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.

Elimination of fluconazole during continuous renal replacement therapy. An in vitro assessment

Introduction: Continuous renal replacement therapy (CRRT) efficiently eliminates fluconazole. However, the routes of elimination were not clarified. Adsorption of fluconazole by filters is a pending question. We studied the elimination of fluconazole in a model mimicking a session of CRRT in humans using the NeckEpur® model. Two filters were studied. Methods: The AV1000®-polysulfone filter with the Multifiltrate Pro. Fresenius and the ST150®-polyacrylonitrile filter with the Prismaflex. Baxter-Gambro were studied. Continuous filtration used a flowrate of 2.5 L/h in post-dilution only. Session were made in duplicate. Routes of elimination were assessed using the NeckEpur® model. Results: The mean measured initial fluconazole concentration (mean ± SD) for the four sessions in the central compartment (CC) was 14.9 ± 0.2 mg/L. The amount eliminated from the CC at the end of 6 h-session at a 2.5 L/h filtration flowrate for the AV1000®-polysulfone and the ST150®-polyacrylonitrile filters were 90%–93% and 96%–94%, respectively; the clearances from the central compartment (CC) were 2.5–2.6 and 2.4–2.3 L/h, respectively. The means of the instantaneous sieving coefficient were 0.94%–0.91% and 0.99%–0.91%, respectively. The percentages of the amount eliminated from the CC by filtration/adsorption were 100/0%–95/5% and 100/0%–100/0%, respectively. Conclusion: Neither the ST150®-polyacrylonitrile nor the AV1000®-polysulfone filters result in any significant adsorption of fluconazole.

P0293FRACTIONAL EXCRETION OF TOTAL PROTEIN IS AN ACCURATE INDICATOR OF PROTEINURIA IN NPHROTIC PATIENTS

Background and Aims Urinary total protein/creatinine ratio (U-TP/Cr) is a simple and useful indicator of proteinuria. And it had been shown to correlate well with 24-hour urinary protein test (24hr UPT). However, U-TP/Cr is not always accurately reflecting the degree of proteinuria, especially in cases with heavy proteinuria. Proteinuria in nephrotic syndrome could be defined as the result of changed sieving coefficient (SC) of plasma total protein through the glomerular capillary wall. Therefore, we studied fractional excretion of total protein (FETP; total protein clearance/creatinine clearance %) instead of directly unmeasurable SC. The accuracy of the FETP was verified by 24hr UPT in comparison with U-TP/Cr. Method Sixty-three serum and urine samples were collected from 35 pediatric patients with various age (age: 3 − 20 y; mean: 10.3 y, 22 male, 13 female) with hypoproteinemia (TP≦ 5.0 mg/dL), heavy proteinuria (FETP≧ 0.01%), and normal GFR (creatinine clearance ≧ 100 ml/min). The correlations between 24hrUPT and U-P/Cr and FETP were studied using samples obtained the same time and the superiority was statistically examined. Results Mean±SE of 24hUPT, U-TP/Cr and FETP (%) were 5.53±0.71 (g/day), 10.23±1.26 (g/gCr), and 0.12±0.016 (%) respectively. R values for the correlation between 24hrUPT and U-TP/Cr and 24hr UPT and FETP were 0.64 and 0.86 respectively. FETP showed a statistically better correlation with 24hrUPT than with U-TP/Cr (P: 0.0001). Conclusion FETP is an accurate indicator of 24hr UPT for nephrotic patients under conditions of heavy proteinuria and hypoproteinemia in comparison with UTP/CR.

In vivo Elimination of Clonidine by Continuous Venovenous Hemofiltration in Critically Ill Patients

Background: Clonidine is an α2-agonist that is commonly used for sedation in the intensive care unit. When patients are on continuous venovenous hemofiltration (CVVH) in the presence of kidney dysfunction, the sieving coefficient of clonidine is required to estimate how much drug is removed by CVVH. In the present study, we measured the sieving coefficient of clonidine in critically ill, ventilated patients receiving CVVH. Methods: A total of 20 samples of plasma and ultrafiltrate of 3 patients on CVVH, using a standard 1.5 m2 polyacrylonitrile AN69 membrane, during continuous clonidine infusion were collected. After correction for the effect of predilution, we calculated the sieving coefficient for clonidine. Results: The mean sieving coefficient of clonidine was 0.52 (SD 0.097). Conclusion: Using a polyacrylonitrile AN69 membrane in a CVVH machine, the in vivo sieving coefficient of clonidine was 0.52.

