Continuous renal replacement therapy principles.

Continuous renal replacement therapy (CRRT) is an extracorporeal blood purification therapy that aims to support kidney function over an extended period of time. One of the main objectives of CRRT is the removal of excess fluid and solutes retained as a consequence of acute kidney injury. Because prescription of CRRT requires goals to be set with regard to the rate and extent of solute and fluid removal, a comprehensive understanding of the mechanism by which solute and fluid removal occurs during CRRT is essential. Basic mechanisms of fluid transport and solute removal (ultrafiltration, diffusion, convection, and adsorption) and the factors influencing these processes in CRRT are described. From the combination of the different transport mechanisms, a number of CRRT modalities are identified and described. Finally, these principles are applied to provide a brief overview of the concept of effluent-based CRRT dose.

Extracorporeal Blood Purification and Organ Support in the Critically Ill Patient during COVID-19 Pandemic: Expert Review and Recommendation.

Critically ill COVID-19 patients are generally admitted to the ICU for respiratory insufficiency which can evolve into a multiple-organ dysfunction syndrome requiring extracorporeal organ support. Ongoing advances in technology and science and progress in information technology support the development of integrated multi-organ support platforms for personalized treatment according to the changing needs of the patient. Based on pathophysiological derangements observed in COVID-19 patients, a rationale emerges for sequential extracorporeal therapies designed to remove inflammatory mediators and support different organ systems. In the absence of vaccines or direct therapy for COVID-19, extracorporeal therapies could represent an option to prevent organ failure and improve survival. The enormous demand in care for COVID-19 patients requires an immediate response from the scientific community. Thus, a detailed review of the available technology is provided by experts followed by a series of recommendation based on current experience and opinions, while waiting for generation of robust evidence from trials.

Uremic Toxins and their Relation to Dialysis Efficacy.

Toxin retention is felt to be a major contributor to the development of uremia in patients with advanced chronic kidney disease and end-stage renal disease (ESRD). Uremic retention compounds are classically divided into 3 categories: small solutes, middle molecules, and protein-bound toxins. Compounds comprising the first category, for which the upper molecular weight limit is generally considered to be 500 Da, possess a high degree of water solubility and minimal or absent protein binding. The second category of middle molecules has largely evolved now to be synonymous with peptides and proteins that accumulate in uremia. Although not precisely defined, low-molecular weight proteins as a class have a molecular weight spectrum ranging from approximately 500 to 60,000 daltons. The final category of uremic retention compounds is protein-bound uremic toxins (PBUTs). As opposed to the above small, highly water-soluble toxins, which are largely by-products of protein metabolism, PBUTs have diverse origins and possess chemical characteristics that preclude the possibility of circulation in an unbound form despite being of low molecular weight. This review is the first in a series of papers designed to provide the current state of the art for extracorporeal treatment of ESRD. Subsequent papers in this series will address membranes, mass transfer mechanisms, and future directions. For small solutes and middle molecules, particular emphasis is placed on the important clinical trials that comprise the evidence base regarding the influence of dialytic solute removal on outcome. Because such trials do not exist for PBUTs, the discussion here is instead focused on solute characteristics and renal elimination mechanisms.

The future of critical care: renal support in 2027.

Since its inception four decades ago, both the clinical and technologic aspects of continuous renal replacement therapy (CRRT) have evolved substantially. Devices now specifically designed for critically ill patients with acute kidney injury are widely available and the clinical challenges associated with treating this complex patient population continue to be addressed. However, several important questions remain unanswered, leaving doubts in the minds of many clinicians about therapy prescription/delivery and patient management. Specifically, questions surrounding therapy dosing, timing of initiation and termination, fluid management, anticoagulation, drug dosing, and data analytics may lead to inconsistent delivery of CRRT and even reluctance to prescribe it. In this review, we discuss current limitations of CRRT and potential solutions over the next decade from both a patient management and a technology perspective. We also address the issue of sustainability for CRRT and related therapies beyond 2027 and raise several points for consideration.

Quantification and Dosing of Renal Replacement Therapy in Acute Kidney Injury: A Reappraisal.

BACKGROUND/AIMS: Delivered dialysis therapy is routinely measured in the management of patients with end-stage renal disease; yet, the quantification of renal replacement prescription and delivery in acute kidney injury (AKI) is less established. While continuous renal replacement therapy (CRRT) is widely understood to have greater solute clearance capabilities relative to intermittent therapies, neither urea nor any other solute is specifically employed for CRRT dose assessments in clinical practice at present. Instead, the normalized effluent rate is the gold standard for CRRT dosing, although this parameter does not provide an accurate estimation of actual solute clearance for different modalities. METHODS: Because this situation has created confusion among clinicians, we reappraise dose prescription and delivery for CRRT. RESULTS: A critical review of RRT quantification in AKI is provided. CONCLUSION: We propose an adaptation of a maintenance dialysis parameter (standard Kt/V) as a benchmark to supplement effluent-based dosing of CRRT. Video Journal Club "Cappuccino with Claudio Ronco" at http://www.karger.com/?doi=475457.

