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Hemodiafiltration (HDF) increases the removal of middle-molecular-weight uremic toxins and may improve outcomes in patients with end-stage kidney disease (ESKD), but it requires complex equipment and comes with risks associated with infusion of large volumes of substitution solution. New high-flux hemodialysis membranes with improved diffusive permeability profiles do not have these limitations and offer an attractive alternative to HDF. However, both strategies are associated with increased albumin loss into the dialysate, raising concerns about the potential for decreased serum albumin concentrations that have been associated with poor outcomes in ESKD. Many factors can contribute to hypoalbuminemia in ESKD, including protein energy wasting, inflammation, volume expansion, renal loss and loss into the dialysate; of these factors, loss into the dialysate is not necessarily the most important. Furthermore, recent studies suggest that mild hypoalbuminemia per se is not an independent predictor of increased mortality in dialysis patients, but in combination with inflammation it is a poor prognostic sign. Thus, whether hypoalbuminemia predisposes to increased morbidity and mortality may depend on the presence or absence of inflammation. In this review we summarize recent findings on the role of dialysate losses in hypoalbuminemia and the importance of concomitant inflammation on outcomes in patients with ESKD. Based on these findings, we discuss whether hypoalbuminemia may be a price worth paying for increased dialytic removal of middle-molecular-weight uremic toxins. [ABSTRACT FROM AUTHOR]

Surface waters are increasingly contaminated by cyanobacteria, which may produce potent cyanotoxins harmful to animals and humans. Hemodialysis patients are at high risk of injury from waterborne contaminants in the water used to prepare dialysate. Episodes of acute illness and death among hemodialysis patients have been reported following exposure to dialysate prepared from drinking water contaminated with elevated concentrations of cyanotoxins. Protecting dialysis patients from these toxins is complicated by a lack of monitoring and regulation of cyanotoxins in drinking water, uncertainty as to their safe levels in dialysate, and incomplete knowledge of how well current dialysate preparation and water treatment practices remove them. Until these issues are adequately addressed, hemodialysis centers should be aware of the potential for cyanotoxins to be present in their potable water supply, particularly when it comes from surface water sources prone to cyanobacterial blooms. [ABSTRACT FROM AUTHOR]

Summary: Improving outcomes by manipulating the prescription of renal replacement therapy to increase the removal of uremic toxins has had limited success. Failure to achieve better outcomes can be attributed to the heterogenic nature of uremic toxins, the complex distribution of some toxins in the body, and the predominant regimen of thee times weekly, in-center hemodialysis. This review summarizes the various mechanisms and kinetics of removal for the three major classes of uremic toxin—small water-soluble solutes, middle molecules, and protein-bound solutes—from both a theoretical and an experimental perspective. Taken together, the available data suggest that contemporary dialyzers are not a significant impediment to the removal of water-soluble uremic toxins, particularly when combined with commonly used blood and dialysis fluid flow rates and in online convective therapies. Enhancing the removal of those solutes will require a change in paradigm to longer and more frequent treatment sessions. Whether or not such a strategy also would improve the removal of protein-bound uremic toxins is less clear; that goal might require the development of different, more complex devices than those currently used for renal replacement therapy. [Copyright &y& Elsevier]

The general objective assigned to the EUropean DIALlysis (EUDIAL) Working Group by the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) was to enhance the quality of dialysis therapies in Europe in the broadest possible sense. Given the increasing interest in convective therapies, the Working Group has started by focusing on haemodiafiltration (HDF) therapies. Several reports suggest that those therapies potentially improve the outcomes for end-stage renal disease patients. Europe is the leader in the field, having introduced the concept of ultra-purity for water and dialysis fluids and with notified bodies of the European Community having certified water treatment systems and online HDF machines. The prevalence of online HDF-treated patients is steadily increasing in Europe, averaging 15%. A EUDIAL consensus conference was held in Paris on 13 October 2011 to revisit terminology, safety and efficacy of online HDF. This is the first report of the expert group arising from that conference. [ABSTRACT FROM PUBLISHER]

