A prospective study of pyrogenic reactions in hemodialysis patients using bicarbonate dialysis fluids filtered to remove bacteria and endotoxin.

Pyrogenic reactions (PR) are a well-recognized complication of hemodialysis and have been associated with dialyzer reuse, high-flux dialysis, and bicarbonate dialysate. However, the roles of bacteria and endotoxin in dialysate for producing PR are not well defined. To determine the effect of removing most bacteria and endotoxin from the dialysate on the incidence of PR, a cohort of chronic hemodialysis patients receiving high-flux, high-efficiency, or conventional hemodialysis at three centers with bicarbonate dialysis fluids that had been filtered with a polysulfone high-flux hemodialyzer was prospectively studied. Unfiltered bicarbonate concentrate had median bacterial and endotoxin concentrations of 479,000 CFU/mL and 39,800 pg/mL, respectively. After filtration of the bicarbonate concentrate at the central proportioner, dialysate had a median 9.2 CFU/mL of bacteria and 17.8 pg/mL of endotoxin. Dialysate filtered at individual proportioning dialysis machines had a median 0.001 CFU/mL of bacteria and 0.19 pg/mL of endotoxin. Nine PR were identified among 303 patients after 28,007 hemodialysis treatments (0.3 PR/1,000 treatments). The rate of PR was similar for the three hemodialysis treatment modalities and for first-use compared with reused dialyzers. Although the PR rate in this study was lower (P = 0.046) than the PR rate of a previous study with unfiltered dialysis fluids (0.7 PR/1,000 treatments), it represents a difference of only 10 PR in over 28,000 treatments. It was concluded that filtration of hemodialysis fluids is efficacious in removing bacterial and endotoxin contamination and can result in a lower incidence of PR in patients receiving high-flux, high-efficiency, or conventional hemodialysis.     

Bacteria and endotoxin removal from bicarbonate dialysis fluids for use in conventional, high-efficiency, and high-flux hemodialysis

The use of bicarbonate-based dialysis fluids in hemodialysis centers in the United States has increased with the advent of high-efficiency and high-flux hemodialysis. However, bicarbonate dialysis fluids can support rapid bacterial growth and high endotoxin concentrations. This study determined the efficacy of an ultrafiltration device in reducing the bacterial and endotoxin concentrations in bicarbonate dialysis fluids. A polysulfone hollow fiber dialyzer was used to ultrafilter bicarbonate concentrate before entering the central proportioner and bicarbonate dialysate after exiting the proportioner in single patient dialysis machines. Pre- and post-ultrafilter samples were collected for bacterial and endotoxin assays over 10 months. Ultrafiltration of bicarbonate concentrate reduced bacterial and endotoxin concentrations from 288,330 colony forming units (CFU)/ml and 42,804 pg/ml to 0.47 CFU/ml and 109 pg/ml, respectively. Ultrafiltration of the dialysate in single patient systems decreased bacterial and endotoxin concentrations from 15,889 CFU/ml and 1,746 pg/ml to 0.003 CFU/ml and 0.109 pg/ml, respectively. These results demonstrate that ultrafiltration of bicarbonate dialysis fluids is effective in reducing bacterial and endotoxin contamination inherently associated with the use of bicarbonate-based dialysates.     

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.     

An Outbreak of Pyrogenic Reactions in Chronic Hemodialysis Patients Associated with Hemodialyzer Reuse

Abstract: In February 1992, 22 patients undergoing chronic hemodialysis at an outpatient dialysis center experienced pyrogenic reactions (PR). The PR rate was significantly greater (p < 0.001) during the epidemic (February 3–5) than the pre-epidemic period (November 1, 1992-February 1, 1992). All patients with PR used dialyz-ers that had been manually reprocessed either on February 1 or 3. These dialyzers contained up to 120.8 EU/ml of endotoxin in the blood compartment. The only dialyzer reprocessed before February 1 that was available for analysis was found to contain no detectable endotoxin, while dialyzers reprocessed during the epidemic period contained a median endotoxin concentration of 52.8 EU/ ml. The bioburden of water used to prepare dialysate was in excess of the Association for the Advancement of Medical Instrumentation (AAMI) standard for water, ≤200 colony forming units (CFU)/ml. Samples of treated water collected in the reuse area were within AAMI standards at the time of the investigation (February 11 and February 26), but before the investigation, water samples were assayed with a culture method that could not detect micro-bial concentrations below 10³ CFU/ml. In addition, the treated water feed line to the disinfectant container may never have been disinfected. However, no samples were collected from this line during the investigation. This outbreak emphasizes the need to use water that meets the AAMI bacteriologic and endotoxin standards of ≤200 CFU/ml and/or 5 EU/ml, respectively, for reprocessing hemodialyzers and to ensure that appropriate culture techniques are used for treated water and dialysate.     