Nomenclature for renal replacement therapy in acute kidney injury: basic principles.

This article reports the conclusions of a consensus expert conference on the basic principles and nomenclature of renal replacement therapy (RRT) currently utilized to manage acute kidney injury (AKI). This multidisciplinary consensus conference discusses common definitions, components, techniques, and operations of the machines and platforms used to deliver extracorporeal therapies, utilizing a "machine-centric" rather than a "patient-centric" approach. We provide a detailed description of the performance characteristics of membranes, filters, transmembrane transport of solutes and fluid, flows, and methods of measurement of delivered treatment, focusing on continuous renal replacement therapies (CRRT) which are utilized in the management of critically ill patients with AKI. This is a consensus report on nomenclature harmonization for principles of extracorporeal renal replacement therapies. Devices and operations are classified and defined in detail to serve as guidelines for future use of terminology in papers and research.

Phase 1/2 study of orteronel (TAK-700), an investigational 17,20-lyase inhibitor, with docetaxel-prednisone in metastatic castration-resistant prostate cancer.

BACKGROUND: Docetaxel-prednisone (DP) is an approved therapy for metastatic castration-resistant prostate cancer (mCRPC). Orteronel (TAK-700) is an investigational, selective, non-steroidal inhibitor of 17,20-lyase, a key enzyme in androgenic hormone production. This phase 1/2 study evaluated orteronel plus DP in mCRPC patients. METHODS: Adult men with chemotherapy-naïve mCRPC, serum prostate-specific antigen (PSA) ≥5 ng/mL, and serum testosterone <50 ng/dL received oral orteronel 200 or 400 mg twice-daily (BID) in phase 1 to determine the recommended dose for phase 2, plus intravenous docetaxel 75 mg/m(2) every 3 weeks, and oral prednisone 5 mg BID. Phase 2 objectives included safety, pharmacokinetics, and efficacy. RESULTS: In phase 1 (n = 6, orteronel 200 mg; n = 8, orteronel 400 mg), there was one dose-limiting toxicity of grade 3 febrile neutropenia at 400 mg BID. This dose was evaluated further in phase 2 (n = 23). After 4 cycles, 68, 59, and 23% of patients achieved ≥30, ≥50, and ≥90% PSA reductions, respectively; median best PSA response was -77%. Seven of 10 (70%) RECIST-evaluable patients achieved objective partial responses. Median time to PSA progression and radiographic disease progression was 6.7 and 12.9 months, respectively. Dehydroepiandrosterone-sulfate (DHEA-S) and testosterone levels were rapidly and durably reduced. Common adverse events were fatigue (78%), alopecia (61%), diarrhea (48%), nausea (43%), dysgeusia (39%), and neutropenia (39%). Orteronel and docetaxel pharmacokinetics were similar alone and in combination. CONCLUSIONS: Orteronel plus DP was tolerable, with substantial reductions in PSA, DHEA-S, and testosterone levels, and evidence for measurable disease responses.

InAlAs/InGaAs avalanche photodiode arrays for free space optical communication.

In free space optical communication, photodetectors serve not only as communications receivers but also as position sensitive detectors (PSDs) for pointing, tracking, and stabilization. Typically, two separate detectors are utilized to perform these tasks, but recent advances in the fabrication and development of large-area, low-noise avalanche photodiode (APD) arrays have enabled these devices to be used both as PSDs and as communications receivers. This combined functionality allows for more flexibility and simplicity in optical system design without sacrificing the sensitivity and bandwidth performance of smaller, single-element data receivers. This work presents the development of APD arrays rated for bandwidths beyond 1 GHz with measured carrier ionization ratios of approximately 0.2 at moderate APD gains. We discuss the fabrication and characterization of three types of APD arrays along with their performance as high-speed photodetectors.

Pleistocene and ecological effects on continental-scale genetic differentiation in the bobcat (Lynx rufus).