Nephrologists are presented with a range of choices when selecting a dialyzer for chronic hemodialysis. Dialyzers differ in the material, structure, permeability and surface area of their membrane, and how the dialyzer is sterilized. Opinions vary regarding the impact of dialyzer characteristics on patient outcomes and which, if any, of these properties to take into account when choosing a dialyzer can be confusing. In the general dialysis population, there is no compelling evidence that the choice of a membrane material from among those materials currently in clinical use has a significant impact on morbidity or mortality (although there are rare patients who will react adversely to a given dialysis membrane). Similarly, most dialyzers are capable of adequately removing small solutes, such as urea, provided they are used with an appropriate blood flow rate and treatment time to ensure delivery of a single-pool Kt/V of at least 1.25 for men and 1.65 for women. However, in some dialysis patient subpopulations, the results of randomized clinical trials suggest that use of dialyzer containing high-flux membranes confers an outcome advantage. The extent to which this advantage is realized might also depend on how the dialyzer is used, with application in convective therapies such as hemodiafiltration being superior to diffusive therapies such as hemodialysis. This possibility is currently the subject of several large clinical trials. [ABSTRACT FROM AUTHOR]

Background. Diffusive clearance depends on blood and dialysate flow rates and the overall mass transfer area coefficient (KoA) of the dialyzer. Although KoA should be constant for a given dialyzer, urea KoA has been reported to vary with dialysate flow rate possibly because of improvements in flow distribution. This study examined the dependence of KoA for urea, phosphate and β2-microglobulin on dialysate flow rate in dialyzers containing undulating fibers to promote flow distribution and two different fiber packing densities.Methods. Twelve stable haemodialysis patients underwent dialysis with four different dialyzers, each used with a blood flow rate of 400 mL/min and dialysate flow rates of 350, 500 and 800 mL/min. Clearances of urea, phosphate and β2-microglobulin were measured and KoA values calculated.Results. Clearances of urea and phosphate, but not β2-microglobulin, increased significantly with increasing dialysate flow rate. However, increasing dialysate flow rate had no significant effect on KoA or Ko for any of the three solutes examined, although Ko for urea and phosphate increased significantly as the average flow velocity in the dialysate compartment increased.Conclusions. For dialyzers with features that promote good dialysate flow distribution, increasing dialysate flow rate beyond 600 mL/min at a blood flow rate of 400 mL/min is likely to have only a modest impact on dialyzer performance, limited to the theoretical increase predicted for a constant KoA. [ABSTRACT FROM AUTHOR]

Hemodialysis patients are exposed to large volumes of water in the form of dialysate. Contaminants from the dialysate may cross the dialyzer membrane into the blood and have the potential to compromise the adequacy of dialysis. Several chemicals found commonly in drinking water have long been known to be toxic to hemodialysis patients. More recently, it has become apparent that even low levels of bacterial products in dialysate may adversely impact dialysis adequacy through their ability to stimulate an inflammatory response. Minimum levels of water and dialysate quality have been recommended to protect patients from chemical and microbiologic contaminants. Complying with these recommendations requires an appropriately designed water purification and distribution system, combined with a surveillance program designed to maintain dialysate quality. [ABSTRACT FROM AUTHOR]

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 ofβ2-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. [ABSTRACT FROM AUTHOR]

Practicing nephrologists are spending more time caring for end-stage renal disease (ESRD) and chronic kidney disease (CKD) patients. Despite this focus, and considerable advances in the understanding of those aspects of care that impact on clinical outcomes, morbidity, mortality, and quality of life for these patients has not improved substantially over the past decade. One of the possible explanations for this lack of progress is the structure of current nephrology training programs, where ESRD and CKD patient care is not emphasized. To address this issue, we developed a short preceptorship for second-year nephrology fellows, including didactic lectures and workshops. Of 67 participating fellows, 50% were from programs offering 3 or fewer months of exposure to outpatient hemodialysis, and 25% reported no exposure to peritoneal dialysis. Of more concern, 25% reported no ‘official rounds’ with an attending nephrologist on dialysis patients. If nephrologists are to take their appropriate place as leaders of the care delivery team, nephrology fellowships must be restructured with appropriate emphasis placed on the comprehensive care of ESRD and CKD patients. [ABSTRACT FROM AUTHOR]

