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.

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.

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.

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.

Multidimensional Classification of Dialysis Membranes.

Hemodialysis is a process of mass separation by a semipermeable membrane, utilized to cleanse blood from waste products retained in case of kidney failure. Traditionally, dialysis membranes have been classified based on composition and hydraulic conductance, creating the net differentiation between cellulosic versus non-cellulosic on one hand and low-flux versus high-flux on the other. With the evolution of biomaterials and improved spinning technology, new membranes have been introduced in the market with specific characteristics and refined individual properties. Therefore, we should consider new parameters to classify dialysis membranes including polymer blending, surface functionalization, molecular weight cut-off (MWCO), hydrophilic/hydrophobic properties, thickness and architecture, adsorption capacity, and electric potential. All these parameters may be utilized to characterize a membrane alone or in combination. Recently, a new parameter has been identified as an important element to characterize a new class of membranes. Beyond the classic MWCO describing the molecular weight at which the sieving value in pure convection = 0.1, the molecular weight retention onset (MWRO) is a new parameter that defines membrane sieving properties. The retention onset value is the molecular weight at which the sieving value = 0.9. The relationship between MWCO and MWRO describes the steepness of the sieving curve and the membrane pore size distribution with important consequences on the final mass separation process and solute removal.

Modeling of Internal Filtration in Theranova Hemodialyzers.

High retention onset (HRO) is the designation for a new class of hemodialysis membranes. A unique characteristic of this class is the highly selective and controlled porosity resulting in sieving properties that provide a clinically desirable balance between middle/large molecular weight solute removal and albumin loss. Another defining feature of this membrane class is the relatively small fiber diameter, which produces high convective volumes in the form of internal filtration. The aim of the present study was to estimate, by semi-empirical methods, convective volumes for 2 new HRO dialyzers: Theranova 400 and Theranova 500 (Baxter International Inc., Deerfield, IL, USA). Axial blood and dialysate compartment pressure drop along with transmembrane pressure, measured in vitro with blood (Qb = 300 or 400 mL/min; Qd = 500 mL/min; net ultrafiltration rate = 0), served as input parameters for 3 different models: linear, geometric, and (non-linear) mathematical. Based on the most rigorous mathematical model, the estimated convective volumes were 1,661 mL/h (Qb = 300 mL/min) and 1,911 mL/h (Qb = 400 mL/min) for Theranova 400 and 1,864 mL/h (Qb = 300 mL/min) and 1,978 mL/h (Qb = 400 mL/min) for Theranova 500. These results suggest that the unique fiber characteristics of this new class of membranes provide substantial convective volumes without the need for exogenous substitution fluid. As such, HRO membranes are a major end-stage renal disease treatment advance in the quest to enhance the removal of larger-sized uremic toxins.

Renal replacement therapy practices for patients with acute kidney injury in China.

Recent data indicate AKI is very common among hospitalized Chinese patients and continuous renal replacement therapy (CRRT) is increasingly offered for treatment. However, only anecdotal information regarding CRRT's use in relation to other modalities and the specific manner in which it is prescribed exists currently. This report summarizes the results of a comprehensive physician survey designed to characterize contemporary dialytic management of AKI patients in China, especially with respect to the utilization of CRRT. The survey queried both nephrologists and critical care physicians across a wide spectrum of hospitals about factors influencing initial RRT modality selection, especially patient clinical characteristics and willingness to receive RRT, treatment location, and institutional capabilities. For patients initially treated with CRRT, data related to indication, timing of treatment initiation, dose, anticoagulation technique, and duration of therapy were also collected. Among AKI patients considered RRT candidates, the survey indicated 15.1% (95% CI, 12.3%-17.9%) did not actually receive dialysis at Chinese hospitals. The finding was largely attributed to prohibitively high therapy costs in the view of patients or their families. The survey confirmed the dichotomy in RRT delivery in China, occurring both in the nephrology department (with nephrologists responsible) and the intensive care unit (with critical care physicians responsible). For all patients who were offered and received RRT, the survey participants reported 63.9% (56.4%-71.3%) were treated initially with CRRT and 24.8% (19.2%-30.3%) with intermittent hemodialysis (HD) (P<0.001). The mean percentage of patients considered hemodynamically unstable at RRT initiation was 36.2% (31.3%-41.1%), although this figure was two-fold higher in patients treated initially with CRRT (43.1%; 35.8%-50.4%) in comparison to those initially treated with HD (22.4%; 16.4%-28.4%)(P<0.001). An overwhelming majority of intensive care patients were treated initially with CRRT (86.6%; 79.8-93.4%) while it was the initial modality in only 44.6% (33.5-55.7%) of patients treated in a nephrology department (P<0.001). Approximately 70% of respondents overall reported prescribing a CRRT dose in the range of 20-30 mL/kg/hr while approximately 20% of prescriptions fell above this range. Daily prescribed therapy duration demonstrated a marked divergence from values reported in the literature and standard clinical practice. Overall, the most common average prescribed value (50% of respondents) fell in the 10-20 hr range, with only 18% in the 20-24 hr range. Moreover, 32% of respondents reported an average prescribed value of less than 10 hrs per day. While the percentages for the 10-20 hrs range were essentially the same for nephrology and ICU programs, a daily duration of less than 10 hrs was much more common in nephrology programs (48.0%; 38.3%-57.9%) versus ICU programs (16%; 10.0%-24.6%)(P<0.001). Our analysis demonstrates both similarities and differences between RRT practices for AKI in China and those in the developed world. While some differences are driven by non-medical factors, future studies should explore these issues further as Chinese RRT practices are harmonized with those in the rest of the world.

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.

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.

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.

Data analytics for continuous renal replacement therapy: historical limitations and recent technology advances.

PURPOSE: Dialysis is a highly quantitative therapy involving large volumes of both clinical and technical data. While automated data collection has been implemented for chronic dialysis, this has not been done for acute kidney injury patients treated with continuous renal replacement therapy (CRRT). METHODS: After a brief review of the fundamental aspects of electronic medical records (EMRs), a new tool designed to provide clinicians with individualized CRRT treatment data is analyzed, with emphasis on its quality assurance capabilities. RESULTS: The first platform addressing the problem of data collection and management with current CRRT machines (Sharesource system; Baxter Healthcare) is described. The system provides connectivity for the Prismaflex CRRT machine and enables both EMR connectivity and therapy analytics with 2 basic components: the connect module and the report module. CONCLUSIONS: The enormous amount of data in CRRT should be collected and analyzed to enable adequate clinical decisions. Current CRRT technology presents significant limitations with consequent lack of rigorous analysis of technical data and relevant feedback. From a quality assurance perspective, these limitations preclude any systematic assessment of prescription and delivery trends that may be adversely affecting clinical outcomes. A detailed assessment of current practice limitations is provided together with several possible ways to address such limitations by a new technical tool.

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.

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.

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.