Bisphenol A and Bisphenol S in Hemodialyzers.

Bisphenol A (BPA)-based materials are used in the manufacturing of hemodialyzers, including their polycarbonate (PC) housings and polysulfone (PS) membranes. As concerns for BPA's adverse health effects rise, the regulation on BPA exposure is becoming more rigorous. Therefore, BPA alternatives, such as Bisphenol S (BPS), are increasingly used. It is important to understand the patient risk of BPA and BPS exposure through dialyzer use during hemodialysis. Here, we report the bisphenol levels in extractables and leachables obtained from eight dialyzers currently on the market, including high-flux and medium cut-off membranes. A targeted liquid chromatography-mass spectrometry strategy utilizing stable isotope-labeled internal standards provided reliable data for quantitation with the standard addition method. BPA ranging from 0.43 to 32.82 µg/device and BPS ranging from 0.02 to 2.51 µg/device were detected in dialyzers made with BPA- and BPS-containing materials, except for the novel FX CorAL 120 dialyzer. BPA and BPS were also not detected in bloodline controls and cellulose-based membranes. Based on the currently established tolerable intake (6 µg/kg/day), the resulting margin of safety indicates that adverse effects are unlikely to occur in hemodialysis patients exposed to BPA and BPS quantified herein. With increasing availability of new data and information about the toxicity of BPA and BPS, the patient safety limits of BPA and BPS in those dialyzers may need a re-evaluation in the future.

Improved hemocompatibility of polysulfone hemodialyzers with Endexo® surface modifying molecules.

Anticoagulation therapy is widely used to reduce clotting during hemodialysis (HD), but may cause adverse effects in end-stage kidney disease patients. A new hemodialyzer with a membrane modified by surface modifying molecule was developed to improve hemocompatibility that aimed to reduce the need for anticoagulation during dialysis treatments. We compared membrane surface characteristics and in vitro hemocompatibility of the new hemodialyzer to the standard polysulfone (PSF) hemodialyzer membrane. Scanning electron microscopy, contact angle measurement (68° ± 3° test vs. 41.6° ± 6° control), and X-ray photoelectron spectrometry measurement for fluorine atomic % (7.4% ± 0.4% test vs. not detectable control), showed that the membrane surface was modified with surface modifying macromolecule (SMM1) but maintained membrane structure and surface hydrophilicity. Zeta potential of the blood-contacting surface showed that the absolute surface charge was reduced at neutral pH (-3.3 mV ± 1.1 mV test vs. -15.6 mV ± 1.0 mV control). Platelet count reduction was significantly less for the SMM1-modified dialyzer (40.88% ± 21.89%) compared to the standard PSF dialyzer (62.62% ± 34.13%), along with Platelet Factor 4 (1824.10 ng/ml ± 436.26 ng/ml test vs. 2479.00 ng/ml ± 852.96 ng/ml control). These studies demonstrate the successful incorporation of SMM1 into the new hemodialyzer with the expected results. Our in vitro experiments indicate that the SMM1-modified hemodialyzers could improve hemocompatibility compared to standard PSF hemodialyzers and have the potential to minimize the patient's anticoagulant requirements during HD. Additional research with SMM1 additives incorporated into the entire dialysis circuit and use in a clinical settings are required to confirm these promising findings.

Toxicological risk assessment of bisphenol a released from dialyzers under simulated-use and exaggerated extraction conditions.

Bisphenol A (BPA) belongs to a group of chemicals used in the production of polycarbonate, polysulfone, and polyethersulfone which are used, among other applications, in the manufacture of dialyzers. While exposure to BPA is widespread in the general population, dialysis patients represent a population with potentially chronic parenteral BPA exposures. To assess the potential risk of BPA exposure to dialysis patients through dialyzer use, exposure estimates were calculated based on BPA levels measured by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry following extractions from dialyzers manufactured by Fresenius Medical Care. Extraction conditions included both simulated-use leaching and exaggerated extractions to evaluate possible leachable and extractable BPA, respectively, from the devices. The mean BPA concentrations were 3.6 and 108.9 ppb from simulated-use and exaggerated extractions, respectively, from polycarbonate-containing dialyzers. No BPA was detected from polypropylene-containing dialyzers. Margins of Safety (MOS) were calculated to evaluate the level of risk to patients from estimated BPA exposure from the dialyzers, and the resulting MOS were 229 and 45 for simulated-use and exaggerated extractions, respectively. The findings suggest that there is an acceptable level of toxicological risk to dialysis patients exposed to BPA from use of the dialyzers tested in the current study.

Improved dialytic removal of protein-bound uraemic toxins with use of albumin binding competitors: an in vitro human whole blood study.

Protein-bound uraemic toxins (PBUTs) cause various deleterious effects in end-stage kidney disease patients, because their removal by conventional haemodialysis (HD) is severely limited by their low free fraction in plasma. Here we provide an experimental validation of the concept that the HD dialytic removal of PBUTs can be significantly increased by extracorporeal infusion of PBUT binding competitors. The binding properties of indoxyl sulfate (IS), indole-3-acetic acid (IAA) and hippuric acid (HIPA) and their binding competitors, ibuprofen (IBU), furosemide (FUR) and tryptophan (TRP) were studied in uraemic plasma. The effect of binding competitor infusion on fractional removal of PBUT was then quantified in an ex vivo single-pass HD model using uraemic human whole blood. The infusion of a combination of IBU and FUR increased the fractional removal of IS from 6.4 ± 0.1 to 18.3 ± 0.4%. IAA removal rose from 16.8 ± 0.3 to 34.5 ± 0.7%. TRP infusion increased the removal of IS and IAA to 10.5 ± 0.1% and 27.1 ± 0.3%, respectively. Moderate effects were observed on HIPA removal. Pre-dialyzer infusion of PBUT binding competitors into the blood stream can increase the HD removal of PBUTs. This approach can potentially be applied in current HD settings.