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.     

An Economical New Process for Incenter Bicarbonate Dialysate Production: Comparison with Acetate in a Large Dialysis Population

It is generally agreed that bicarbonate dialysate is preferable to acetate dialysate, but the major limiting factors of high cost and technical difficulty in maintaining its stability for prolonged periods preclude its widespread use. The procedure developed by the authors stabilizes bicarbonate dialysate for up to 4 days, rendering bicarbonate dialysate feasible for routine out-patient use. HCO3 dialysate is produced in our dialysis unit after an initial investment of $10,000.00, at a cost per 4-h treatment of $1.22 at a dialysate flow of 500 cc/min. One hundred fifty-one chronic dialysis patients participated in an 18-week study to evaluate clinical symptomatology when bicarbonate was substituted for acetate as the dialysis base buffer. Evaluation of each dialysis treatment (total of 8,183 treatments) consisted of both subjective and objective criteria (vomiting, angina, cramps, hypotension, and frequency of use of mannitol, hypertonic saline, and nitroglycerine). The patients were unaware of the change in dialysate solutions. There was a significant reduction (p less than 0.001) in the incidence of vomiting, cramps, hypotension, nausea, flushing, and the use of mannitol and hypertonic saline during bicarbonate dialysate treatment compared with acetate dialysate. Shortness of breath, angina, mental confusion, and paresthesias were not statistically changed. Although the method of HCO3 dialysate production is associated with occasional higher bacterial count than currently recommended by AAMI standards, no adverse reactions were observed in patients treated with standard efficiency dialyzers. It is concluded that the process for incenter HCO3 production is safe, economical, and better tolerated than acetate dialysate.     

Microbial and Endotoxin Contamination in Water and Dialysate in the Central United States

The purified water supplies and randomly selected dialysates of 51 chronic and acute dialysis centers in the central United States were surveyed to assess the relative risks to dialysis patients from microbial and endotoxin contamination. A culture medium more sensitive than those generally employed in routine quality assurance assays was used for recovery of bacteria from water. With this medium, 35.3% of the water samples and 19% of the dialysate samples were out of compliance with the Association for the Advancement of Medical Instrumentation (AAMI) standards: 200 and 2,000 colony forming units (CFU)/ml, respectively. There was no correlation observed between the type of water purification system or the frequency of disinfection of the system and the bacterial and endotoxin contamination levels. There was also no correlation found between the bacterial and fungal CFU per ml and the endotoxin concentration per ml (EU/ml). It is recommended that more sensitive culturing methods be used to provide adequate bacterial monitoring of dialysate center water supplies. Dialysis centers should monitor endotoxin in dialysate on a regular schedule and immediately after any endotoxemic-like patient reactions. Yeast and fungi were observed in 10% and 64% of the water systems, respectively. Dialysate was contaminated by yeast and fungi in 30% and 70% of the centers, respectively. The concentrations of these microbes in both fluids were much lower than bacteria. However, they were observed often enough to warrant further investigation of their impact on the well-being of dialysis patients.     

Bacteriological contamination of dialyzers. Clinical, bacteriological and scanning electron-microscopic evaluation of different dialysate mixing systems.

Membranes from Gambro Lundia Nova dialyzers were investigated for presence of bacteria after hemodialysis with centrally and peripherally mixed dialysate. Centrally mixed dialysate was found contaminated with Pseudomonas aeruginosa, and bacterial cultures as well as electron scanning micrographs showed the presence of these bacteria on the dialysate side as well as on the blood side of membranes from dialyzers perfused with this dialysate during hemodialysis. No bacteria were found on membranes used with peripherally mixed dialysate, in which very few bacteria were found. Despite this the frequency of febrile episodes in patients submitted to hemodialysis with the two different dialysate mixing systems showed no significant difference in our material.     

