Enhanced Solute Removal Research Articles

Flummoxed by flux: the indeterminate principles of haemodialysis.

ABSTRACTIn haemodialysis (HD), unwanted substances (uraemic retention solutes or ‘uraemic toxins’) that accumulate in uraemia are removed from blood by transport across the semipermeable membrane. Like all membrane separation processes, the transport requires driving forces to facilitate the transfer of molecules across the membrane. The magnitude of the transport is quantified by the phenomenon of ‘flux’, a finite parameter defined as the volume of fluid (or permeate) transferred per unit area of membrane surface per unit time. In HD, as transmembrane pressure is applied to facilitate fluid flow or flux across the membrane to enhance solute removal, flux is defined by the ultrafiltration coefficient (KUF; mL/h/mmHg) reflecting the hydraulic permeability of the membrane. However, in HD, the designation of flux has come to be used in a much broader sense and the term is commonly used interchangeably and erroneously with other measures of membrane separation processes, resulting in considerable confusion. Increased flux is perceived to reflect more ‘porous’ membranes having ‘larger’ pores, even though other membrane and therapy attributes determine the magnitude of flux achieved during HD. Adjectival designations of flux (low-, mid-, high-, super-, ultra-) have found indiscriminate usage in the scientific literature to qualify a parameter that influences clinical decision making and prescription of therapy modalities (low-flux or high-flux HD). Over the years the concept and definition of flux has undergone arbitrary and periodic adjustment and redefinition by authors in publications, regulatory bodies (US Food and Drug Administration) and professional association guidelines (European Renal Association, Kidney Disease Outcomes Quality Initiative), with little consensus. Industry has stretched the boundaries of flux to derive marketing advantages, justify increased reimbursement or contrive new classes of therapy modalities when in fact flux is just one of several specifications that determine membrane or dialyser performance. Membranes considered as high-flux previously are today at the lower end of the flux spectrum. Further, additional parameters unrelated to the rate of diffusive or convective transport (flux) are used in conjunction with or in place of KUF to allude to flux: clearance (mL/min, e.g. of β2-microglobulin) or sieving coefficients (dimensionless). Considering that clinical trials in nephrology, designed to make therapy recommendations and guide policy with economic repercussions, are based on the parameter flux they merit clarification—by regulatory authorities and scientists alike—to avoid further misappropriation.

TO011HEALTH UTILITY BUT NOT UREMIC TOXINS ARE ASSOCIATED WITH ONE YEAR MORTALITY IN HD PATIENTS

Abstract Background and Aims Patient centred care is progressively gaining importance. Standardized outcomes should take into account patient relevant outcomes, such as mortality and quality of life. It is unknown whether the health utility index EQ5D, an objective assessment of quality of life, is associated with mortality in haemodialysis patients. Serum concentrations of different uremic toxins have been associated with survival. We intended to explore whether EQ5D rather than concentrations of representative uraemic toxins (UT) was associated with mortality. Method Prospective longitudinal multicentric cohort study of all haemodialysis patients at 5 representative dialysis centres in Flanders. Total and free concentrations of representative uraemic toxins indoxyl sulfate (IxS), p-cresyl sulfate (pCS), p-cresyl glucuronide (pCG), indole acetic acid (IAA), 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), hippuric acid (HA) and uric acid (UA) were determined at baseline. Mini Nutritional Assessment (MNA) and EQ5D were assessed by dedicated nurses. Mortality was assessed from administrative or medical records. A Cox regression model was built, both fixed and as conditional forward including clinical parameters, MNA, EQ5D and serum concentrations of the different uraemic toxins. Results 216 prevalent patients (62%male, age 67.2 ± 15.7) all on high flux haemodialysis were included. Over the observation period, 59 patients (27%) died. Health utility as assessed by EQ5D was 0.69±0.28; perceived health by visual analogue scale (VAS) (0-100) was 59.6±18.6. Adjusting for age, gender and MNA score, free but not total concentrations of IxS, pCS and IAA and EQ5D score were associated with overall survival in the forced entry model. However, neither in the fixed entry, the forward or backward model were serum concentrations of uraemic toxins retained, and only age, gender, BMI, EQ5D and VAS were consistently associated with survival. Conclusion Measures of health utility, such as EQ5D, and quality of life, such as a simple VAS score, are more predictive of survival in patients on regular haemodialysis than serum concentrations of a panel of relevant uraemic toxins. Health utility and QoL are thus not only directly relevant to patients, but also indirectly through an association with improved survival. The concept of dialysis adequacy has been challenged over the last decade, mainly because it was focusing on small solute clearance. Different authors reported that concentrations of middle molecular and protein bound solutes were more representative. In our study, free but not total solute concentrations were associated with survival. However, adjusting additionally for health utility and/or health perception and/or assessment of nutritional status abolishes this association. Studies assessing interventions to enhance solute removal should not only include solute concentrations as outcome, but also consider EQ5D, VAS and nutritional status as important outcomes to enhance patient centeredness of their findings.

