[The role of pharmacist in a telemedicine collaboration in hemodialysis: Water bacteriological quality monitoring]. / Rôle du pharmacien dans un partenariat de télémédecine en hémodialyse : la surveillance microbiologique de l'eau.

OBJECTIVES: In French health centers, the pharmacist is responsible for the quality of hemodialysis fluids. In an insular hospital, it is difficult to make bacteriological controls because of the lack of an environmental laboratory. Alternative choices of methods must be seek to facilitate water control and ensure the security of hemodialysis for patients. Controlling the microbiological risk is an essential condition for the good operation of a telemedicine partnership in dialysis. METHODS: A review of the different methods that has been tried is presented. The hospital has experienced since 2014 a microorganism detection test by ATPmetry. An overview of the results is discussed. RESULTS: The usability of this technique allows quarterly controls on the water treated by reverse osmosis and on fluids after one and two ultrafiltrations from every generator. Cases of non-compliance were due to false positives, which were squashed by verification control in 50% of the cases, and the other non-compliances were fixed by corrective actions. CONCLUSIONS: The ATPmetry technique permits the collection of rapid results and verification of the effectiveness of the corrective actions immediately after their implementation. This method has been undertaken in a routine use instead of the reference technique (bacteriological cultures). Assuming a constant vigilance in the quality of dialysis fluids that is a part of a quality approach, the pharmacist is at the heart of the telemedicine partnership developed in hemodialysis on the island.

The choice of dialysate bicarbonate: do different concentrations make a difference?

Metabolic acidosis is a common complication of chronic kidney disease; it is typically caused by the accumulation of sulfate, phosphorus, and organic anions. Metabolic acidosis is correlated with several adverse outcomes, such as morbidity, hospitalization, and mortality. Thus, correction of metabolic acidosis is fundamental for the adequate management of many systemic complications of chronic kidney disease. In patients undergoing hemodialysis, acid-base homeostasis depends on many factors including the following: net acid production, amount of alkali given by the dialysate bath, duration of the interdialytic period, and residual diuresis, if any. Recent literature data suggest that the development of metabolic alkalosis after dialysis may contribute to adverse clinical outcomes. Our review is focused on the potential effects of different dialysate bicarbonate concentrations on hard outcomes such as mortality. Unfortunately, no randomized studies exist about this issue. Acid-base equilibrium is a complex and vital system whose regulation is impaired in chronic kidney disease. We await further studies to assess the extent to which acid-base status is a major determinant of overall survival in patients undergoing hemodialysis. For the present, the clinician should understand that target values for predialysis serum bicarbonate concentration have been established primarily based on observational studies and expert opinion. Based on this, we should keep the predialysis serum bicarbonate level at least at 22 mmol/l. Furthermore, a specific focus should be addressed by the attending nephrologist to the clinical and nutritional status of the major outliers on both the acid and alkaline sides of the curve.

Dialysis fluid endotoxin level and mortality in maintenance hemodialysis: a nationwide cohort study.

