Quantification of middle molecular weight solute removal in dialysis.

The pioneering work of Gotch emphasized the critical need to be quantitative with respect to treatment prescription. Through his meticulous derivations and analyses regarding Kt/V(urea), he has provided powerful insight into the standard therapy prescriptions that we now employ clinically. However, time has seen the proliferation of treatment techniques, most of which are too "young" to have been characterized with respect to clinical outcomes. Further, the relationship between removal of urea and removal of middle molecular size solutes associated with these newer techniques deviates from that associated with conventional, clinically qualified techniques. In this article we examine the solute clearance profile of some of these new methodologies and their relationship to current criteria for treatment adequacy. Our approach is to discuss components of the overall transport process and then utilize modeling of surrogate molecules over the size range of interest whose transport characteristics are known. Alteration in the solute clearance profile of these surrogate markers in response to changes in prescription variables will thus offer insight into the spectrum of toxic middle molecules that are removed when size, space of distribution, and generation rate are known.

Renal versus continuous versus intermittent therapies for removal of uremic toxins.

Uremic toxin removal by renal replacement therapies (RRTs) differs from the elimination of waste products by the native kidney in several ways. Specifically, uremic toxin removal by a RRT is achieved by a one-step membrane-based process, without the subsequent modifications that occur in the native kidney after a solute is filtered across the glomerular membrane. Another major difference relates to the continuous nature of native kidney function, which provides constant solute clearances and mass removal rates for a patient in steady state. This constancy of solute clearance, mass removal rate, and serum concentration does not exist for RRTs used in patients with end-stage renal disease (ESRD). The purpose of this review is first to compare solute removal by the native kidney with that by the various RRTs used for uremic patients. Subsequently, the therapy specificity of the relationship between solute clearance and mass removal rate is discussed, and the effective solute removal capabilities of different therapies compared.

Potential of dual-skinned, high-flux membranes to reduce backtransport in hemodialysis.

BACKGROUND: Potential backfiltration of cytokine-inducing material is a clinical concern during hemodialysis conducted with high-flux membranes. Novel hollow-fiber membranes were developed that had asymmetric convective solute transport properties, aimed at reducing the passage of potentially harmful molecules from dialysate to blood, while maintaining the desired fluid and solute movement from blood to dialysate. METHODS: Sieving coefficient as a function of molecular weight was measured in vitro using polydisperse dextrans. Measurements were conducted using two different flat-sheet membranes in series or using hollow fiber membranes having two integrally formed skin layers. Based on measured experimental parameters, model calculations simulated the performance of a clinical-scale dialyzer containing these new membranes versus that of a commercially available high-flux dialyzer. RESULTS: Asymmetric convective solute transport was demonstrated using both commercial flat-sheet and newly developed hollow-fiber membranes. For two flat-sheet membranes in series, the extent of asymmetric transport was dependent on the order in which the solution was filtered through the membranes. For the hollow-fiber membranes, the nominal molecular weight cut-off was 20 kD in the blood-to-dialysate direction and 13 kD in the dialysate-to-blood direction. For this membrane, model calculations predict that clearance of a beta2-microglobulin-sized molecule (11,800 D) would be significantly greater from blood to dialysate than in the reverse direction, even under conditions of zero net ultrafiltration. CONCLUSION: A novel hollow-fiber dialysis membrane was developed that allows greater convective solute transport from blood to dialysate than from dialysate to blood.

Future developments in the treatment of end-stage renal disease: a North American perspective.

New technology for the treatment of end-stage renal disease will need to be pharmacoeconomically persuasive in reducing the life-cost of treatment to obtain entry into the market. Increased automation, with closed-loop sensing technology, will occur in the near term. Clearance-based terminology for quantifying performance of equipment will give way to direct quantification of toxin removal. Experiments on the frequency and duration of treatment will redefine what is considered to be adequate therapy in terms other than simple urea removal. Near-term changes in current vascular access technology will be driven by the current cost of access failure. Automated peritoneal dialysis will displace continuous ambulatory peritoneal dialysis, and online compounding of solution for use is likely for both hemodialysis and peritoneal dialysis. In a longer time frame these technologies will merge. Xenografting from the pig will be a reality, and gene therapy of the mesothelium will provide a more user-friendly therapy for end-stage renal disease.

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.

Dialysis: a 5-year perspective.