Effects of Hemodialysis Therapy Using Dialyzers with Medium Cut-Off Membranes on Middle Molecules.

The removal of larger middle molecules, such as free immunoglobulin light chains (FLC), is poor with most currently used dialysis technologies. While hemodiafiltration (HDF) provides enhanced clearance of middle molecules compared to high-flux hemodialysis (HD), this technique is currently not approved in some regions and, hence, not accessible for all patients. The retention of middle molecules is thought to be one factor, which contributes to excessive morbidity and mortality in HD patients. The development of medium cut-off (MCO) dialysis membranes is aimed at a more efficient clearance of larger uremic toxins while retaining albumin and may extend the benefit of enhanced solute removal to more patients. In 2 pilot studies, the removal of middle molecules using HD with an MCO dialyzer prototype was compared to (1) high-flux HD and (2) high-flux HD and HDF. The primary outcome was the overall clearance of λ FLC, and the secondary outcome was the clearance of other middle molecules and safety. Pre-to-post reduction ratios and instantaneous clearances during HD were also assessed. In both trials, the overall λ FLC clearance with MCO HD was significantly larger than with high-flux HD and HDF. Accordingly, instantaneous clearances at 30 and 120 min showed significantly higher removal of λ FLC compared to high-flux HD and HDF. MCO HD provides a more efficient removal of larger middle molecules compared to high-flux HD and HDF. A potential drawback is slightly increased albumin loss, yet preliminary data suggest that this does not lead to permanently decreased albumin levels. Thus, MCO HD may present a promising approach to further improve middle molecule removal in maintenance dialysis patients and to extend its benefit to more patients.

Innovation in the Treatment of Uremia: Proceedings from the Cleveland Clinic Workshop: Bottom‐Up Nanotechnology: The Human Nephron Filter

Over one million patients worldwide have end-stage renal disease and require dialysis or kidney transplantation. Despite the availability of these forms of renal replacement therapy for nearly four decades, mortality and morbidity are high and patients often have a poor quality of life. We have developed a human nephron filter (HNF) utilizing bottom-up nanotechnology that would eventually make feasible a continuously functioning, wearable or implantable artificial kidney. The device consists of two membranes operating in series within one device cartridge. The first membrane mimics the function of the glomerulus, using convective transport to generate a plasma ultra filtrate, which contains all solutes approaching the molecular weight of albumin. The second membrane mimics the function of the renal tubules, selectively reclaiming designated solutes to maintain body homeostasis. No dialysis solution is used in this device. The HNF has been computer modeled, and operating 12 hour per day, 7 days per week the HNF provides the equivalent of 30 ml/min glomerular filtration rate (compared to half that amount for conventional thrice-weekly hemodialysis). The HNF system, by eliminating dialysate and utilizing a novel membrane system created through applied nanotechnology, represents a breakthrough in renal replacement therapy based on the functioning of native kidneys. The enhanced solute removal and wearable design should substantially improve patient outcomes and quality of life.

