Lee W. Henderson

Biophysics of Ultrafiltration and Hemofiltration

Removal of excess body water is an important function of both the artificial kidney and peritoneal dialysis. More recently, solute removal in conjunction with ultrafiltration has been exploited as an alternative to diffusion as a means for cleaning uremic blood. This chapter deals with the practical and theoretical aspects of ultrafiltration and convective mass transfer across the artificial kidney and peritoneal mass transfer barriers

Symptomatic intradialytic hypotension and mortality: an opinionated review.

The unchanging rate of symptomatic hypotension that attends maintenance hemodialysis and its link to sodium/volume overload are explored. Correlations between interdialytic weight gain, ultrafiltration rate, hypertension, and mortality are found to be strong. Suggestions/opinions for correcting this unfortunate clinical reality are offered.

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/Vurea, 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.

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.

Should Hemodialysis Fluid Be Sterile

There is no question in my mind that hemodialysis fluid should be sterile. This reaches beyond the enculturating forces brought to bear both by generations of grandmothers and the subtly crafted advertising campaigns of such moguls of clean as Lever Brothers and Proctor and Gamble. Unquestionably, in the United States “cleanliness is next to godliness.” My concerns reach even beyond the medical prejudice that we are constantly at war with our microenvironment, whether that battlefield happens to be epidermal, endothelial, or anywhere in between and that anything we as physicians do to tilt the scale in favor of the human organism (as contrasted with its monocelluar invader) is indeed a virtuous act. Rather, I should like to tie this to a chain of scientific and clinical concerns that sterile pyrogenfree dialysis fluid is a logical evolution in upgrading the quality of therapy, as we render it with the artificial kidney. Let me point to several recent publications and the implications thereof. Held et al. ( I ) point to a significantly higher mortality in the U.S. dialysis population when the registry data for the United States are contrasted with those from Europe or Japan. This “statistically robust” observation cannot be easily accepted on the basis of case mix and in the minds of these authors is best explained by a reduction of treatment time causing inadequate dialysis in the United State (2). Many [including Held et al. ( 3 ) ] consider the reduction in treatment time to be driven by a systematic cutback in federal reimbursement for hemodialysis, i.e., economic considerations taking a primary role in the prescription of therapy. We consider urea to be a metabolic waste product with relatively low toxicity that is a surrogate for other more toxic substances that we do no? measure and may not yet be identified. The number of hours spent in treating patients with hemodialysis in a given week may also be considered a surrogate for Dr. Scribner’s “middle molecules.” I recognize that many of you regard middle molecules as nephrological flying saucers (in large measure because their clear-cut biochemical identification is only now beginning to occur). This skepticism does not, however, vitiate the rigorous engineering logic that underlies this kinetic relationship. How then may we reconcile saving personnel time by shortening treatment schedules and the need to

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 tomorrows 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 societys 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.

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.

Modeling and the Middle Molecule

Urea kinetic modeling (UKM) is a powerful tool for measuring the amount of dialysis treatment rendered and has been clinically qualified (single-pool model) as correlating with mortal and morbid outcome for both continuous ambulatory peritoneal dialysis (PD) and hemodialysis (HD) (1, 2). As has been explored in detail elsewhere (3, 4), the widely used parameter K t N for urea is modality specific (i.e., KPD # KHD) due to the differences in the method of calculating clearance (K); therefore, KpDt/V # KHDt/V for urea. With reference to Figs. 1 and 2, K, is a time-averaged clearance and, hence, it declines during the course of an exchange (Fig. 1). KHD is an “instantaneous” value and remains constant (Fig. 2 ) . K,, is measured by direct dialysis quantitation (DDQ), and, whereas KpD in a given patient bears a linear relationship to the amount of urea removed, KHD does not and bears a curvilinear or logarithmic relationship to the amount of urea removed (4). Urea’s status as a surrogate for more toxic retention products of kidney failure may be defined by the conditions noted in Table 1. The relationship between the plasma concentration of urea during the weekly therapy cycle and other toxic solutes will be different than that qualified by clinical studies if the prescription is materially altered from that used in the clinically qualifying studies. For example, the small-solute-removal properties of a particular membrane cannot be rationally interpreted without knowledge of its accompanying middleand large-solute-removal capabilities. The overall efficacy of a treatment achieving a certain delivered urea K t N with a low-flux membrane cannot be equated with a second treatment achieving the same delivered urea Kt/V but with a more permeable membrane. This explains why data from the National Cooperative Dialysis Study (1 ), performed solely with low-permeability membranes and relatively low flow rates, are not useful for contemporary dialysis practice, which employs highflow rates and more efficient and permeable membranes. Further, changes in specific prescriptive parameters such as flow rates or duration of treatment may also influence the surrogate status of a small-solute like urea by altering the relationship between its removal and that of larger solutes. For a given type of regimen (i.e., thriceweekly HD), changes in flow rates of blood or dialysate more significantly influence small-solute removal than

Hemofiltration: From the origin to the new wave

Abstract A brief historical review of the major developments for continuous renal replacement therapy (CRRT) is given, followed by several observations on present CRRT membrane design characteristics and transport performance. It is projected that evolution of the CRRT methodology will eventually lead to the holy grail of artificial kidney therapy, namely, a continuously operating wearable device.

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.