopherol-stabilized, PVP-enriched membrane, and link the results to the level of platelet loss during dialysis as a maker of biocompatibility. Method Six synthetic, PVP containing, dialyzers (FX CorAL, FX CorDiax [Fresenius Medical Care]; Polyflux, THERANOVA [Baxter]; ELISIO [Nipro]; xevonta [B. Braun]) were investigated in the present study. The content of PVP on blood-side surface was determined with X-ray photoelectron spectroscopy (XPS). The amount of elutable PVP was measured photometrically after 5h recirculation. The level of platelet loss was evaluated in an ex vivo recirculation model with human blood. Results Highest PVP content on the blood-side surface was found for the polysulfone-based FX CorAL (26.3%), while the polyethersulfone-based THERANOVA (15.6%) had the lowest PVP content. Elution of PVP was highest for the autoclave steam sterilized THERANOVA (9.1 mg/1.6m² dialyzer) and Polyflux (9.0 mg/1.6m² dialyzer), while the lowest PVP elution was found for the INLINE steam sterilized FX CorAL and FX CorDiax (&lt; 0.5 mg/1.6m² dialyzer, for both). Highest platelet loss was found for xevonta (+164.4% compared to the reference) and the lowest for the FX CorAL (-225.2%) among the polysulfone-based dialyzers; among the polyethersulfone-based dialyzers, THERANOVA (+95.5%) had the highest and ELISIO (-52.1%) the lowest platelet loss. Conclusion PVP content and elution differs between commercially available dialyzers and was found to be linked to the membrane material and sterilization method. The amount of non-eluted PVP on the blood-side surface may be an important determinant for the hemocompatibility of dialyzers.

MO1046DOPING POLYSULFONE DIALYSIS MEMBRANES WITH HUMAN NEUTROPHIL ELASTASE INHIBITORS - A PILOT STUDY

Background and Aims During hemodialysis (HD) therapy, the long-term intradialytic contact of blood with large surfaced artificial materials (HD membranes) leads to continuous neutrophil activation, with the release of neutrophil elastase (NE), among other products. NE appears to contribute to enhance inflammation favoring the development of atherosclerosis, which is the main cause of mortality and morbidity in End-Stage Renal Disease patients. The modification of polysulfone (PSF) HD membranes by incorporating selective human NE inhibitors (NEIs) might reduce the inflammatory response and prevent HD associated complications. Thus, the present study aimed to dope PSF membranes with NEIs and assess their bioactivity and biocompatibility. Method As NEIs, it was used the commercially available Sivelestat (SIV), from Abcam, and an in house synthetized 4-oxo-β-lactam (D4L-3) based compound, selected from our library, and prepared as described elsewhere [1]. The PSF membranes were prepared according to [2] and further doped with each NEI by adsorption. Three independent assays were performed (in triplicates) where PSF membrane circles (2 cm in diameter) were incubated with ultrapure water (blank), NEIs vehicle (2.5% DMSO) or with 10 - 2000 nM SIV or D4L-3. The bioactivity of these modified PSF membranes was evaluated by a human NE activity assay [1]. The same method was used to determine the IC50 of both NEIs in solution. Biocompatibility assays (n = 3) were carried-out using duplicates of modified PSF membranes circles with Ø 2 cm incubated with 1.0 mL of whole-blood. After incubation, platelet (PLT) poor and PLT rich plasma were used to assess the levels of plasma hemoglobin (Hb) and PLT activation, respectively [2]. Results The IC50 of SIV and D4L-3 in solution were 30.9 and 87.6 nM, respectively. For PSF membranes doped with NEIs, their bioactivity increased in a concentration-dependent manner, with the highest NE inhibition of 44 and 22 % at 2000 nM SIV and D4L-3, respectively. The blank membranes showed the highest hemolytic capacity, whereas SIV and D4L-3 PSF membranes presented lower plasma Hb levels when compared with the blank or the vehicle; on average, SIV-PSF membranes presented 31% less plasma Hb than vehicle, while in D4L-3-PSF this decrease was of 51%. Regarding the thrombotic potential of these biomaterials, blank membranes presented slightly increased PLT activation levels when compared to vehicle, and modified SIV-PSF membranes showed, on average, 58% more PLT activation than the vehicle, while D4L-3-PSF membranes displayed 25% less, on average. Conclusion The successful adsorption of NEIs into PSF membranes was achieved and the NE inhibition ability was directly dependent on the concentration of the inhibitor utilized. Moreover, the bioactivity of SIV and D4L-3 when immobilized into PSF membranes it appears to follow their inhibitory capacity occurring in solution, with SIV showing a greater affinity for NE. However, concerning biocompatibility, D4L-3 displayed a greater safety performance than SIV, especially regarding the potential for triggering platelet activation. To ensure the applicability of these modified PSF membranes as a medical device, extensive further studies have to be carried-out by tweaking the conditions of the immobilization process in order to obtain an optimal equilibrium between bioactivity and biocompatibility, as well test new NEIs. Acknowledgments This work was supported by UIDB/50006/2020 and UIDB/04378/2020 with funding from FCT/MCTES through national funds, and by the project Dial4Life co-financed by FCT/MCTES (PTDC/MEC-CAR/31322/2017) and FEDER/COMPETE 2020 (POCI-01-0145-FEDER-031322).