A new neutral-pH low-GDP peritoneal dialysis fluid.

BACKGROUND: Conventional peritoneal dialysis fluids (PDFs) consist of ready-to-use solutions with an acidic pH. Sterilization of these fluids is known to generate high levels of glucose degradation products (GDPs). Although several neutral-pH, low-GDP PD solutions have been developed, none are commercially available in the United States. We analyzed pH and GDPs in Delflex Neutral pH (Fresenius Medical Care North America, Waltham, MA, USA), the first neutral-pH PDF to be approved by the US Food and Drug Administration. METHODS: We evaluated whether patients (n = 26; age range: 18 - 78 years) could properly mix the Delflex Neutral pH PDF after standardized initial training. We further analyzed the concentrations of 10 different glucose degradation products in Delflex Neutral pH PDF and compared the results with similar analyses in other commercially available biocompatible PDFs. RESULTS: All pH measurements (n = 288) in the delivered Delflex Neutral pH solution consistently fell within the labeled range of 7.0 ± 0.4. Analysis of mixing errors showed no significant impact on the pH results. Delflex Neutral pH, Balance (Fresenius Medical Care, Bad Homburg, Germany), BicaVera (Fresenius Medical Care), and Gambrosol Trio (Gambro Lundia AB, Lund, Sweden) exhibited similar low total GDP concentrations, with maximums in the 4.25% solutions of 88 µmol/L, 74 µmol/L, 74 µmol/L, and 79 µmol/L respectively; the concentration in Physioneal (Baxter Healthcare Corporation, Deerfield, IL, USA) was considerably higher at 263.26 µmol/L. The total GDP concentration in Extraneal (Baxter Healthcare Corporation) was 63 µmol/L, being thus slightly lower than the concentrations in the 4.25% glucose solutions, but higher than the concentrations in the 1.5% and 2.5% glucose solutions. CONCLUSIONS: The new Delflex Neutral pH PDF consistently delivers neutral pH with minimal GDPs.

New pH-neutral peritoneal dialysis solution, low in glucose degradation products, in a double-chamber bag.

Fresenius Medical Care-North America has developed a neutral-pH version of its Delflex peritoneal dialysis (PD) solution with low glucose degradation products (GDPs): Delflex Neutral pH. The Delflex Neutral pH system stores the PD solution in a dual-chamber bag. The product is admixed by the patient before use. The new design facilitates GDP reduction in two ways. First, GDPs are reduced because the dextrose solution is stored at a pH that minimizes degradation during sterilization and that optimizes dextrose stability over time. Second, the design minimizes generation of acetaldehyde by separating dextrose from lactate during heat sterilization of the product. Mixing the contents of the two chambers before use produces a physiologically compatible pH of approximately 7.0, with minimal GDPs. Analysis of GDP content was conducted by high-performance liquid chromatography. The GDP reduction across all sizes and formulations of Delflex Neutral pH ranged between 74% and 93% as compared with conventional Delflex PD solution. Testing of the new delivery system by prevalent PD patients demonstrated that, with minimal training, patients can obtain a homogeneous PD solution low in GDPs with a physiologically compatible pH of approximately 7.0.

In vitro assessment of dialysis membrane as an endotoxin transfer barrier: geometry, morphology, and permeability.

High-flux dialysis membranes used with bicarbonate dialysis fluid increase the risk of back diffusion of bacterial endotoxin into the blood during hemodialysis. Endotoxin transfer of various synthetic fiber membranes was tested with bacterial culture filtrates using an in vitro system testing both diffusive and convective conditions. Membranes were tested in a simulated dialysis mode with endotoxin challenge material (approximately 420 EU/mL) added to the dialysis fluid, with saline used to model both blood and dialysis fluid. Samples were taken of both blood and dialysis fluid, and analyzed using a kinetic turbidimetric Limulus amoebocyte lysate assay. Endotoxin was found in all of the blood circuit samples, except for the Fresenius Optiflux F200NR(e) and thick-wall membranes. All membranes tested removed approximately 95% of the endotoxin from solution, with the residual approximately 5% recirculating within the dialysis fluid compartment. Endotoxin distribution through the fiber membrane was examined using a fluorescent-labeled endotoxin conjugate. Fluorescence images indicate that adsorption occurs throughout the membrane wall, with the greatest concentration of endotoxin located at the inner lumen. Contact angle analysis was able to show that all membranes exhibit a more hydrophilic lumen and a more hydrophobic outer surface except for the polyethersulfone membranes, which were of equal hydrophobicity. Resulting data indicate that fiber geometry plays an important role in the ability of the membrane to inhibit endotoxin transfer, and that both adsorption and filtration are methods by which endotoxin is retained and removed from the dialysis fluid circuit.