BACKGROUND: The quality of dialysis fluid water might play an important role in hemodialysis patient outcomes. Although targeted endotoxin levels of dialysis fluid vary among countries, evidence of the contribution of these levels to mortality in hemodialysis patients is lacking. STUDY DESIGN: Retrospective cohort study using data from the Japan Renal Data Registry, a nationwide annual survey. SETTING & PARTICIPANTS: 130,781 patients receiving thrice-weekly in-center hemodialysis for more than 6 months were enrolled at 2,746 facilities in Japan at the end of 2006. None of the patients changed facility or treatment modality during 2007. PREDICTOR: Highest endotoxin level in dialysis fluid reported by each facility during 2006. Patients were categorized by facility endotoxin level into the following groups: <0.001, 0.001 to <0.01, 0.01 to <0.05, 0.05 to <0.1, and ≥0.1EU/mL. Age, sex, dialysis vintage, diabetes mellitus as a primary cause of end-stage renal disease, Kt/V, normalized protein catabolic rate, dialysis session duration, serum albumin, and hemoglobin were measured as potential confounders. OUTCOME: All-cause mortality, censored by transplantation; withdrawal from dialysis treatment; or end of follow-up. RESULTS: Of 130,781 hemodialysis patients, 91.2% had facility endotoxin levels below the limit set for dialysis fluid in Japan (<0.05EU/mL). During a 1-year follow-up, 8,978 (6.9%) patients died of all causes. The rate of all-cause mortality at 1 year was highest in the ≥0.1-EU/mL category (88.0 deaths/1,000 person-years). Patients in the ≥0.1-EU/mL group exhibited an increased risk of all-cause mortality of 28% (95% CI, 10%-48%) compared to the <0.001-EU/mL group. LIMITATIONS: Endotoxin level in dialysis fluid is reported as categorical data. No information about variation in endotoxin levels in dialysis fluid over time. CONCLUSIONS: Higher facility endotoxin levels in dialysis fluid may be related to increased risk for all-cause mortality among hemodialysis patients. Correcting this modifiable facility water management practice might improve the outcome of hemodialysis patients.

The impact of membrane permeability and dialysate purity on cardiovascular outcomes.

The effects of high-flux dialysis and ultrapure dialysate on survival of hemodialysis patients are incompletely understood. We conducted a randomized controlled trial to investigate the effects of both membrane permeability and dialysate purity on cardiovascular outcomes. We randomly assigned 704 patients on three times per week hemodialysis to either high- or low-flux dialyzers and either ultrapure or standard dialysate using a two-by-two factorial design. The primary outcome was a composite of fatal and nonfatal cardiovascular events during a minimum 3 years follow-up. We did not detect statistically significant differences in the primary outcome between high- and low-flux (HR=0.73, 95% CI=0.49 to 1.08, P=0.12) and between ultrapure and standard dialysate (HR=0.90, 95% CI=0.61 to 1.32, P=0.60). Posthoc analyses suggested that cardiovascular event-free survival was significantly better in the high-flux group compared with the low-flux group for the subgroup with arteriovenous fistulas, which constituted 82% of the study population (adjusted HR=0.61, 95% CI=0.38 to 0.97, P=0.03). Furthermore, high-flux dialysis associated with a lower risk for cardiovascular events among diabetic subjects (adjusted HR=0.49, 95% CI=0.25 to 0.94, P=0.03), and ultrapure dialysate associated with a lower risk for cardiovascular events among subjects with more than 3 years of dialysis (adjusted HR=0.55, 95% CI=0.31 to 0.97, P=0.04). In conclusion, this trial did not detect a difference in cardiovascular event-free survival between flux and dialysate groups. Posthoc analyses suggest that high-flux hemodialysis may benefit patients with an arteriovenous fistula and patients with diabetes and that ultrapure dialysate may benefit patients with longer dialysis vintage.

Dialysate calcium concentration and mineral metabolism in long and long-frequent hemodialysis: a systematic review and meta-analysis for a Canadian Society of Nephrology clinical practice guideline.