The potential for widespread, mobile species to exhibit genetic structure without clear geographic barriers is a topic of growing interest. Yet the patterns and mechanisms of structure--particularly over broad spatial scales--remain largely unexplored for these species. Bobcats occur across North America and possess many characteristics expected to promote gene flow. To test whether historical, topographic or ecological factors have influenced genetic differentiation in this species, we analysed 1 kb mtDNA sequence and 15 microsatellite loci from over 1700 samples collected across its range. The primary signature in both marker types involved a longitudinal cline with a sharp transition, or suture zone, occurring along the Great Plains. Thus, the data distinguished bobcats in the eastern USA from those in the western half, with no obvious physical barrier to gene flow. Demographic analyses supported a scenario of expansion from separate Pleistocene refugia, with the Great Plains representing a zone of secondary contact. Substructure within the two main lineages likely reflected founder effects, ecological factors, anthropogenic/topographic effects or a combination of these forces. Two prominent topographic features, the Mississippi River and Rocky Mountains, were not supported as significant genetic barriers. Ecological regions and environmental correlates explained a small but significant proportion of genetic variation. Overall, results implicate historical processes as the primary cause of broad-scale genetic differentiation, but contemporary forces seem to also play a role in promoting and maintaining structure. Despite the bobcat's mobility and broad niche, large-scale landscape changes have contributed to significant and complex patterns of genetic structure.

Mass Transport in High-Flux Hemodialysis: Application of Engineering Principles to Clinical Prescription.

An understanding of the processes underlying mass transfer is paramount for the attainment of adequate solute removal in the dialytic treatment of patients with kidney failure. In this review, engineering principles are applied to characterize the physical mechanisms behind the two major modes of mass transfer during hemodialysis, namely diffusion and convection. The manner in which flow rate, dialyzer geometry, and membrane microstructure affect these processes is discussed, with concepts such as boundary layers, effective membrane diffusivity, and sieving coefficients highlighted as critical considerations. The objective is to improve clinicians' understanding of these concepts as important factors influencing the prescription and delivery of hemodialysis therapy.

Stochastic population dynamics in populations of western terrestrial garter snakes with divergent life histories.

Comparative evaluations of population dynamics in species with temporal and spatial variation in life-history traits are rare because they require long-term demographic time series from multiple populations. We present such an analysis using demographic data collected during the interval 1978-1996 for six populations of western terrestrial garter snakes (Thamnophis elegans) from two evolutionarily divergent ecotypes. Three replicate populations from a slow-living ecotype, found in mountain meadows of northeastern California, were characterized by individuals that develop slowly, mature late, reproduce infrequently with small reproductive effort, and live longer than individuals of three populations of a fast-living ecotype found at lakeshore locales. We constructed matrix population models for each of the populations based on 8-13 years of data per population and analyzed both deterministic dynamics based on mean annual vital rates and stochastic dynamics incorporating annual variation in vital rates. (1) Contributions of highly variable vital rates to fitness (lambda(s)) were buffered against the negative effects of stochastic variation, and this relationship was consistent with differences between the meadow (M-slow) and lakeshore (L-fast) ecotypes. (2) Annual variation in the proportion of gravid females had the greatest negative effect among all vital rates on lambda(s). The magnitude of variation in the proportion of gravid females and its effect on lambda(s) was greater in M-slow than L-fast populations. (3) Variation in the proportion of gravid females, in turn, depended on annual variation in prey availability, and its effect on lambda(s) was 4 23 times greater in M-slow than L-fast populations. In addition to differences in stochastic dynamics between ecotypes, we also found higher mean mortality rates across all age classes in the L-fast populations. Our results suggest that both deterministic and stochastic selective forces have affected the evolution of divergent life-history traits in the two ecotypes, which, in turn, affect population dynamics. M-slow populations have evolved life-history traits that buffer fitness against direct effects of variation in reproduction and that spread lifetime reproduction across a greater number of reproductive bouts. These results highlight the importance of long-term demographic and environmental monitoring and of incorporating temporal dynamics into empirical studies of life-history evolution.

A real-time assay for cell-penetrating peptide-mediated delivery of molecular cargos.

