Operational characteristics of continuous renal replacement modalities used for critically ill patients with acute kidney injury.

Renal replacement therapy (RRT) is required in a significant percentage of patients developing acute kidney injury (AKI) in an intensive care unit (ICU) setting. One of the foremost objectives of continuous renal replacement therapy (CRRT) is the removal of excess fluid and blood solutes that are retained as a consequence of decreased or absent glomerular filtration. Because prescription of CRRT requires goals to be set with regard to the rate and extent of both solute and fluid removal, a thorough understanding of the mechanisms by which solute and fluid removal occurs during CRRT is necessary. The following provides an overview of solute and water transfer during CRRT and this information is placed in the appropriate clinical context with a discussion of recent clinical trials assessing the relationship between CRRT dose and patient survival. Moreover, the differences between solute removal in CRRT and other dialysis modalities, especially sustained low-efficiency dialysis (SLED) and extended daily dialysis (EDD), along with the potential clinical implications are discussed.

Ultrafiltration rate as a dose surrogate in pre-dilution hemofiltration.

For critically ill patients treated with continuous hemofiltration (HF), doses recently shown to improve survival can usually be achieved only in the pre-dilution mode. However, use of the pre-dilution mode results in reduced treatment efficiency, relative to post-dilution at the same ultrafiltration rate (Qf ) and blood flow rate (Qb ). The objective of this study is to determine the effect of Qf on removal parameters for solutes over a wide molecular weight spectrum in pre-dilution HF. Experiments were performed in an isovolemic, plasma-based pre-dilution system with Qb=200 ml/min. Removal parameters were measured for a 1.2 m2 polysulfone hemofilter (HF1200, Minntech) at Qf values of 20, 40, and 60 ml/min, corresponding to 17, 34 and 51 ml/h/kg for a 70 kg patient (N=3 hemofilters for each Qf ). Clearance of urea and creatinine (small solute surrogates) was derived from plasma and ultrafiltrate concentrations at 30, 60, 120, 180, and 240 min while clearance of vancomycin and inulin (middle molecule surrogates) was estimated from changes in plasma concentrations over time. In addition, the sieving coefficient (SC) of vancomycin and inulin was measured at the same time points and at baseline (T=0 min). Our findings indicate pre-dilution had a predictable effect on clearance for each solute, as clearance increased linearly with Qf. Sieving coefficient values were not significantly influenced by either Qf or time and the equivalence of SC values in the middle molecule range suggest attenuation of secondary membrane effects. These data indicate filter performance can largely be preserved despite high Qf values by use of predilution. Moreover, Qf appears to be a reasonable dose surrogate in pre-dilution HF.

Extracorporeal ultrafiltration for acute exacerbations of chronic heart failure: report from the Acute Dialysis Quality Initiative.

This report from a work group affiliated with the Acute Dialysis Quality Initiative is a critical assessment of the use of extracorporeal ultrafiltration (UF) in the management of acutely decompensated heart failure (HF). In addition to assessing UF in this setting, the report also provides background information on HF, including classification, pathophysiology, and the importance of concomitant renal failure. A summary of important results from clinical trials in this area is provided, along with a discussion of technical considerations. Finally, specific recommendations for future clinical evaluations are given.

Reflections on an unsolved problem of biology: the evolution of senescence and death.

The evolutionary theory of senescence is based largely on principles first outlined by Williams in 1957, and consists of two relatively independent parts. The first part builds on ideas first put forward by Medawar, Haldane and others, to explain how something as negative as senescence could have been positively selected in evolution, particularly since most animals in the wild do not reach an age where senescence is expressed. Williams proposed that the genes responsible for the negative effects of senecence (senescence effector genes) were fixed in evolution by a process he called antagonistic pleiotropy, wherein a subset of genes selected because they confer a reproductive advantage early in life may have harmful effects in the post-reproductive period; negative selection against these harmful effects fails because, as pointed out by Medawar, the force of natural selection declines with age. The evolutionary history of senescence-causing genes is seen as a nondirected accumulation of genes selected on a basis independent of senescence per se. In the second portion of his paper, Williams made a series of predictions about how the age of organisms at reproductive maturity, fecundity, lifespan and the timing of the onset of senescence would all interact in the life history of a species. These latter predictions, which do not depend at all on details of the mechanisms of selection of senescence effector genes, have been validated by numerous experiments over the past several decades. On the other hand, it has become increasingly evident that the senescence effector genes did not, as would be predicted by antagonistic pleiotropy, accumulate in a random, non-directed fashion in various species over evolutionary time. Rather, everything we know about these genes suggests they were present in eukaryotic founder cells shortly after, or even congruent with, the emergence of eukaryotes from their prokaryotic ancestors, and have been stringently conserved ever since. Complicated explanations of how so-called "death genes" may have evolved in eukaryotes are thus not required. It is suggested that the evolutionary theory of senescence should be focused on those evolutionary principles that have been validated experimentally, and that the notion of antagonistic pleiotropy--which cannot be experimentally validated--be dropped from our thinking about the evolution of senescence.