Dialyzer performance may change with reuse depending on whether or not the dialyzer is cleaned with bleach. Bleach is usually used in conjunction with formaldehyde as the germicide. Because few data are available for dialyzers cleaned with bleach and disinfected with peracetic acid, we examined dialyzer performance in a cross-over study of dialyzers containing polysulfone membranes reprocessed using bleach and peracetic acid or peracetic acid alone. Each dialyzer was used for a total of 16 treatments, or until it failed standard criteria for continued use. Urea, β2-microglobulin, and albumin removal were determined during the first, second, seventh, and 16th use of each dialyzer. Urea removal did not differ between the two reprocessing methods and did not change with reuse. Overall, β2-microglobulin removal remained unchanged in dialyzers reprocessed with peracetic acid alone, but tended to increase after the seventh use in dialyzers reprocessed with bleach and peracetic acid. Approximately 60% of β2-microglobulin removal resulted from trapping of β2-microglobulin at the dialyzer membrane. Albumin loss into the dialysate was clinically insignificant throughout the study with both reprocessing methods. These data show that the clearance of both small and large molecules by dialyzers containing polysulfone membranes is well maintained by reprocessing with peracetic acid and that additional cleaning with bleach has limited impact on performance. [ABSTRACT FROM AUTHOR]

Oxidant stress contributes to morbidity in hemodialysis patients. Three possible causes of oxidant stress have been suggested: the uremic state, the dialyzer membrane, and bacterial contaminants from the dialysate. Oxidant stress occurs in uremia before dialysis therapy is initiated, as evidenced by increased production of reactive oxygen species, increased levels of oxidized plasma proteins and lipids, and decreased antioxidant defenses. It has been proposed that increased production of reactive oxygen species during hemodialysis is also an important contributor to oxidant stress. Hemodialysis is associated with a transient increase in production of reactive oxygen species, particularly with cellulose membranes. In addition, surveys have shown widespread contamination of dialysate by endotoxin, which may cross membranes and prime production of reactive oxygen species by phagocytic cells. Recent studies, however, show a decrease in protein oxidation from pre- to post-dialysis and a normalization of neutrophil reactive oxygen species production. Taken together, these data suggest that uremia, per se, is the most important cause of oxidant stress in hemodialysis patients. Dialysate quality may also contribute to oxidant stress, but evidence that the dialyzer membrane plays a role is weak. [ABSTRACT FROM AUTHOR]

Effects of high-flux hemodialysis on oxidant stress. Background. Neutrophil oxygen radical production is increased in end-stage renal disease (ESRD) patients and it is further enhanced during dialysis with low-flux cellulosic membranes. This increased oxygen radical production may contribute to the protein and lipid oxidation observed in ESRD patients. We tested the hypothesis that high-flux hemodialysis does not increase oxygen radical production and that it is not associated with protein oxidation. Methods. Neutrophil oxygen radical production was measured during dialysis with high-flux dialyzers containing polysulfone and cellulose triacetate membranes. Free sulfhydryl and carbonyl groups and advanced oxidation protein products were measured to assess plasma protein oxidation. Results. Pre-dialysis, neutrophil oxygen radical production was significantly greater than normal and increased significantly as blood passed through the dialyzer in the first 30 minutes of dialysis. Post-dialysis, however, neutrophil oxygen radical production had decreased and was not different from normal. Pre-dialysis, significant plasma protein oxidation was evident from reduced free sulfhydryl groups, increased carbonyl groups, and increased advanced oxidation protein products. Post-dialysis, plasma protein free sulfhydryl groups had increased to normal levels, while plasma protein carbonyl groups increased slightly, and advanced oxidation protein products remained unchanged. Conclusions. The results of this study show that neutrophil oxygen radical production normalizes during high-flux dialysis, despite a transient increase early in dialysis. This decrease in oxygen radical production is associated with an improvement in some, but not all, measures of protein oxidation. [ABSTRACT FROM AUTHOR]

Comments on the factors that influence dialyzer urea clearance and presents developments that may lead to improvements in dialyzer performance. Discussion on the basic relationship on diffusive clearance by a dialyzer; Impact of the dialysate flow rate on clearance; Effects of the changes on the design of the dialyzer.

Focuses on anticoagulation for intermittent hemodialysis. Measurement of bioactivity of heparin; Heparin pharmacodynamics; Dosing schedules.