Cell-penetrating peptides (CPPs) are capable of transporting molecules to which they are tethered across cellular membranes. Unsurprisingly, CPPs have attracted attention for their potential drug delivery applications, but several technical hurdles remain to be overcome. Chief among them is the so-called 'endosomal escape problem,' i.e. the propensity of CPP-cargo molecules to be endocytosed but remain entrapped in endosomes rather than reaching the cytosol. Previously, a CPP fused to calmodulin that bound calmodulin binding site-containing cargos was shown to efficiently deliver cargos to the cytoplasm, effectively overcoming the endosomal escape problem. The CPP-adaptor, "TAT-CaM," evinces delivery at nM concentrations and more rapidly than we had previously been able to measure. To better understand the kinetics and mechanism of CPP-adaptor-mediated cargo delivery, a real-time cell penetrating assay was developed in which a flow chamber containing cultured cells was installed on the stage of a confocal microscope to allow for observation ab initio. Also examined in this study was an improved CPP-adaptor that utilizes naked mole rat (Heterocephalus glaber) calmodulin in place of human and results in superior internalization, likely due to its lesser net negative charge. Adaptor-cargo complexes were delivered into the flow chamber and fluorescence intensity in the midpoint of baby hamster kidney cells was measured as a function of time. Delivery of 400 nM cargo was observed within seven minutes and fluorescence continued to increase linearly as a function of time. Cargo-only control experiments showed that the minimal uptake which occurred independently of the CPP-adaptor resulted in punctate localization consistent with endosomal entrapment. A distance analysis was performed for cell-penetration experiments in which CPP-adaptor-delivered cargo showing wider dispersions throughout cells as compared to an analogous covalently-bound CPP-cargo. Small molecule endocytosis inhibitors did not have significant effects upon delivery. The real-time assay is an improvement upon static endpoint assays and should be informative in a broad array of applications.

Blood-membrane interactions during dialysis.

In extracorporeal renal replacement therapies, the dialyzer is not only the site at which solute removal occurs but also the extracorporeal circuit component having the largest surface area exposed to blood. Therefore, it is not surprising that interactions between blood components and the dialyzer membrane influence the dialysis procedure in several ways. Based on engineering principles, fluid flow along a surface such as membrane results in the development of a boundary layer which can influence solute removal. Furthermore, the exposure of blood to any extracorporeal artificial surface results in the activation of several pathways within the body, including those involving coagulation and complement activation. One of the byproducts of this generalized activation process is protein adsorption to the membrane surface, another phenomenon which can have a significant impact on solute removal. In this article, a detailed review of the ways in which blood-membrane interactions influence solute removal during hemodialysis and related therapies is provided. The influences of secondary membrane formation and boundary layer/concentration polarization effects on solute removal are specifically discussed. Furthermore, the importance of adsorption as a specific removal mechanism for low-molecular weight proteins by highly permeable synthetic membranes is highlighted.

Emergency medical services education and licensure--a road map for the future.

Fragmentation exists nationwide in regards to Emergency Medical Services (EMS). This fragmentation is evident throughout the EMS system in the way we educate, train, certify, and recertify the pre-hospital professional. In Louisiana EMS, there are two facets of our education system: the training/education institution and the instructors who facilitate the education. However, there is no mandated credentialing of the institution doing the teaching. Currently, the State of Louisiana utilizes both the National Registry of Emergency Medical Technicians computer-based written examination as well as their practical examination. Louisiana has four provider levels of EMS professionals: First Responder (FR), Emergency Medical Technician-Basic (EMT-B), EMT-Intermediate/85 (EMT-I/85), and EMT-Paramedic. Creating consistency in the levels of EMS will enhance both education and patient care ensuring that all citizens of the state will receive the most appropriate and up to date pre-hospital care. Louisiana will also be adopting the National Registry's Accreditation Policy, which will require all advanced level education (Paramedic) to be conducted by CoAEMSP (Committee on Accreditation of Educational Programs for the EMS Profession) institutions. Louisiana's challenge will exist with the adoption of the Scope of Practice Model levels and the movement of our current certification system to a licensure system. The goal is to create an EMS system in Louisiana that is substantiated by a national curriculum, national accreditation, a national scope of practice and the passage of a national examination.

Haemodialysis membranes.

Haemodialysis is an extracorporeal process in which the blood is cleansed via removal of uraemic retention products by a semipermeable membrane. Traditionally, dialysis membranes have been broadly classified on the basis of their composition (cellulosic or noncellulosic) and water permeability (low flux or high flux). However, advances in materials technology and polymer chemistry have led to the development of membranes with specific characteristics and refined properties that mandate a reconsideration of traditional membrane classification systems. For adequate characterization of these newer types of membranes, additional parameters are now relevant, including new permeability indices, the hydrophilic or hydrophobic nature of membranes, adsorption capacity and electrical potential. In this Review, we provide clinicians with an updated analysis of dialysis membranes and dialysers. We discuss the basic mechanisms that underlie solute and water removal in dialysis (that is, diffusion, convection, adsorption and ultrafiltration) in the context of treatments that use highly permeable membranes. Specifically, we highlight online haemodiafiltration and new therapies (for example, expanded haemodialysis) that utilize membranes designed to produce a high degree of internal filtration. Finally, we discuss the considerations that govern the clinically acceptable balance between large-solute clearance and albumin loss for extracorporeal therapies.