Ultrapure dialysate

To prevent pyrogenic reactions during hemodialysis, it is recommended that bacteria and endotoxin in dialysate not exceed 100-200 colony forming units (CFU)/ml and 0.25-2 endotoxin units (EU)/ml, respectively. While these limits are adequate to prevent acute pyrogenic reactions, data are accumulating to suggest they may not prevent stimulation of chronic inflammation in hemodialysis patients. Fragments of endotoxin and other bacterial products capable of stimulating immune cells cross low-flux and high-flux membranes in vitro. In clinical studies, use of ultrapure dialysate (bacteria < 0.1 CFU/ml and endotoxin < 0.03 EU/ml) is associated with lower concentrations of inflammatory markers and acute phase reactants than are observed with dialysate meeting current quality recommendations. Moreover, observational studies suggest a link between clinical outcomes and dialysate purity. Treatment of patients with ultrapure dialysate is reported to improve nutritional status, increase responsiveness to erythropoietin, slow the decline in residual renal function, lessen cardiovascular morbidity, and decrease the incidence of beta(2)-microglobulin amyloidosis. To date, however, none of these studies has shown a cause-and-effect relationship between dialysate purity and outcome. Further, there are no data defining the concentration dependence of outcomes on dialysate purity and the relative importance of dialysate purity as a trigger of inflammation remains unclear. While the technology exists to routinely provide ultrapure dialysate, controlled clinical trials are still needed to answer the question of whether or not introducing ultrapure dialysate into routine clinical practice represents an efficient use of limited resources in terms of decreasing inflammation and improving outcomes in hemodialysis patients.     

Lack of plasma interleukin-1 beta or tumor necrosis factor-alpha elevation during unfavorable hemodialysis conditions.

Plasma interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) were determined by ELISA in 17 healthy controls, 23 HD patients, 10 continuous ambulatory peritoneal dialysis patients, and 15 chronic renal failure patients, as well as in 2 HD patients experiencing pyrogenic reactions. Another group of 10 chronic HD patients were dialyzed for 2.5 h, 5 with first-use Cuprophan membranes and 5 with first-use high-flux cellulose triacetate membranes. The mean bacterial and endotoxin concentrations of the dialysate used for HD treatments during the study period were 18,440 +/- 530 CFU/mL (mean +/- SEM) and 976 +/- 205 pg/mL, respectively. Blood specimens were obtained intradialysis and postdialysis for cytokine assay and were incubated to augment cytokine production. There was no difference in plasma IL-1 beta or TNF-alpha concentrations among the healthy controls, continuous ambulatory peritoneal dialysis patients, chronic renal failure patients, or HD patients. Neither cytokine increased significantly during or after HD. Two patients experiencing pyrogenic reactions had plasma TNF-alpha concentrations of 537 and 413 pg/mL, compared with matched controls of 6 and 0 pg/mL. Il-1 beta concentration did not differ from controls. We conclude that: (1) plasma IL-1 beta and TNF-alpha are not chronically elevated in chronic renal failure, continuous ambulatory peritoneal dialysis, or HD patients; (2) HD with new Cuprophan or cellulose triacetate membranes and high concentrations of dialysate endotoxin and bacteria does not cause elevation of circulating IL-1 beta or TNF-alpha; and (3) pyrogenic reactions might be mediated by TNF-alpha.     

Bacteriology of Hemodialysis Fluids: Are Current Methodologies Meaningful?

Reports of increasing endotoxic reactions in dialysis centers using high-flux dialyzers and high contamination in liquid bicarbonate concentrates have resulted in concern for the microbial contamination of dialysate. The influence of salt-supplemented media on the recovery of bacterial contaminants from the fluids used in hemodialysis has been examined. This study found a negative influence of a 2% NaCl supplementation of growth media for both purified water and dialysate. Salt-supplemented pour plate cultures of bicarbonate concentrate samples were not statistically different from nonsupplemented cultures (p = 0.2). The influence of the bicarbonate salt on recovery in the pour plates was not addressed. The different media recommended for monitoring microbial contamination of dialysis fluids were compared. As previously reported, both water and dialysate collected from a relatively large geographic area showed higher recoveries on Reasoner's R2A agar than on media recommended by the Association for Advancement of Medical Instrumentation (AAMI) standards (p < 0.0001). Standard methods agar (SMA) and trypticase soy agar (TSA) produced the next highest recovery for water and dialysate, respectively. The higher recoveries generally observed on R2A or SMA suggest that to provide better patient safety these media should be selected for monitoring bacterial contamination of water, and R2A, SMA, or TSA for dialysate. The variability in the species identified across the three fluids and variability in counts observed in the different fluids suggest that significant dialysate contamination may occur from sources other than the water and bicarbonate concentrates.     