The view of dialysis in the next 5 years will, by requirement, deal with ideas presently in the laboratories of industry and academics. The healthcare environment is heavily cost constrained and will likely only yield to more expensive therapies if one measures them in pharmacoeconomic terms and shows that they reduce the life costs for a patient with end-stage renal disease. The technologies of hemodialysis and peritoneal dialysis appear to be moving toward one another in terms of generating sterile pyrogen-free dialysis fluid online and moving toward customization of therapy for the individual patient. Sensors will provide closed loop feedback to modulate therapy prescription intradialytically for hemodialysis and on an exchange-to-exchange basis for continuous ambulatory peritoneal dialysis. Hemodialysis will, in part, move back into the home as new, smart, and smaller equipment prospectively designed for that purpose becomes available. Renewed interest in vascular access will provide alternatives to the present shunt and fistula. The recognition of middle molecule toxicity may require selective removal of identified toxins by immunoadsorption. Patient, rather than physician, quality of life will largely dictate the acceptance of technical innovation over the next 5 years.

Impact of terminal heat sterilization on the quality of peritoneal dialysis solutions.

In order to meet the sterility requirements imposed by the various regulatory bodies around the world, peritoneal dialysis solutions are terminally heat-sterilized at an acid pH. There is growing concern that both acid pH and the glucose degradation products formed during terminal heat sterilization adversely affect the quality of the therapy provided to the end-stage renal failure patient on peritoneal dialysis. Acid pH and glucose degradation products are thought to contribute to impaired host defense and hence to increased risk of infection, loss of ultrafiltration, and peritoneal fibrosis. On the other hand, peritoneal dialysis solutions prepared by aseptic processing are devoid of in vitro cytotoxicity and hence are considered more biocompatible than heat-sterilized solutions. With new technologies permitting aseptic processing to achieve sterility assurance levels approaching solutions manufactured by terminal heat sterilization, it is possible to produce solutions that are more biocompatible than heat-sterilized products without increasing the risk of microbial contamination.

Dialysis in the 21st century.

Dialysis has moved from a halfway technology to a full contributor to the therapeutic armamentarium of the nephrologist who treats end-stage renal failure. The scientific future for this therapy is bright and limited only by cost pressure in the changing health care environment of today in North America. For the awesome potential of tomorrow's science to arrive at the bedside, there will have to be a collaborative interaction between industry, the nephrologist researcher, and third-party payers, both private and federal. This consortium must direct therapeutic innovation to ensure that new products serve quality as well as quantity of life, so that society's investment in this new science will show a satisfactory return in reduced hospitalization costs and increased patient productivity. The innovations described were selected to meet this "pharmacoeconomic" requirement.

The role of plasma in the transfer of Escherichia coli cytokine-inducing substances across high-flux cellulosic membranes.

It has been previously reported that the presence of plasma in the blood side compartment of cellulosic membranes enhances the transfer of cytokine-inducing substance (CIS) present in the dialysate compartment. This apparent enhancement could either be a result of (1) improved membrane permeability to CIS, (2) transfer of plasma components to the dialysate compartment thereby causing dissaggregation of CIS with subsequent backtransfer to the blood compartment, or (3) improved detection of transferred CIS resulting from carryover of plasma from the blood compartment to the mononuclear cell incubation step. An in vitro dialysis model was used to determine which of the above mechanisms were involved in this phenomenon. Results showed that enhanced detection of CIS could not be attributed to improved detection resulting from carryover plasma. Both addition of plasma to the dialysate compartment of pre-exposure of membranes to plasma resulted in enhanced transfer of CIS in a fashion similar to that seen when plasma was added to the blood compartment. These observations suggest that the transfer of Escherichia coli culture filtrate-derived CIS across cellulosic membranes is enhanced on exposure to 10% plasma because of alterations in the permselectivity of the membrane.

Biocompatibility of hemodialysis membranes: a study in healthy subjects.

The effect of blood-membrane interaction on several biocompatibility parameters has been investigated. Four groups of healthy subjects underwent sham hemodialysis, i.e. the establishment of blood-dialysis membrane contact, but without circulating dialysate, using cellulose-based membranes (regenerated cellulose and cellulose acetate) or synthetic membranes (polysulfone and polyacrilonitrile). Contact between blood and cellulose-based membranes resulted in pronounced complement activation and leukopenia whereas contact between blood and synthetic membranes induced weak complement reaction. The release of granulocytic elastase comparable to that obtained during clinical dialysis seemed to correlate directly with the types of membrane used. The gradual increase in the level of plasma elastase during blood-membrane contact, as opposed to the transient nature of the increase in the levels of complement, suggests that different mechanisms are responsible for these reactions. Nutritional implications of dialysis membrane bioincompatibility are discussed in the light of recently published metabolic data obtained in these subjects.