Membranes and Sorbents.

For continuous renal replacement therapy (CRRT), the extracorporeal filter provides solute depuration, fluid removal, and control of electrolyte and acid-base balance in critically ill patients with acute kidney injury (AKI). The membranes comprising CRRT filters are almost exclusively based on hollow fiber designs and, while adapted from the chronic hemodialysis field, have features that are specific to the requirements of CRRT nevertheless. In addition, these devices have evolved through the 40 years of CRRT in response to changes in clinical practice and the desire to extend the solute removal spectrum. For some critically ill patients, more targeted removal of specific compounds poorly cleared by standard CRRT can be attempted with techniques based on adsorption. Sorbent hemoperfusion is now being applied more broadly in critically ill patients, especially in those with sepsis and systemic inflammation. In this review, the manner in which CRRT membranes and extracorporeal sorbents have evolved over the past 40 years for the treatment of critically ill patients with AKI and other disorders is described.

Advances in Machine Technology.

Continuous renal replacement therapy (CRRT) machines have evolved into devices specifically designed for critically ill over the past 40 years. In this chapter, a brief history of this evolution is first provided, with emphasis on the manner in which changes have been made to address the specific needs of the critically ill patient with acute kidney injury. Subsequently, specific examples of technology developments for CRRT machines are discussed, including the user interface, pumps, pressure monitoring, safety features, and anticoagulation capabilities.

Renal replacement therapy for AKI: When? How much? When to stop?

Severe acute kidney injury (AKI) requiring renal replacement therapy (RRT) is a serious clinical disorder in the intensive care unit (ICU), occurring in a significant proportion of critically ill patients. However, many questions remain about the optimal administration of RRT with regard to several important considerations, including treatment dose, timing of treatment initiation and cessation, therapy mode, type of anticoagulation, and management of fluid overload. While Level 1 evidence exists for RRT dosing in AKI, all the studies contributing to this evidence base employed fixed-dose regimens throughout a patient's continuous RRT (CRRT) course, without regard for the possibility of individualizing treatment dose according to the clinical status of a given patient at a specific time. As opposed to CRRT dose, no consensus about the timing of RRT in critically ill AKI patients exists currently. While numerous clinical trials over the past 40 years have attempted to assess "early" versus "late" initiation of RRT, they have been plagued by a myriad of methodological problems, including their largely observational nature and the widely varying definitions of early and late initiation. Although questions about the appropriate timing of CRRT discontinuation arise very frequently in clinical practice, even less information is available in the literature to guide this important decision. The aim of this review is to provide a comprehensive update on RRT delivery to critically ill AKI patients, with specific attention paid to treatment dose and timing and emphasis on addressing the practical questions that arise in daily clinical practice.

Solute Transport in Hemodialysis: Advances and Limitations of Current Membrane Technology.

Extracorporeal therapy for end-stage renal disease is now provided to more than three million patients globally. Nearly all treatments are performed with filters containing hollow fiber membranes, removing solutes and water by diffusion, convection, and ultrafiltration. In this review, we will provide a detailed quantitative analysis of the transport processes involved in different hemodialysis (HD) therapies. We will also report some technical aspects of hollow fiber membranes and filters composed of them along with the mechanisms of solute and water removal for such devices. Diffusive mass transfer will be assessed according to the three major aspects of a hollow fiber filter (blood compartment, membrane, and dialysate compartment). With regard to convective transport, the importance of internal filtration as a solute removal mechanism in high-flux HD will be highlighted, along with the critical role that blood/membrane interactions assume in filtration-based therapies.

Extracorporeal Sorbent Technologies: Basic Concepts and Clinical Application.

Limitations imposed by the characteristics of some solutes and the structure of dialysis membranes have spurred new interest in the use of mechanisms beyond diffusion and convection for extracorporeal solute removal. Sorbents have been utilized for more than 50 years in extracorporeal blood treatments for specific purposes, and better understanding of their basic aspects may further expand the potential for their clinical application. In this chapter, the basic principles applying to sorbents are discussed, including composition and structure, along with the fundamental mechanisms of solute removal. The critical importance of sorbent biocompatibility is also highlighted. With these basic principles in mind, the clinical application of sorbents is discussed, with an emphasis on the use of hemoperfusion and coupled plasma filtration-adsorption for sepsis-related disorders. Finally, new sorbent-based clinical approaches for acute conditions and end-stage renal disease are presented, emphasizing that sorbent technologies may assume a larger role for a variety of clinical disorders in the future.