Enhanced solute removal with intermittent, in‐center, 8‐hour nocturnal hemodialysis

Advances in the dialysis technique and increasing urea Kt/V have not improved outcomes for end-stage renal disease patients maintained on hemodialysis (HD) therapy. Attention has, thus, focused on enhancing solute removal via prolonged HD sessions. A reduction in the serum levels of phosphorus and beta-2-microglobulin (B2M) with longer HD treatments has been linked to improved patient outcomes. We have shown that serum phosphorus levels are significantly lowered in patients maintained on thrice-weekly, in-center, 8-hour nocturnal HD performed at a blood flow rate of 400 mL/min. The kinetics of this modality were examined. A total of 8 patients participated in the study (age 45+/-7 years). Serum creatinine levels decreased from 9.2+/-1.9 to 3.0+/-1.0 mg/dL at 8 hours while serum phosphorus decreased from 5.7+/-1.9 to 2.5+/-0.7 mg/dL at 8 hours. The initial decrease from predialysis values to 1 hour after the start of HD was significant for both creatinine (P<0.0001) and phosphorus (P<0.001). Serum B2M decreased from 26.8+/-5.5 mg/L predialysis to 14.9+/-7.0 mg/L at 8 hours (P<0.01). Dialysate-side clearances of phosphorus and creatinine were 136+/-13 and 143+/-27 cm(3)/min, respectively. Phosphorus clearances were steadily maintained during the 8-hour session. A total of 904+/-292 mg of phosphorus was removed during the 8-hour treatment, with 501+/-174 mg (55%) removed during the first 4 hours and the remaining 45% continuously removed during the latter one-half of the session. The overall calculated B2M clearance was 55.1+/-40.3 cm(3)/min using the immediate post-B2M value and 28.4+/-34.2 mg/L using the 30-minute postdialysis value for the calculation. Serum levels of phosphorus and B2M decrease dramatically during an 8-hour session. Future studies are necessary to determine whether the enhanced solute removal with longer HD sessions translates into an improved outcome for HD patients.

New Options to Improve Hemodialysis Patient Outcomes

Nearly three decades after the National Cooperative Dialysis Study showed that survival was related to time on dialysis and urea removal (1), little progress has been made to improve outcomes. The Hemodialysis Study (HEMO), a prospective randomized, controlled trial (RCT) comparing high- versus low-dosage and high- versus low-flux thrice-weekly dialysis failed to show improvement in survival for patients receiving the higher dosage dialysis (2). A move away from conventional thrice-weekly hemodialysis (HD) to more intensive treatments seems more promising. Enhanced solute removal is possible with hemodiafiltration (HDF), whereby diffusion and convection are combined across a highly permeable membrane. Several HDF techniques that may reduce morbidity and dialysis adverse effects have been developed (3). Although a meta-analysis of mortality showed no advantage of HDF (4), a more recent analysis of 2165 patients reported lower mortality for patients treated with HDF when compared with those receiving HD (5). Two intensive dialysis techniques are addressed in this issue of CJASN . Bujega et al. (6) describe their experience with in-center nocturnal HD (INHD). Thirty-nine patients who might benefit from more intensive HD were converted from standard HD to thrice-weekly overnight treatments lasting 7 to 8 h, with reduced blood pump speeds targeted at 300 ml/min. After conversion to INHD, serum phosphorus and calcium-phosphorus product improved, antihypertensive medication needed to control BP …

Hemodiafiltration History, Technology, and Clinical Results

Hemodiafiltration (HDF) is an extracorporeal renal-replacement technique using a highly permeable membrane, in which diffusion and convection are conveniently combined to enhance solute removal in a wide spectrum of molecular weights. In this modality, ultrafiltration exceeds the desired fluid loss in the patient, and replacement fluid must be administered to achieve the target fluid balance. Over the years, various HDF variants have emerged, including acetate-free biofiltration, high-volume HDF, internal HDF, paired-filtration dialysis, middilution HDF, double high-flux HDF, push-pull HDF, and online HDF. Recent technology has allowed online production of large volumes of microbiologically ultrapure fluid for reinfusion, greatly simplifying the practice of HDF. Several advantages of HDF over purely diffusive hemodialysis techniques have been described in the literature, including a greater clearance of urea, phosphate, beta(2)-microglobulin and other larger solutes, reduction in dialysis hypotension, and improved anemia management. Although randomized controlled trials have failed to show a survival benefit of HDF, recent data from large observational studies suggest a positive effect of HDF on survival. This article provides a brief review of the history of HDF, the various HDF techniques, and summary of their clinical effects.