A modified equivalent annulus model for the hollow fiber hemodialyzer.

Experimental approaches to optimize hollow fiber hemodialyzer design are expensive and time-consuming. Computer modeling is an effective way to study mass transfer in the hemodialyzer because a substantial reduction in experimental time and cost can be achieved. This paper presents a two-dimensional modified "equivalent annulus" model, which employs Navier-Stokes (N-S) equations to describe blood and dialysate flow, and Kedem-Katchalsky (K-K) equations to calculate transmembrane flow. N-S equations and K-K equations must be coupled together in the process of computing. The corresponding experiments were designed to validate this model, and experimental results agreed well with numerical results. The distribution of velocity, pressure and solute concentration were investigated in detail, presenting a clear insight into dialyzer mass transfer. This model can be applied to help optimize hemodialyzer design.

Dialysis in acute renal failure: is more better?

An increasing body of evidence indicates therapy dose and intensity influence the outcome of dialyzed ARF patients. However, a number of unanswered questions remain on this issue. These questions need to be addressed in future prospective, controlled trials that assess the effect of dose and intensity on outcome both within and between the various ARF renal replacement therapies, with appropriate and clinically relevant control arms. Such investigations should provide guidelines ultimately for the dialytic management of critically ill patients with ARF.

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.

Reconciling differences in effective solute removal between intermittent and continuous therapies.

Solute removal by various forms of renal replacement therapy (RRT) differs from that occurring in the native kidney in several ways. Among the dialytic therapies, the relationship between clearance and mass removal rate may differ substantially. The purpose of this article is to review the various approaches that have been proposed to account for this differing relationship among the various types of RRT. Specific quantitative approaches along with clinical applications are provided.

Determinants of haemodialyser performance and the potential effect on clinical outcome.

The performance of a dialyser is determined by several factors. Many of these factors relate to the dialyser membrane, including mean pore size, pore size distribution, wall thickness, surface area, and adsorptivity. In this article, several of these factors are reviewed. The potential impact of these factors on the clinical outcome of chronic haemodialysis patients is also discussed.

Quantitative characterization of hemodialyzer solute and water transport.

Clinicians are frequently faced with the task of selecting a hemodialyzer for a dialysis-dependent patient. Several quantitative dialyzer parameters, such as clearance, sieving coefficients, and ultrafiltration coefficient, are routinely used in this selection process. However, the quantitative basis and exact meaning of these indices are often unclear or misinterpreted. The purpose of this article is to provide a detailed description of several of these parameters with the hope that this information will enable clinicians to make dialyzer selection from a more quantitative perspective.

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.

Initial and superior experience with 30 minute TUMT.

Transurethral microwave thermotherapy (TUMT) is an evolving technique with different machines, protocols, intraprostatic temperatures, marketing claims, and clinical outcomes that can be confusing to the clinician. We report our initial and superior results with 30 Minute TUMT over previous treatment protocols in 16 patients. Patient discomfort and acceptance are greatly improved, with reduced analgesic requirements (11 vs. 24 mL of remifentanil), visual analogue pain scores of 0-2, and no power interruption required in any patients. All four patients in urinary retention are catheter-free 1 week after therapy. Post-treatment catheterization was required in only one patient who was voiding spontaneously before the procedure. Urinary flow rates and postvoid residuals improved in all patients. Prostatic cavities were found in all patients having prostate ultrasound 3 months after TUMT. 30 Minute TUMT is not simply a shortened 30-minute TUMT treatment. Rather it is a very different TUMT with an initial power of 80 W and initial urethral cooling water of 48 degrees F/8 degrees C. Mean maximum intraprostatic temperatures achieved are 154 degrees F/68 degrees C or 43 degrees F/24 degrees C greater than previous versions of microwave thermotherapy. 30 Minute TUMT s increased cooling and shorter times result in minimal discomfort and elimination of routine catheterization, but the initial 80-W energy and avoidance of power interruption provide higher intraprostatic temperatures and prostatic cavities in almost all patients in this office-based treatment.

