Endotoxin-retentive Filters Research Articles

Particulates formed in online prepared substitution fluid-Effect of acetic acid cleaning on endotoxin retentive filters.

There is no standard for insoluble particulate matters in dialysate. We evaluated the insoluble particulate matters in online prepared substitution fluid. We evaluated particle diameters and constituent elements of particles in online prepared substitution fluid and the final endotoxin retentive filter (ETRF). The measurement results with particles in the online prepared substitution fluid and particles attached to the final ETRF revealed that Ca-containing particles accounted for 11 particles and Si-containing particles accounted for 19 particles of 30 particles detected in the online prepared substitution fluid and the final ETRF. We presume that insoluble particulates in online prepared substitution fluid were Ca and Mg precipitated from dialysate and Si precipitated from dialysis water. Even if two ETRFs were connected in series, these particles were formed in the final ETRF.

Basic prerequisites for on-line, high-volume hemodiafiltration.

High-volume hemodiafiltration involves filtration of >23 L/treatment and its replacement by sterile non-pyrogenic substitution fluid, while maintaining the patient's fluid balance. That volume of substitution fluid precludes the use of prepackaged sterile fluid. Instead, substitution fluid must be prepared on-line using machines that incorporate a series of bacteria- and endotoxin-retentive filters. The sterilizing ultrafilters are validated to deliver sterile, non-pyrogenic fluid to the patient when operated according to the machine manufacturer's instructions and in compliance with international standards and regulatory oversight. A successful hemodiafiltration program also places important responsibilities on the user. Specifically, the user is responsible for ensuring that the dialysis water or dialysis fluid delivered to the sterilizing filters of the hemodiafiltration machine meets the machine manufacturer's specifications and is consistent with the quality used in the sterilization validation process. The user is also responsible for ensuring that the treatment prescription allows a filtration volume >23 L/treatment to be achieved by careful selection of a dialyzer, blood flow rate and treatment time. Questions related to assurance that the substitution fluid will routinely be sterile and non-pyrogenic have limited the uptake of on-line hemodiafiltration as a therapeutic option in some countries, such as the United States.

Clinical evaluation of a newly developed automated hemodialysis system as a clinical trial

BackgroundTo cope with the increasing number of patients on long-term hemodialysis (HD), especially those with diabetic nephropathy, we designed a fully automated HD system to decrease staff workload and hence human errors related to HD treatment. In this study, we evaluated this new system as a clinical trial.MethodsBased on a dialysis machine combined with a central dialysate delivery system (CDDS), the new system is characterized by the use of back ultrafiltrated dialysate (BUD) as a substitute fluid for priming, bonus shot and blood return, and the attachment of double endotoxin retentive filters (ETRFs).ResultsThe subjects comprised 61 patients from five HD facilities enrolled in a randomized, open-labeled crossover study after giving written informed consent.A total of 348 HD treatments for 58 of the 61 patients were studied under a protocol designed in accordance with good clinical practice (GCP) guidelines and approved by the respective institutional review boards. No severe adverse effects were observed with either the test or control systems. The incidence of clinical events, including blood pressure decline, residual blood, and error in fluid removal, was not statistically significant in either group. Neither endotoxins nor bacteria were detected in the dialysate passing through the double filters.ConclusionsThis study confirmed the safety and effectiveness of an automated HD system based on CDDS.(This Clinical Trial No. is 21500BZZ00045000)

2011 JSDT Standard on the Management of Endotoxin Retentive Filter for Dialysis and Related Therapies

The contamination of the fluids for dialysis therapy is an important factor that deteriorates the biocompatibility of HD and related therapies. In particular, microbiological contamination is considered to be an important factor that causes dialysis amyloidosis and malnutrition due to the strong physiological activity of endotoxin (ET) (1). High-performance dialyzers are more frequently used in Japan than in other countries; hence, dialysis facilities in Japan are particularly affected by the bacterial contamination of dialysis fluid when it occurs. Moreover, most of the dialysis facilities in Japan use central dialysis fluid delivery systems (CDDSs), which are considered to be less effective in suppressing microbiological contamination than systems used in other countries, which adopt single-patient dialysis machines. Although ET retentive filters (ETRFs) are indispensable for increasing the microbiological quality of dialysis fluid, they may be a source of contamination if not appropriately handled (2). Therefore, the installation of an ETRF, which is the final safety step in the purification of dialysis fluid, does not always guarantee the purity of the final fluid. Rather, it is important to manage the quality of dialysis fluid that passes through the ETRF. In 2008, the Japanese Society for Dialysis Therapy (JSDT) established the Microbiological Quality Standard for Dialysis Fluid, which merely states that users of ETRFs should handle them according to the manufacturer’s instructions (3). To date, however, no consistent standard for handling ETRFs has been given by the Japan Medical Devices Manufacturers Association. ETRFs from different manufacturers have been deployed in various dialysis facilities using procedures at the discretion of each facility. Considering this situation, the JSDT has recommended that the management of ETRFs should be standardized and has formulated the JSDT original standard for managing ETRFs with the aim of supplying safe and stable dialysis fluid. The Working Group on the Development of the ETRF Management Standard consisted of members of the JSDT Subcommittee of Scientific Academy for the Function and Efficiency of Blood Purification Therapy as well as representatives of the Japan Medical Devices Manufacturers Association and the Japan Association for Clinical Engineers. To the best of our knowledge, there are few reports with high-level evidence regarding ETRF management. Moreover, CDDSs are predominantly used in Japan and rarely used in the US and Europe, so that makes it extremely difficult to refer to overseas evidence and standards on ETRF management. Therefore, we summarized the opinion of experts based on the results of joint research with related societies, including the Japan Association for Clinical Engineers and the Japanese Society for Hemodiafiltration, as well as the standards presented by the Japan Medical Devices Manufacturers Association and the dialysisrelated International Organization for Standardization (ISO) standards. We then formulated the ETRF Management Standard through a Consensus Conference at the 55th Annual Meeting of the JSDT. Received October 2012. Address correspondence and reprint requests to Dr. Ikuto Masakane, Yabuki Hospital, 1-6-17 Honcho, Yamagata City, Yamagata 990-0885, Japan. Email: imasakan.aipod@seieig.or.jp bs_bs_banner