Continuously functioning artificial nephron system: The promise of nanotechnology

Nearly 900,000 patients worldwide have end-stage renal disease and require dialysis or kidney transplantation. Despite the availability of these forms of renal replacement therapy for nearly four decades, mortality and morbidity are high and patients often have a poor quality of life. We have developed a human nephron filter (HNF) utilizing nanotechnology that would eventually make feasible a continuously functioning, wearable or implantable artificial kidney. The device consists of two membranes operating in series within one device cartridge. The first membrane mimics the function of the glomerulus, using convective transport to generate a plasma ultrafiltrate containing all solutes approaching the molecular weight of albumin. The second membrane mimics the function of the renal tubules, selectively reclaiming designated solutes to maintain body homeostasis. No dialysis solution is used in this device. The HNF has been computer-modeled, and operating 12 hr per day, 7 days per week the HNF provides the equivalent of 30 mL/min glomerular filtration rate (compared to half that amount for conventional thrice-weekly hemodialysis). Animal studies should begin in the next 1 to 2 years, and clinical trials would then follow 1 to 2 years subsequent. The HNF system, by eliminating dialysate and utilizing a novel membrane system created through applied nanotechnology, represents a breakthrough in renal replacement therapy based on the functioning of native kidneys. The enhanced solute removal and wearable design should substantially improve patient outcomes and quality of life.

CROSSOVER COMPARISON OF CONVENTIONAL HIGH-FLUX HEMODIALYSIS; ULTRAPURE HIGH-FLUX HEMODIALYSIS AND ONLINE HEMODIAFILTRATION

Purpose of the Study: Hemodiafiltration combines removal of solutes by diffusion and convection. Theoretically, it may represent the best available form of renal replacement therapy but long-term clinical outcome data are unavailable. Used Methods: 76 hemodialysis patients treated with high-flux dialysers and conventional dialysate were randomised either to online postdilution hemodiafiltration or to ultrapure high-flux hemodialysis for 24 months.Thereafter, they crossed to the other form of RRT for another 24 months. Results: The two study groups did not differ significantly in demographic data, renal characteristics or treatment parameters at recruitment. 61 patients completed the study and their data were included in the analysis. Compared to the high-flux hemodialysis therapies online hemodiafiltration therapy resulted in a significant and sustained decrease in serum beta-2-microglobulin concentrations and in a higher Kt/V urea. However, enhanced solute removal did not cause differences in anemia control, degree of hyperparathyroidism, nutritional status and global perception of quality of life (with the exception of physical activity) between patients treated with ultrapure high-flux hemodialysis or with online hemodiafiltration. Given the small numbers of patients and the limited long-term follow up of our study, it was not possible to show a definitive clinical benefit from the use of hemodiafiltration compared to ultrapure hemodialysis.

Solute removal characteristics of continuous recirculating peritoneal dialysis in experimental and clinical studies.

Continuous recirculating peritoneal dialysis (CRPD) was introduced to enhance solute removal efficiency in conventional peritoneal dialysis (PD) therapies such as continuous ambulatory peritoneal dialysis (CAPD). In CRPD, a portion of the dwell dialysate in the patient's peritoneal cavity is drained through a double-lumen catheter and purified by an extracorporeal dialyzer. In this study, solute removal characteristics and safety of CRPD are examined in ex vivo and clinical studies. Recirculation dialysis experiments using nine dogs (13.6 +/- 2.5 kg of body weight) were carried out for 240 min in the ex vivo study, whereas another seven dogs (12.1 +/- 2.8 kg) received conventional peritoneal dialysis (CPD) (120 min dwelling x 2) and six additional dogs (11.9 +/- 2.7 kg) received a Tidal PD (20 min dwelling x 12; 50% of tidal volume ratio) as controls. The ex vivo study revealed that CRPD has a higher efficiency for solute removal than CPD and is equivalent to Tidal PD. In the BUN reduction rate, the 19.4 +/- 5.5% in 240 min CRPD (n = 9) was significantly higher (p < 0.05) than the 3.5 +/- 3.6% in 240 min CPD (n = 7) and equivalent to the 17.3 +/- 4.7% in 240 min Tidal PD (n = 6). Continuous recirculating peritoneal dialysis maintained a low UN level in the peritoneal cavity due to dialysis with an extracorporeal dialyzer. This tendency was also seen in creatinine removal. In the clinical study, CRPD (n = 10) and CPD (n = 5) treatments were used in three renal failure patients. Higher solute removal efficiency was shown in CRPD than in CPD treatments, and the urea peritoneal clearance was 14.1 +/- 4.4 ml/min in CRPD (n = 10), significantly higher (p < 0.05) than the 7.3 +/- 2.1 ml/min in CPD (n = 5). No fibrin formation occurred during CRPD treatments.