MO676COMPLEMENT ACTIVATION BY DIALYSIS MEMBRANES AND ITS ASSOCIATION WITH SECONDARY MEMBRANE FORMATION AND SURFACE CHARGE

Background and Aims Activation of the complement system may occur during blood-membrane interactions in hemodialysis and contribute to chronic inflammation of patients with end-stage renal disease (ESRD). Hydrophilic modification with polyvinylpyrrolidone (PVP) has been suggested to increase the biocompatibility profile of dialysis membranes. In the present study we compared complement activation of synthetic and cellulose-based membranes, including the polysulfone membrane with α-tocopherol-stabilized, PVP-enriched inner surface of the novel FX CorAL dialyzer, and linked the results to their physical characteristics. Method Eight synthetic and cellulose-based dialyzers (FX CorAL, FX CorDiax [Fresenius Medical Care]; Polyflux, THERANOVA [Baxter]; ELISIO, SUREFLUX [Nipro]; xevonta [B. Braun]; FDX [Nikkisio Medical]) were investigated in the present study. Complement activation (C3a, C5a, sC5b-9) was evaluated in a 3h ex vivo recirculation model with human blood. Albumin sieving coefficients were determined over a 4h ex vivo recirculation model with human plasma as a surrogate of secondary membrane formation. Zeta potential was measured as an indicator for the surface charge of the membranes. Results The FX CorAL dialyzer induced the lowest activation of the three complement factors (C3a: -39.4%; C5a: -57.5%; sC5b-9: -58.9% compared to the reference). Highest complement activation was found for the cellulose-based SUREFLUX (C3a: +154.0%) and the FDX (C5a: +335.0%; sC5b-9: +287.9%) dialyzers. Moreover, the FX CorAL dialyzer had the nearest-to-neutral zeta potential (-2.38 mV) and the lowest albumin sieving coefficient decrease over time. Albumin sieving coefficient decrease was associated with complement activation by the investigated dialyzers. Conclusion Our present results indicate that the surface modification implemented in the FX CorAL dialyzer reduces secondary membrane formation and improves the biocompatibility profile. Further clinical studies are needed to investigate whether these observations will result in a lower inflammatory burden of hemodialysis patients.

Disruptive technologies for hemodialysis: medium and high cutoff membranes. Is the future now?

In the past decade, a new class of hemodialysis (HD) membranes (high retention onset class) became available for clinical use. The high cutoff (HCO) and the medium cutoff (MCO) membranes have wider pores and more uniformity in pore size, allowing an increased clearance of uremic toxins. Owing to the mechanism of backfiltration/internal filtration, middle molecules are dragged by the convective forces, and no substitution solution is needed. The HCO dialyzer is applied in septic patients with acute kidney injury requiring continuous kidney replacement therapy. The immune response is modulated thanks to the removal of inflammatory mediators. Another current application for the HCO dialyzer is in hematology, for patients on HD secondary to myeloma-kidney, since free light chains are more efficiently removed with the HCO membrane, reducing their deleterious effect on the renal tubules. In its turn, the MCO dialyzer is used for maintenance HD patients. A myriad of clinical trials published in the last three years consistently demonstrates the ability of this membrane to remove uremic toxins more efficiently than the high-flux membrane, an evolutionary disruption in the HD standard of care. Safety concerns regarding albumin loss as well as blood contamination from pyrogens in the dialysate have been overcome. In this update article, we explore the rise of new dialysis membranes in the light of the scientific evidence that supports their use in clinical practice.