Positively Charged Polyethersulfone Membranes: The Influence of Furosemide on the Zeta Potential

The aim of the present work is to measure changes in the Zeta potential of uncharged (PES0) and positively charged (PES+) polyethersulfone membranes, and to investigate their chemical composition. Endotoxin-retentive filters with a 0.2 μm PES0 and PES+ membranes are used for filtration of a furosemide sodium solution, with an increasing concentration up to 60 μmol/l. To analyze the chemical composition of both membranes, X-Ray photoelectron spectroscopy (XPS) was used. The Zeta potential was determined by a streaming current electrokinetic analyzer. The positive charge of the PES+ membrane corresponding to a positive Zeta potential decreased with increasing furosemide sodium concentration. In contrast, the Zeta potential of PES0 membranes hardly changes with increasing drug concentration. XPS allows the determination of the chemical composition of the investigated membranes. Both membranes only contain oxygen, carbon, sulfur and nitrogen. On the surface of the PES+ membrane, the positive charge is caused by ammonium nitrogen. No ionic additives could be detected. The manufacturer’s intended period of PES+ filter use (96 h), should only be applied to nonionic infusion solutions. Hence, information should be given on the maximum period of filter use, if ionic infusion solutions are applied.

The Performance Evaluation of Endotoxin Retentive Filters in Haemodialysis

Hemodialysis is a method for removing uremic toxins and water directly from the blood into a dialysis fluid through an artificial semipermeable membrane called a dialyzer. The ability of the dialyzer to remove uremic toxins has steadily improved, but the likelihood has also increased that bioactive substances, such as bacterial endotoxin (ET) fragments, can be transferred from the dialysis fluid into the patient's blood through the phenomena of back-diffusion and back-filtration in the dialyzer. Therefore, further efforts to improve the quality of water are required. In 2008, the Committee of Scientific Academy of the Japanese Society for Dialysis Therapy presented its new recommendations for the quality standards of dialysis fluid, but achieving and maintaining these standard values would seem difficult without installing an ET-retentive filter (ETRF). In the present study, we evaluated whether the standards for ultrapure dialysis fluid of the Japanese Society for Dialysis Therapy can be achieved and maintained by installing 3 types of ETRF for a period of 12 months. To evaluate the quality of dialysis fluid, ET values were measured with nephelometry, and viable cell counts were determined with the membrane filter method. Changes in the basic performance of the ETRFs were evaluated by measuring their water permeability, ET-retentive capacity, and hollow-fiber membrane intensity. Moreover, the hollow-fiber membrane surfaces of the ETRFs were observed with scanning electron microscopy, and the elements of the adherent substances were identified by means of energy dispersive X-ray spectrometry. The ET concentrations were less than the limit of detection during the evaluation period for samples obtained at post-ETRF sites. The viable cell counts for pre-ETRF sites were approximately 10 colony-forming units/mL. However, colonies had not formed in samples obtained from the post-ETRF sites. The substances adhering to hollow fibers included the silicon from the dialysate powder, the iron from the fluid path, and the elements derived from stainless steel. Scanning electron microscopy of the ETRF hollow fibers showed no substances except the hollow fibers and the elements derived from the dialysis fluid. Installation of an ETRF is useful for achieving and maintaining the quality standards for ultrapure dialysis fluid and for preventing the entry into the blood of ETs, viable cells, and such substances as silicon and metals.