In vitro Evaluation of Linezolid and Doripenem Clearance with Different Hemofilters

Introduction: Renal replacement therapy (RRT) is widely used in the treatment of septic acute kidney injury. However, little is known about how the adsorption properties of hemofilters used in RRT affect antibiotic concentration. Because a cytokine-adsorption membrane is frequently used in RRT, it is important to determine the antibiotic adsorption capacity of this membrane. Objective: The present study aimed to investigate the antibiotic adsorption capacity of different hemofilter membranes by in vitro experiments using 2 antibacterial agents (linezolid and doripenem). Methods: We performed experimental hemofiltration in vitro using polyacrylonitrile (AN69ST), polymethylmethacrylate (PMMA), and polysulfone (PS) hemofilters for 1,440 min. The test solution was a 1,000-mL substitution fluid containing 30 µg/mL linezolid and 120 µg/mL doripenem. We measured drug concentrations at the inlet, outlet, and filtrate ports of the hemofilters for 1,440 min and calculated the sieving coefficient (SC) and adsorption rate (Ra) of the drugs onto the hemofilters. Results: The amount of linezolid adsorbed onto AN69ST, PMMA, and PS membranes was decreased relative to that in the control group at 15 min (p < 0.05). However, no SC for linezolid was obtained thereafter. The Ra of linezolid onto AN69ST, PMMA, and PS membranes was higher than that in the control group (p < 0.05). In contrast, no significant differences were observed in the concentrations and Ra values of doripenem adsorbed onto AN69ST, PMMA, and PS membranes compared with those in the control group. Conclusions: Doripenem was not adsorbed onto PMMA, PS, and AN69ST membranes. Linezolid was adsorbed onto PMMA, PS, and AN69ST membranes, but only temporarily, and this did not affect drug bioavailability.

Ex vivo Rezafungin Adsorption and Clearance During Continuous Renal Replacement Therapy

Background/Aims: To determine adsorption and transmembrane clearances (CLTM) of rezafungin, a novel long-acting echinocandin, in continuous venovenous hemofiltration (CVVH). Methods: A validated ex vivo bovine blood CVVH model using polysulfone and AN69 hemodiafilters was used to evaluate urea and rezafungin CLTM at 3 different ultrafiltrate flow rates. Rezafungin adsorption to the CRRT apparatus was determined for each hemodiafilter. Results: The sieving coefficient (SC) from CVVH with 3 different ultrafiltrate flow rates was 0 for both HF1400 and Multiflow-150 hemodiafilters, while urea SC was approximately 1 at all flow rates. Hemodiafilter type and ultrafiltrate flow rate did not influence CLTM. Rezafungin adsorption to the CVVH apparatus was not observed for either hemodiafilter. Conclusion: Rezafungin is not removed by CVVH by membrane adsorption or via CLTM. Ultrafiltrate flow rates and hemodiafilter types are unlikely to influence rezafungin CLTM. No dosage adjustment of rezafungin is likely required for critically ill patients receiving CVVH.

Hemodialysis Membrane Coated with a Polymer Having a Hydrophilic Blood-Contacting Layer can Enhance Diffusional Performance

Purpose Currently, the foreign surfaces of various extracorporeal circulation devices are coated with a biocompatible polymer coating agent (BPA), which creates a hydrophilic blood-contacting layer to reduce thrombogenicity, while the membranes in hemodialyzers are not. We aimed to clarify other side effects of BPA-coated membranes by examining the diffusion performance in in vitro experiments. Methods We used a polyethersulfone membrane (sieving coefficient of albumin is ≤0.01) coated with BPA product, SEC-1™ (Toyobo), in a hemodialyzer. To estimate the diffusion rates of a wide range of molecules, 2 L of saline containing vancomycin, lysozyme, and albumin were recirculated in the circuit configured with a hemodialyzer, and dialyzed continuously using water. The concentrations of sodium, vancomycin, lysozyme, and albumin were measured every 5 minutes for 30 minutes and compared in experiments with BPA-coated (n = 4) and BPA-noncoated (n = 4) membranes. Results The removal rates of sodium and vancomycin after 5 minutes of dialysis (n = 24) were significantly higher in BPA-coated than noncoated membranes, while those of lysozyme and albumin were not significantly different. The removal rates of sodium and vancomycin after 30 minutes of dialysis (n = 4) were significantly higher, and those of lysozyme were significantly lower in BPA-coated than noncoated membranes, while those of albumin were not significantly different. Conclusions The preliminary study suggests that BPA-coated membranes enhanced the diffusion rate of molecules with low and middle molecular weight without affecting the sieving coefficient of albumin. Thus, BPA coating can enhance the dialysis performance of membranes.