BACKGROUND: Patients treated with conventional hemodialysis (HD) develop disorders of mineral metabolism that are associated with increased morbidity and mortality. More frequent and longer HD has been associated with improvement in hyperphosphatemia that may improve outcomes. STUDY DESIGN: Systematic review and meta-analysis to inform the clinical practice guideline on intensive dialysis for the Canadian Society of Nephrology. SETTING & POPULATION: Adult patients receiving outpatient long (≥5.5 hours/session; 3-4 times per week) or long-frequent (≥5.5 hours/session, ≥5 sessions per week) HD. SELECTION CRITERIA FOR STUDIES: We included clinical trials, cohort studies, case series, case reports, and systematic reviews. INTERVENTIONS: Dialysate calcium concentration ≥1.5 mmol/L and/or phosphate additive. OUTCOMES: Fragility fracture, peripheral arterial and coronary artery disease, calcific uremic arteriolopathy, mortality, intradialytic hypotension, parathyroidectomy, extraosseous calcification, markers of mineral metabolism, diet liberalization, phosphate-binder use, and muscle mass. RESULTS: 21 studies were identified: 2 randomized controlled trials, 2 reanalyses of data from the randomized controlled trials, and 17 observational studies. Dialysate calcium concentration ≥1.5 mmol/L for patients treated with long and long-frequent HD prevents an increase in parathyroid hormone levels and a decline in bone mineral density without causing harm. Both long and long-frequent HD were associated with a reduction in serum phosphate level of 0.42-0.45 mmol/L and a reduction in phosphate-binder use. There was no direct evidence to support the use of a dialysate phosphate additive. LIMITATIONS: Almost all the available information is related to changes in laboratory values and surrogate outcomes. CONCLUSIONS: Dialysate calcium concentration ≥1.5 mmol/L for most patients treated with long and long-frequent dialysis prevents an increase in parathyroid hormone levels and decline in bone mineral density without increased risk of calcification. It seems prudent to add phosphate to the dialysate for patients with a low predialysis phosphate level or very low postdialysis phosphate level until more evidence becomes available.

Hemodialysis and water quality.

Over 383,900 individuals in the U.S. undergo maintenance hemodialysis that exposes them to water, primarily in the form of dialysate. The quality of water and associated dialysis solutions have been implicated in adverse patient outcomes and is therefore critical. The Association for the Advancement of Medical Instrumentation has published both standards and recommended practices that address both water and the dialyzing solutions. Some of these recommendations have been adopted into Federal Regulations by the Centers for Medicare and Medicaid Services as part of the Conditions for Coverage, which includes limits on specific contaminants within water used for dialysis, dialysate, and substitution fluids. Chemical, bacterial, and endotoxin contaminants are health threats to dialysis patients, as shown by the continued episodic nature of outbreaks since the 1960s causing at least 592 cases and 16 deaths in the U.S. The importance of the dialysis water distribution system, current standards and recommendations, acceptable monitoring methods, a review of chemical, bacterial, and endotoxin outbreaks, and infection control programs are discussed.

Purity and stability of online-prepared hemodiafiltration fluid after storage.

BACKGROUND/AIMS: Previous studies have suggested that online hemodiafiltration (OL-HDF) fluid can be used as dialysate for continuous renal replacement therapies, and thus HDF costs can be reduced. The aims of this study were to determine the purity of OL-HDF fluid and to verify the stability of the electrolyte composition and acid-base balance during its storage. METHODS: OL-HDF fluid was collected in 70 individual bags and stored for up to 7 days. The following tests were performed daily in 10 bags: natural visible precipitation (macrocrystallization), sample collection for chemical analysis and fluid culture, limulus amebocyte lysate endotoxin test, standard culture of NALGENE® filters after passing of the fluid, and molecular analysis of bacterial DNA. RESULTS: The values of pH and pCO(2) showed a significant change starting at 24 h (p < 0.001); after 72 h, their values were beyond the measurable range. Coefficient of variation for pCO(2) was as high as 25.7%. Electrolyte composition (Na(+), K(+), Cl(-), Ca(2+) and glucose) showed a statistically significant difference over time (p < 0.05); however, their coefficients of variation were low (1.7, 1.4, 0.6, 2.3 and 0.9%, respectively), which might not be considered clinically significant. Negative results were obtained at all points by fluid and filter cultures, endotoxin test and molecular analysis. No macrocrystallization was observed at any time point. CONCLUSIONS: We demonstrate the microbiological purity of OL-HDF fluid stored for up to 7 days. The electrolyte composition was stable, except for a relevant change in pCO(2) and consequently in pH (first noted at 24 h), emphasizing the need to reassess the acid-base balance in multilayer plastic bags in future studies.

Pre-emptive replacement of water treatment components improves responsiveness to erythropoiesis-stimulating agents in maintenance haemodialysis patients: a quality improvement report.