High‐Flux Dialyzers, Backfiltration, and Dialysis Fluid Quality

Currently, high-flux hemodialysis is the most common mode of dialysis therapy worldwide. Its steadily increasing use is largely based on the desire to reduce the excessively high morbidity and mortality of end-stage renal disease patients maintained on conventional dialysis (low-flux, mostly cellulosic membranes) by offering better biocompatibility and enhanced removal of uremic toxins. Two large randomized trials suggest a survival benefit for selected subgroups of high-flux dialysis patients such as diabetics, patients with hypoalbuminemia, or patients who have been on dialysis for a long period (>3.7 years). The major disadvantage of high-flux hemodialysis relates to the use of dialysis fluid, which is commonly not pure and may endanger patients treated with high-flux hemodialysis. Endotoxin fragments and other bacterial substances derived from bacteriologically contaminated dialysis fluid may, even at bacterial counts or endotoxin concentrations within the limits of accepted standards of dialysis fluid purity, enter from the dialysate into the patient's blood either by convective transfer (backfiltration) or by movement down the concentration gradient (backdiffusion). Repeated exposure of high-flux hemodialysis patients to backtransport of dialysate contaminants aggravates the uremia-associated inflammatory response syndrome and contributes to long-term morbidity. At present, the only solution to circumvent the risks of backtransport is the use of dry powder cartridges for bicarbonate concentrate and the use of bacteria- and endotoxin-retentive filters for the online production of ultrapure dialysis fluid. Use of ultrapure dialysis fluid (bacteria <0.1 CFU/ml and endotoxin <0.03 IU/ml) has been found to reduce inflammation and comorbidities in clinical investigations compared to commercial dialysis fluid. The European Renal Association and a number of national societies in Europe or in Japan strongly recommend the use of ultrapure dialysis for high-flux hemodialysis.

Removal of an endotoxin fragment (lipid A) with an endotoxin-retentive filter

Endotoxin-retentive filters are used to purify the dialysate used for hemodialysis, but endotoxin fragments whose molecular weight is below the molecular weight cut-off point of the filter may pass through the filter. The objective of the present study was to determine whether lipid A, an endotoxin fragment, is sufficiently removed by an endotoxin-retentive filter. A filtration test for lipid A was carried out using an endotoxin-retentive filter. The filtrate was tested for the presence of lipid A by a biochemical analysis: the Limulus lysate test and a bioassay: the lymphocyte stimulation test. The endotoxin-retentive filter removed lipid A to below the limit of detection by the Limulus lysate test. However, the filtrate stimulated lymphocytes, suggesting that a small amount of lipid A whose concentration was below the limit of detection by the Limulus lysate test had passed through the filter. In conclusion, the endotoxin-retentive filter was capable of removing lipid A to a concentration below the limit of detection by the Limulus lysate test but the filtrate still stimulated lymphocytes.

Bacteriological Qualities of Dialysis Fluid in Japan as of 31 December 2006

The Japanese Society for Dialysis Therapy (JSDT) collected the data from 3488 dialysis facilities about the status of bacteriological qualities and quality controls for dialysis fluid as of 31 December 2006. The data included the endotoxin (ET) levels, bacterial counts and usage of ET retentive filters (ETRFs). It was found that ET level measurements were performed in 2873 facilities (82.4%). The JSDT standard for ET level in dialysis fluid (<0.050 EU/mL) was achieved in 89.0%, and an ET level less than 0.001 EU/mL was achieved in 29.8%; however, bacterial counts were examined in only 1049 facilities (34.1%). The JSDT standard for the bacterial cell count in dialysis fluid (<100 cfu/mL) was achieved in 96.9%, and a count of 0.1 cfu/mL, which guarantees ultra-pure dialysis fluid, was achieved in 48.4%. ETRFs were installed in 78.5% of all facilities and in 53.4% of all dialysis machines. Although the JSDT standard is the most stringent in the world, the compliance rate was excellent. Bacteriological water qualities of dialysis fluid are extremely high in most Japanese dialysis facilities and this might have a close relationship to the high dialysis patient survival rate in Japan.

Ultrapure Dialysate for Home Hemodialysis?

Use of ultrapure dialysate (bacteria < 0.1 CFU/mL and endotoxin < 0.03 EU/mL) is associated with a reduction in inflammation and morbidity in patients treated with conventional thrice-weekly dialysis. The improved outcomes obtained with more frequent dialysis schedules have reawakened interest in home hemodialysis. More frequent dialysis also appears to reduce inflammation, and whether combining more frequent dialysis with use of ultrapure dialysate will have an additive effect on inflammation and its consequences remains unclear. Routinely producing ultrapure dialysate in a home environment with a conventional hemodialysis machine poses technical challenges related to the design of the equipment and the intermittent nature of hemodialysis. Solutions to these problems include use of a system in which the water-treatment equipment is fully integrated with the dialysis machine, use of dry-powder cartridges or sterile prepackaged liquids for bicarbonate concentrate, and use of a bacteria-retentive and endotoxin-retentive filter for final purification of the dialysate immediately before it enters the dialyzer. Alternatively, ultrapure dialysate may be achieved with newer machines designed specifically for home hemodialysis that use a new batch of dialysate for each treatment. The volume of dialysate available with these machines, however, currently limits their use to short-daily dialysis.