A new synthetic dialyzer with advanced permselectivity for enhanced low-molecular weight protein removal

Optimizing solute removal at minimized albumin loss is a major goal of dialyzer engineering. In a prospective, randomized, crossover study on eight patients (age 63 +/- 14 years) on maintenance hemodialysis, the new Baxter Xenium 170 high-flux dialyzer (BX), which contains a 1.7-m(2) PUREMA H dialysis membrane, was compared with two widely used reference high-flux dialyzers currently available for hemodialysis in North America, the Fresenius Optiflux 180 NR (FO) and the Gambro Polyflux 170 H (GP). Solute removal and biocompatibility were assessed in hemodialysis for 240 min at blood and dialysate flow rates of 300 and 500 mL/min, respectively. Additional ex vivo experiments detecting the interleukin-1beta (IL-1b) generation in recirculated donor blood were performed to demonstrate the pyrogen retention properties of the dialyzers. The instantaneous plasma clearances were similar for the three dialyzers except for cystatin c (cysc), for which a lower clearance was measured with FO as compared with BX and GP after 30 and 180 min of hemodialysis. The reduction ratios (RRs) corrected for the hemoconcentration of beta(2)-microglobulin and cysc were lower in FO (44 +/- 9 and 35 +/- 9%, respectively) versus BX (62 +/- 6 and 59 +/- 7%, respectively) and GP (61 +/- 7 and 56 +/- 8%, respectively). The RRs of the cytokine tumor necrosis factor alpha and interleukin-6 were not different between the dialyzers. The albumin loss was <300 mg for all filters. No differences between the dialyzers were found in the biocompatibility parameters showing very low leukocyte and complement activation. The ex vivo recirculation experiments revealed a significantly higher IL-1b generation for GP (710 +/- 585 pg/mL) versus BX (317 +/- 211 pg/mL) and FO (151 +/- 38 pg/mL). BX is characterized by a steep solute sieving profile with high low-molecular weight protein removal at virtually no albumin loss and an excellent biocompatibility. This improved performance may be regarded as a contribution to optimal dialysis therapy.     

Membranes for endotoxin removal from dialysate: considerations on feasibility of commercial ceramic membranes

As the quality of water in dialysis fluid varies considerably, dialysate is often contaminated by large amounts of bacteria and endotoxins. Membrane properties and operating pressures are acknowledged to give high-flux dialysis with bicarbonate the bacteriological potential to favor passage of endotoxin fragments from the dialysate into the blood stream. Therefore, a sterile dialysate will have to become a standard. Ultrafiltration across hydrophobic synthetic membranes was shown to remove endotoxins (and their fragments) from dialysis water by the combined effect of filtration and adsorption. However, each module can be used for a limited time only. Ceramic membranes may represent an alternative to polymeric membranes for endotoxin removal. In this article, we tested the capacity of different commercial ceramic membranes with nominal molecular weight cut-off down to 1,000 to retain endotoxins from Ps. aeruginosa. The tested membranes did not generally produce dialysate meeting the Association for the Advancement of Medical Instrumentation standard. When using aluminum-containing membranes, we detected aluminum leaking into the dialysate that could possibly be transported into the blood stream.     

Pyrogen transfer across high- and low-flux hemodialysis membranes

The extent to which bacterial products from contaminated dialysate enter a patient's blood depends upon the type and permeability of the hemodialysis membrane in use. This study was performed to assess the transfer of pyrogenic substances across both high- and low-flux membranes (DIAPES, Fresenius Polysulfone, Helixone, Polyamide S). All experiments were carried out in the saline-saline model. The dialysate pool was contaminated either with purified lipopolysaccharide (LPS) (250 and 500 EU/mL) or with sterile bacterial culture filtrates (20 EU/mL), and in vitro dialysis was performed under diffusive and convective conditions. A significant transfer of endotoxin was observed for both low- and high-flux DIAPES challenged with either LPS or with bacterial culture filtrates. Under identical conditions, no transfer of endotoxins was detectable across Fresenius Polysulfone and Helixone upon challenge with purified LPS. With bacterial culture filtrates, endotoxin concentrations for Polyamide S and Fresenius Polysulfone were about 10% and 1%, respectively, of those measured for DIAPES, whereas no transfer of endotoxin was detectable for Helixone. Using an alternative assay (induction of interleukin-1 receptor antagonist, IL-1Ra, in whole blood), only the DIAPES membrane showed the passage of cytokine-inducing substances. Thus, when saline is present in both the blood and dialysate compartments (i.e., the situation during predialysis priming procedures), dialysis membranes differ profoundly with respect to their permeability to endotoxins.     