Hypo-responsiveness to erythropoiesis-stimulating agents (ESAs) has been associated with increased mortality. We examined the effect of water treatment component replacement on declining ESA responsiveness in the absence of chemical or microbiological standards failure. Pre-emptive renewal of the water treatment system supplying 802 standard-flux haemodialysis patients resulted in a significant rise in haemoglobin from (mean ± SD) 12.1 ± 1.2 to 12.3 ± 1.0 g/dl (p < 0.0001), accompanied by a significant decrease in prescribed dose of darbepoetin alfa from 47.9 ± 27.3 to 44.7 ± 27.6 µg/week (p < 0.0001). ESA responsiveness improved significantly from 0.060 ± 0.041 to 0.055 ± 0.040 µg/kg/g · dl(-1) (p < 0.0001) and the number of patients no longer requiring ESA therapy increased threefold. These benefits were derived in the absence of haemolysis or significant changes in water quality. Renewal of water system components should be conducted even in the absence of proven microbiological and chemical failure.

The evolution of technological strategies in the prevention of dialysis water pollution: sixteen years' experience.

AIM: This report attempts to illustrate the positive impact on the quality of dialysis water produced over a 16-year period through the progressive optimization of technological procedures. METHODS: Fundamental steps included the following: elimination of polyvinyl chloride (PVC), periodical controls, introduction of stainless steel and/or polyethylene polymer and substitution of single-pass reverse osmosis (SRO) with double-pass reverse osmosis (DRO). Daily overnight automatic thermal disinfection of distribution piping rings represented the final step. RESULTS: A dramatic improvement was observed in 645 water samples obtained from distribution piping. The measures applied resulted in a significant improvement of water quality, featuring levels of colony-forming units per milliliter ranging from 247.4 ± 393.7 in the presence of PVC and SRO to 14.1 ± 28.0 with stainless steel and DRO and 2.8 ± 3.2 with cross-linked polyethylene thermoplastic polymer and DRO (p < 0.01). CONCLUSIONS: Dialysis water should be viewed by nephrologists as a medicinal product, and every effort should be made to ensure a high-quality liquid.

[The quality of dialysis fluid]. / La qualita' dei fluidi per dialisi.

Dialysis water optimization is not only a medical but also a moral and legal obligation, especially with the now widespread use of online systems requiring ultrapure, close to sterile water as well as strict staff adherence to protocol. Public health should allow expenditure for the most modern and secure equipment to ensure maximum safety to our hemodialysis patients and less morbidity, mortality and hospitalization. Doctors, nurses and technicians alike must acquire the necessary knowledge and procedures to consider and treat dialysis water on a par with a drug to be administered.

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.

Water for haemodialysis and related therapies: recent standards and emerging issues.

Dialysis is a well-established and widely used procedure. For a number of years, the focus has been on ensuring that water used in the preparation of dialysis fluid meets the required chemical and microbiological quality and complies with national or international standards which have recently been updated. Continued vigilance is required, in particular when new chemicals such as silver-stabilized hydrogen peroxide and chlorine dioxide are used to prevent growth of Legionella bacteria in hospital water systems, since residues are harmful to patients receiving dialysis. To achieve the required quality, large volumes of water are processed, and a substantial portion is sent to waste via the municipal sewer systems with little attempt to reuse such water on site. In view of concern about global warming and climate change, there is a need to adopt a more environmentally conscious attitude requiring dialysis providers to focus on this aspect of water usage.

The level of endotoxins in hemodialysis water and dialysate in Lithuanian hemodialysis centers.

The composition and quality of the dialysis fluid play an important role in the modulation of dialysis-related complications. During hemodialysis, patient's blood has a contact with dialysate through a semipermeable membrane. Bacterial endotoxins can pass through the membrane pores into the patient's blood and cause a silent chronic microinflammation. The aim of this study was to determine the level of endotoxins in hemodialysis water and dialysate in Lithuanian hemodialysis centers. Dialysis water (n=50) and dialysate (n=50) were collected from 91% (n=50) of all hemodialysis centers. The presence of bacterial endotoxins was evaluated using a sensitive Limulus amebocyte lysate test, which detects intact lipopolysaccharides. The level of endotoxins was lower than 0.25 EU/mL in 43 (86%) dialysis water samples and in 46 (92%) dialysate samples, and complied with the recommendations of the European Pharmacopoeia and the European Best Practice Guidelines for pure dialysis fluid. The dialysate of 39 (78%) Lithuanian hemodialysis centers complied with the definition of an ultrapure dialysis fluid. The water and dialysate were of insufficient quality in 14% and in 8% of Lithuanian hemodialysis centers, respectively, and this could be improved by the establishment of routine investigation of endotoxins.