Hemodialyzer membranes and configurations: a historical perspective.

The principle of hemodialysis (HD) was first described over a century ago while the first human HD treatment was performed in 1923 with collodion tubes. Since that time, a variety of different hemodialyzer configurations and membranes have been used. The purpose of this article is to provide a historical review of these various configurations and membranes. The rotating drum, coil, parallel flow, and hollow fiber artificial kidneys are discussed. Emphasis is placed on the factors that have influenced the shaping of the contemporary HD market.

Clinical evaluation of a new high efficiency hemodialyzer: polysynthane.

Two increasingly common characteristics of the American chronic hemodialysis (HD) population, high hematocrit and large body size, may render the currently recommended adequacy targets difficult to achieve, even with very efficient dialyzers. In a group of patients with these characteristics, we assessed the ability of a new high efficiency dialyzer (PSN210; Baxter Healthcare Corporation) to achieve the currently recommended adequacy targets. Six patients (mean pre-HD weight and hematocrit, 90.3 +/- 18.0 kg and 0.40 +/- 0.03 kg, respectively) were evaluated. At prescribed blood and dialysate flow rates of 400 and 800 ml/min, respectively, and a mean treatment duration of 4 hrs, mean delivered urea Kt/V and reduction ratio (URR) were 1.38 +/- 0.25 and 0.73 +/- 0.07, respectively. For the same flow rates, whole blood clearances for urea, creatinine, and phosphate were 315 +/- 13, 246 +/- 28, and 260 +/- 27 ml/min, respectively. These data indicate this dialyzer has an efficient mass transfer design allowing adequate dialysis to be delivered even to very large patients under high efficiency conditions.

Effect of membrane composition and structure on solute removal and biocompatibility in hemodialysis.

Effect of membrane composition and structure on solute removal and biocompatibility in hemodialysis. Significant changes in extracorporeal membranes have occurred over the past five decades in which hemodialysis (HD) has been available as a therapy for both acute renal failure (ARF) and end-stage renal disease (ESRD). For cellulosic membranes, these changes have included a reduction in thickness, hydroxyl group substitution, and an increase in pore size. These modifications have resulted in enhanced efficiency of small solute removal, a broader spectrum of overall solute removal, and an attenuation of complement activation in comparison to the thick, unsubstituted cellulosic membranes of low permeability used in the early days of HD therapy. Synthetic membranes, originally developed specifically for use in high-flux HD and hemofiltration, have also evolved during this same time period. In fact, the initially clear distinction between low-flux regenerated cellulosic and high-flux synthetic membranes has become blurred, as membrane formulators have developed products designed to appeal to enthusiasts for both membrane formats. The purpose of this review is to characterize both the solute removal and biocompatibility characteristics of dialysis membranes according to their composition (that is, polymeric makeup) and structure. In this regard, the manner in which membrane biocompatibility interacts with flux is highlighted.

CRRT efficiency and efficacy in relation to solute size.

Removal of blood solutes in patients with decreased or absent glomerular filtration is the prime objective of continuous renal replacement therapies (CRRTs). However, because these blood solutes are of different molecular weights, factors such as the porosity and hydrophobicity of the filter membranes and the extracorporeal flow rates determine the CRRT that is the most effective filtration system. This article discusses both small and large solute removal, the interaction of convection and diffusion, and the potential for CRRTs to remove particular inflammatory mediators of acute renal failure.

Effect of gender on the pharmacokinetics of ofloxacin.

STUDY OBJECTIVES: To assess the influence of gender on the pharmacokinetics of ofloxacin. DESIGN: Open-label study. SETTING: Academic medical center. PATIENTS: Five healthy men and seven healthy women volunteers. INTERVENTIONS: Subjects received a single oral dose of ofloxacin 400 mg, and serial blood samples were collected for 24 hours. Plasma concentrations of ofloxacin were determined by high-performance liquid chromatography and pharmacokinetic parameters were determined. Statistical comparisons between genders were made with the Wilcoxon rank sum test. MEASUREMENTS AND MAIN RESULTS: Median volume of distribution at steady state/systemic bioavailability (V(ss)/F) was significantly smaller in women than in men, although when normalized for total body weight there were no differences. Except for terminal elimination half-life, which was 10% shorter in women, no other pharmacokinetic values were significantly different between genders. Median peak concentrations, although not statistically different, were 28% higher in women. CONCLUSION: Ofloxacin V(ss)/F values were smaller in women than in men, explained by gender-related differences in weight.