We Use Impure Water to Make Dialysate for Hemodialysis

Patients receiving hemodialysis are exposed to a large volume of water, used to prepare dialysate for each treatment session. Technological advancements now make it possible to generate ultrapure dialysate that has substantially lower bacterial and endotoxin counts than the standard dialysate used in the United States. Low‐level water contamination is thought to propagate a state of chronic inflammation seen in hemodialysis patients, and a number of studies demonstrate that the use of ultrapure dialysate has a favorable effect on laboratory parameters of inflammation, nutrition, erythropoietin responsiveness, dialysis‐associated amyloidosis, and atherosclerosis. Few studies even suggest a direct clinical benefit of adopting ultrapure dialysate. As there is no proven harm with use of ultrapure dialysate and the economic implication appears to be minimal when using modern dialysis machines, it is imperative for regulatory agencies and the dialysis community to ensure that our vulnerable patients are no longer exposed to impure water during their hemodialysis treatments.     

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.     

The Effects of Endotoxin–Contaminated Dialysate and Polysulfone or Cellulosic Membranes on the Release of TNFα during Simulated Dialysis

Abstract: Simulated dialysis of whole blood was used to determine whether membrane factors (biocompatibility), endotoxin (ET) membrane diffusion, or transmembrane monocyte–ET interactions would stimulate tumor necrosis factor (TNFα) release. Whole blood containing EDTA and aprotinin was recirculated in the blood compartment of hollow fiber dialyzers containing either regenerated cellulose or polysulfone membranes. ET–free and ET–spiked dialysate were recirculated consecutively in the dialysate compartment for 30 min each. Blood and dialysate samples were collected at t _o and after each 30 min of simulated dialysis for determination of TNFa and ET concentrations. TNFa was not detected in any blood samples collected after simulated dialysis with regenerated cellulose (RC) membranes and ET–free or ET–spiked dialysate. However, blood ET concentrations, as determined by the Limulus amebocyte lysate (LAL) assay, increased in RC dialyzers after each 30 min of simulated dialysis even with ET–free dialysate. Since TNFa was not detected in these blood samples, the material detected by the LAL assay probably was not ET but an LAL–reactive material. After simulated dialysis with polysulfone dialyzers and ET–free dialysate, TNFa and ET were not detected in blood samples. ET also was not detected in blood samples after dialysis with ET–spiked dialysate. However, TNFa was detected in 7 of 13 (54%) of the blood samples following the 500 ng/ml of ET dialysate spike. TNFα release during simulated dialysis with polysulfone membranes and ET–contaminated dialysate may be due to transmembrane stimulation of circulating mononuclear cells and not diffusion of ET across the membrane.     

Ultrapure dialysate: facts and myths

During hemodialysis, blood comes in contact with a large volume of dialysate. Since the purity of dialysate has been linked to acute and long-term complications in hemodialysis patients, the limit of bacterial and endotoxin contamination has been reduced in recent years. Questions have been raised as to whether ultrapure dialysate is required to prevent such complications; in particular, the chronic inflammatory status frequently found in chronically hemodialyzed patients. In vivo and in vitro data suggest that cytokine stimulation in the blood depends on the concentration of bacteria or endotoxin in the dialysate and on the endotoxin permeability of the dialysis membrane. It is not proven whether ultrapure dialysate reduces significantly proinflammatory cytokine generation compared with standard dialysate within the limits of recent recommendations, if rather impermeable dialysis membranes are used. Cuprophane membranes are more permeable to cytokine-inducing substances compared with synthetic membranes such as polysulfone and polyamide. Clinical reports have also attempted to link several acute and chronic complications of hemodialysis to dialysate purity. To date, however, there is no large randomized clinical trial demonstrating that ultrapure dialysate significantly reduces biomarkers of inflammation and other consequential putative complications, including dialysis-related amyloidosis, erythropoietin requirement, and cardiovascular morbidity and mortality. In conclusion, based on the existing clinical data, ultrapure dialysate is recommended in the setting of suboptimal bacteriologic quality of standard dialysate and the use of permeable dialysis membranes.