[Dialysis dose quantification in critically ill patients]. / Quantificazione della dose di dialisi in area critica.

Acute kidney injury affects about 35% of intensive care unit patients. Renal replacement therapy is required in about 5% of such patients and is associated with a mortality rate as high as 50% to 80%. The latter is likely more related to the failure of extrarenal organs than to an insufficient dialysis dose. This could explain, at least in part, the findings of 2 recent trials (VA/ NIH and RENAL) where the expected dose-outcome relationship was not confirmed. These results cannot be taken to infer that assessing the dialysis dose is no longer required. The contrary is true, in that the common finding of large differences between prescribed and delivered doses calls for accurate dose assessment, at least to avoid underdialysis. The minimum adequate levels are now a Kt/V urea of 1.2 to 1.4 three times a week (3x/wk) on intermittent hemodialysis (IHD), and an effluent of 20 mL/kg/h for 85% of the time on continuous renal replacement therapy (CRTT). Both these parameters can be easily measured but are far from ideal indices because they account neither for residual renal function nor for irregular dose delivery. The equivalent renal urea clearance (EKRjc), by expressing the averaged renal+dialytic urea clearance over the whole treatment period, is able to account for the above factors. Although assessing EKRjc is quite complex, for regular 3x/wk IHD one could use the formula EKRjc=10 Kt/V+1 to compute that a Kt/V of 1.2 and 1.4 corresponds to an EKRjc of 13 and 15 mL/min, respectively. On the other hand, the hourly effluent per kg is numerically similar to EKRjc. On this basis it can be calculated that in non-prediluted really continuous treatment, the recommended CRRT dose (EKRjc=20 mL/min) is 33% higher than the EKRjc of 15 mL/min, corresponding to the recommended Kt/V of 1.4 on 3x/wk IHD.

The new standard of fluids for hemodialysis in Japan.

The standard of fluids for hemodialysis is being evaluated by the International Organization for Standardization (ISO), and will be decided within a few years. In 2008, the Japanese Society for Dialysis Therapy (JSDT) proposed the standard of fluids for hemodialysis by taking the draft ISO standard into consideration and the circumstances in Japan. It was characteristically a standard for Japan, where the central dialysis fluid delivery system (CDDS) is routinely used. In addition, the therapeutic application of each dialysis fluid is clarified. Since high-performance dialyzers are frequently employed in Japan, the standard recommends that ultrapure dialysis fluid be used for all dialysis modalities at all dialysis facilities. It also recommends that the dialysis equipment safety management committee at each facility validate the microbiological qualities of online-prepared substitution fluid, making the responsibility of the dialysis facility clear. This standard is more rigid than those of other countries, and is expected to contribute to improvements in the survival outcome of dialysis patients.

Worldwide guidelines for the preparation and quality management of dialysis fluid and their implementation.

Quality standards for dialysis water have existed for more than 25 years. Current standards generally agree concerning the maximum allowable levels of chemical contaminants; however, significant differences exist concerning the maximum allowable levels of microbiological contaminants and the methods used to measure them. While quality standards for dialysis water are common, there are relatively few standards or recommendations for dialysis fluid quality and these also differ markedly in the maximum allowable level for microbiological contaminants. Compliance with quality standards for dialysis water and dialysis fluid appears to have improved over the past 20 years, although the actual extent of compliance is difficult to assess. A universal standard for fluid quality might be of benefit to the wider dialysis community; however, progress towards that goal will depend on resolution of important issues, including how the standard is to be applied, if it should be limited to substances with documented toxicity for hemodialysis patients, and how to address microbiological contaminants.