All systems currently used for routine hemodialysis require heparin administration to prevent blood clotting in the extracorporeal circuit. We tested the hypothesis that population-based statistical techniques can be used to predict heparin concentrations during routine hemodialysis. Two predictive models were developed, one based on nonlinear mixed effects modeling (NONMEM) and the other on a multilayer perceptron neural network. Serial clotting time data were obtained from forty-nine patients and used to develop the models. The models were used to predict the clotting times of 70 patients in a prospective test. We determined that the neural network provided greater precision, had fewer outliers in its predictions, and did not have the model misspecification in bolus administration that the NONMEM predictions demonstrated. A final NONMEM model was developed using all data from 119 patients to identify important covariates for predicting the heparin pharmacodynamic parameters, volume of distribution, and clearance. Both the volume of distribution and clearance increased following the initiation of dialysis and as the patient's baseline clotting time increased. The volume of distribution also increased as the patient's weight increased but was decreased by smoking and diabetes. Population-based statistical techniques may provide a useful alternative to existing methods for prescribing heparin. [ABSTRACT FROM AUTHOR]

Patient safety has become an important focus of the Institute of Medicine and the medical community. Although hemodialysis is a routine therapy, it is nonetheless a complex procedure where errors can occur. In particular, errors related to water quality can lead to patient injury and to increased medical costs. Using the Institute of Medicine report on errors in medicine as a basis, this article discusses previously published incidents of patient injury related to water quality in terms of the types of errors that occurred. Epidemiologic techniques provide a framework to identify, correct, and possibly avert these types of errors in the future. While the ultimate responsibility for ensuring water quality rests with the medical director of the hemodialysis unit, patient safety should be a concern of all members of the nephrology community. [ABSTRACT FROM AUTHOR]

Modern methods in analytical biochemistry have established that uraemia is associated with the retention of proteins, both in their native state and post-translationally modified, over a wide range of molecular weights up to 60 kDa. Evidence is accumulating that these higher molecular weight retention solutes are important uraemic toxins, and therapies such as online haemodiafiltration (HDF), which enhance their removal, are associated with improved outcomes. However, HDF has limitations regarding cost, clinical implementation and the need for an external source of sterile substitution solution to maintain fluid balance. New membranes that have a solute removal profile more closely approaching that of the glomerular filtration barrier when used for conventional haemodialysis, while at the same time not allowing the passage of clinically significant amounts of beneficial proteins, are needed to address these limitations. Tighter control of the molecular characteristics of the polymers used for membrane fabrication, along with the introduction of additives and improvements in the manufacturing process, has led to membranes with a tighter pore size distribution that allows the use of an increased absolute pore size without leaking substantial amounts of albumin. At the same time, the wall thickness and internal diameter of membrane fibres have been decreased, enhancing convective transport within the dialyser without the need for an external source of substitution solution. These new expanded range membranes provide a solute removal profile more like that of the native kidney than currently available membranes when used in conventional haemodialysis. [ABSTRACT FROM AUTHOR]

This commentary discusses a small multicenter, prospective clinical trial in which patients with end-stage renal disease were randomized to treatment with online high-flux hemofiltration or low-flux hemodialysis. Over a 3-year follow-up period, survival was significantly better in patients who received online hemofiltration than in patients who received low-flux hemodialysis. In addition, the average duration, but not the frequency, of hospitalization, and the incidence of intradialytic hypotension, were lower in the hemofiltration group than in the hemodialysis group. The study supports the hypothesis that increased removal of large molecules can decrease the high morbidity and mortality associated with end-stage renal disease. However, the applicability of the findings to the general population of patients with end-stage renal disease might be limited by the small size of the study, the demographics of the study population, and the high dropout rate. Larger trials are needed to confirm this study's results and to establish the appropriate dose of convection for optimal outcomes. [ABSTRACT FROM AUTHOR]

Contaminants commonly found in tap water are toxic to hemodialysis patients. To prevent patient injury from these contaminants, standards for the quality of water used to prepare dialysate have been developed. These standards are in general agreement concerning maximum allowable levels of inorganic chemical contaminants known to have adverse consequences for dialysis patients. There is less agreement about inorganic chemical contaminants that may be toxic, and most standards omit any requirements for organic chemical contaminants. There are considerable differences between standards regarding the maximum allowable levels of microbiological contaminants, as well as the methods to be used for measuring them. Harmonization of existing standards may improve patient protection by promoting demonstrated best practices. Harmonization will require innovation and compromise to produce a standard that is widely applicable, provides patients with the necessary safeguards, and whose requirements can be routinely achieved within the constraints imposed by local reimbursement practices. [ABSTRACT FROM AUTHOR]