Quantifying the effect of changes in the hemodialysis prescription on effective solute removal with a mathematical model.

One potential benefit of chronic hemodialysis (HD) regimens of longer duration or greater frequency than typical three-times-weekly schedules is enhanced solute removal over a relatively wide molecular weight spectrum of uremic toxins. This study assesses the effect of variations in HD frequency (F: per week), duration (T: min per treatment), and blood/dialysate flow rates (QB/QD: ml/min) on steady-state concentration profiles of five surrogates: urea (U), creatinine (Cr), vancomycin (V), inulin (I), and beta2-microglobulin (beta2M). The regimens assessed for an anephric 70-kg patient were: A (standard): F = 3, T = 240, QB = 350, QD = 600; B (daily/short-time): F = 7, T = 100, QB = 350, QD = 600; C/D/E (low-flow/long-time): F = 3/5/7, T = 480, QB = 300, QD = 100. HD was simulated with a variable-volume double-pool model, which was solved by numerical integration (Runge-Kutta method). Endogenous generation rates (G) for U, Cr, and beta2M were 6.25, 1.0, and 0.17 mg/min, respectively; constant infusion rates for V and I of 0.2 and 0.3 mg/min, respectively, were used to simulate middle molecule (MM) G values. Intercompartment clearances of 600, 275, 125, 90, and 40 ml/min were used for U, Cr, V, I, and beta2M, respectively, For each solute/regimen combination, the equivalent renal clearance (EKR: ml/min) was calculated as a dimensionless value normalized to the regimen A EKR, which was 13.4, 10.8, 6.6, 3.7, and 4.8 ml/min for U, Cr, V, I, and beta2M, respectively. For regimens B, C, D, and E, respectively, these normalized EKR values were U: 1.04, 0.96, 1.58, and 2.22; Cr: 1.03, 1.08, 1.80, and 2.55; V: 1.06, 1.32, 2.21, and 3.12; I: 1.05, 1.54, 2.57, and 3.62; beta2M: 1.00, 1.27, 1.73, and 2.19. The extent of post-HD rebound (%) was highest for regimens A and B, ranging from 16% (urea) to 50% (inulin), and lowest for regimen E, ranging from 6% (urea) to 28% (beta2M). The following conclusions can be made: (1) Relative to a standard three-times-weekly HD regimen of approximately the same total (weekly) treatment duration, a daily/short-time regimen results in modest (3 to 6%) increases in effective small solute and MM removal. (2) Relative to a standard three-times-weekly HD regimen, a three-times-weekly low-flow/long-time regimen results in comparable effective small solute removal and progressive increases in MM and beta2M removal. A daily low-flow/long-time regimen substantially increases the effective removal of all solutes.

Impact of Peritoneal Membrane Function on Long Term Clinical Outcome in Peritoneal Dialysis Patients

It is increasingly clear that peritoneal membrane transport status has clinical implications. The role of the peritoneum in dialysis delivery becomes paramount once residual renal function is lost, particularly as the membrane characteristics may change for the worse with time on treatment. These findings have several important implications: Clinicians need to take solute transport characteristics into account as they assess their patients. Adverse effects of high solute transport include reduced ultrafiltration, solute removal (in particular, sodium), and increased peritoneal protein losses. A need exists to replace lost residual renal function, not just with enhanced solute removal, but also with adequate salt and water removal. The interpretation of urea and creatinine clearances in anuric PD patients needs further consideration and validation. Hypoalbuminemia in PD patients will result from the combined effects of high protein losses, over-hydration, comorbidity, and malnutrition.