Bacteriological water quality in the central dialysis fluid delivery system from the survey of the Japanese Society for Dialysis Therapy.

The Japanese Society for Dialysis Therapy (JSDT) surveyed all dialysis facilities for bacteriological quality of dialysis fluid and quality controls for dialysis fluid in 2006 and 2007. The JSDT collected the data for endotoxin (ET) levels, bacterial count and usage of ET retentive filters (ETRF). The JSDT standard for ET level in dialysis fluid (<0.050 EU/ml) was achieved in 89.0% in 2006 and in 93.6% in 2007. The JSDT standard for bacterial cell counts in dialysis fluid (<100 cfu/ml) was achieved in 96.9% in 2006 and in 97.4% in 2007. The central dialysis fluid delivery system (CDDS) is a unique system developed in Japan which has easy handling for daily maintenance of delivery systems, but it has been pointed out that CDDS has a weak point for the protection of biofilms. However, the bacteriological water qualities of dialysis fluid in CDDS were proven to be extremely high in most Japanese dialysis facilities by JSDT surveys. Bacteriological water quality has a strong impact on the patient outcome. The acceptable level of ET of dialysis fluid should be <0.1 EU/ml based on the results of JSDT survey. The excellent water quality in CDDS might be one of the important factors which help good patient survival in chronic dialysis in Japan.

Purification of dialysis fluid: historical background and perspective.

When dialysis became a chronic therapy, certain clinical symptoms could be connected to the fluid quality and some form of water treatment had to be introduced. The required equipment was empirically developed and consisted of sedimentation filters, carbon filters and softeners. In the mid-1970s the toxic effect of aluminum accumulation was discovered and led to the introduction of reverse osmosis modules. When these components - prefilters, softeners and RO modules - are properly maintained, they produce water of a quality that should meet modern standards. However, the water quality could be ruined by bacterial contamination from the distribution pipes, unless the entire flow path is hygienically designed and frequently disinfected. The quality of the concentrate is also important, especially the bicarbonate component which is prone to bacterial growth. The extent of the microbiological burden in water and dialysis fluid has been brought to the attention of the dialysis community through new and sensitive detection and quantification methods for bacteria and endotoxin.

Clinical effect of purification of dialysis fluids, evidence and experience.

Microinflammation in renal failure has been the subject of numerous contributions to the literature. The bacterial contamination of dialysate and subsequent transfer of bacterial products onto the blood side is an important cause for microinflammation in hemodialysis patients. It has been suggested that the inflammatory process may not merely be an epiphenomenon but rather a pathogenetic factor in the genesis of atherosclerosis [1,2,3]. Thus, by promoting microinflammation, dialysate contamination may contribute directly to cardiovascular morbidity and mortality.

Guidance of technical management of dialysis water and dialysis fluid for the Japan Association for Clinical Engineering Technologists.

There has been remarkable medical and technological progress in Japanese dialysis therapy where more than 270 thousand patients had been treated with dialysis by the end of 2007. Clinical engineering technologists have played an important role not only in the safety treatment but also in the technological development of dialysis therapy. It is very important to supply pure dialysis fluid for both the efficacy and the safety of hemodialysis in which high permeable dialysis membranes are used. The Japanese Society for Dialysis Therapy recently issued the standard for bacterial management of fluids for hemodialysis and related therapies according to the International Organization for Standardization (ISO)/DIS 23500. In order to achieve the standard, the management of dialysis water treatment is important as well as the role of clinical engineering technologists in daily dialysis practice. Purification is defined as no contamination by chemical substances and/or microorganisms and its components. The purification consists of the design and the system structure of the water treatment equipment and dialysis fluid-supplying equipment, and the operation and management of the equipment. The guideline aims to show the minimum standard and the management method of the water treatment system and dialysis fluid-supplying equipment in order to perform hemodialysis safely. They should outline safer dialysis by the management of purification of dialysis fluid.