Fiorenza Ferrari

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.

Prospective, randomized, multicenter, controlled trial (TRIATHRON 1) on a new antithrombogenic hydrophilic dialysis membrane

Introduction Hemodialysis treatment requires anticoagulation to prevent thrombosis of the dialyzer. The Hydrolink® (NV series; Toray) has been designed to reduce thrombotic complications by increasing membrane hydrophilic properties. Previous studies have confirmed reduced platelet activation, improved removal of β2-microglobulin and excellent small-solute removal. Methods We designed a prospective, multi-centered, randomized clinical study to compare the antithrombogenic effects (platelet count) of NV dialyzers versus conventional treatment. To compare the possibility of performing heparin-free dialysis, we carried out progressive heparin reduction tests. Patients with an average platelet count lower than 170,000 cells/mm3 using standard high flux membranes in the 6 months prior to the study were enrolled and randomized. Patients were either dialyzed for 6 months without changing the previous membrane (control group) or treated with the Hydrolink® membrane (NV group). After the third week, the heparin reduction test was conducted for 5 weeks in order to assess the minimum amount of anticoagulant needed to safely perform a 4-hour dialysis treatment. Performance and safety were evaluated measuring platelet count and activation, middle-molecule removal rate and nutritional status. Results We found no significant difference in platelet count, platelet activation factors β-thromboglobulin and platelet factor 4 (PF-4), between the groups. More patients in the study group reached heparin-free dialysis without clotting events during the heparin reduction test. The NV dialyzers displayed anti-thrombogenic effects as compared to conventional dialyzers. Conclusions The NV dialyzer series is safe with no adverse events reported. Further studies are required to understand the mechanisms of anti-thrombogenic effects.

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.

Routine Adoption of TIMP2 and IGFBP7 Biomarkers in Cardiac Surgery for Early Identification of Acute Kidney Injury

Background and purpose Acute Kidney Injury (AKI) is a severe complication affecting many hospitalized patients after cardiac surgery, with negative impacts on short- and long-term clinical outcomes and on healthcare costs. Recently, clinical interest has been aimed at defining and classifying AKI, identifying risk factors and developing diagnostic strategies to identify patients at risk early on. Achieving an early and accurate diagnosis of AKI is a crucial issue, because prevention and timely detection may help to prevent negative clinical outcomes and avoid AKI-associated costs. In this retrospective study, we evaluate the NephroCheck Test as a diagnostic tool for early detection of AKI in a high-risk population of patients undergoing cardiac surgery at the San Bortolo Hospital of Vicenza. Methods We assessed the ability of the NephroCheck Test to predict the probability of developing CSA-AKI (cardiac surgery-associated AKI) and evaluated its accuracy as a diagnostic test, by building a multivariate logistic regression model for CSA-AKI prediction. Results Based on our findings, when the results of the NephroCheck Test are included in a multivariate model its performance is substantially improved, as compared to the benchmark model, which only accounts for the other clinical factors. We also define a rule – in terms of a probability cut-off – for discriminating cases that are at higher risk of developing AKI of any stage versus those in which AKI is less likely. Conclusions Our study has implications in clinical practice: when a Nephrocheck Test result is >0.3 ng/dL, an automated electronic alert prompts the physician to intervene by following a checklist of preventive measures.

The Influence of Glucose Exposure Load and Peritoneal Membrane Transport on Body Composition and Nutritional Status Changes after 1 Year on Peritoneal Dialysis

Background: The characteristics of peritoneal membrane transport differ among patients, affecting the prescription of peritoneal dialysis (PD) modality and glucose exposure in order to achieve an effective dialysis. This study aims to verify the influence of glucose exposure load and peritoneal membrane transport on body composition and nutritional status changes after the first year of PD. Methods: We examined a cohort of 85 incident PD patients during the first year of treatment. We established a cut-off of 5% to define changes in dry weight (DW), lean tissue mass (LTM), and fat mass (FM). Results: In total, 50.6% of the patients presented DW gain, 41.2% showed LTM loss, and 65.9% presented FM gain. Over the time (T0 – T12), we found significant differences in DW, body mass index (BMI), adipose tissue mass (ATM), FM and fat tissue index (FTI). Patients with lower dialysate-to-plasma creatinine ratio showed DW and FM gain. We observed a higher percentage of nonfast transporters in DW gain when comparing with DW no gain. As for glucose exposure load, no body composition changes were seen. Conclusions: Most patients presented DW gain, FM gain, and LTM loss. The characteristics of peritoneal membrane transport affected DW during the first year, changes being greater in nonfast than in fast transporters.

Kinetics of Linezolid in Continuous Renal Replacement Therapy: An in Vitro Study

Background: Continuous veno-venous hemofiltration (CVVH) could affect the pharmacokinetic profile of linezolid (LZD). The aim of this study was to evaluate the LZD extracorporeal clearance using an in vitro CVVH model. Methods: A sham miniaturized CVVH circuit (CARPEDIEM; Bellco, Mirandola, Italy) was set up with a polysulfone hemofilter (0.25 m2; cutoff 50,000 Da) for 240 minutes using normal saline solution (0.9% wt/vol NaCl) and blood (n = 6) spiked with LZD. Drug solution samples were collected during CVVH at 10, 30, 60, 120, and 240 minutes. LZD levels were measured by high-performance liquid chromatography. Results: Results were used to estimate pharmacokinetic parameters. The LZD baseline level decreased from 17.24 ± 0.54 to 9.73 ± 4.85 mg/L and from 11.75 ± 0.08 to 5.01 ± 0.67 mg/L in the first 10 minutes, and then increased to 13.2 ± 3.10 and 7.4 ± 0.71 mg/L in normal saline solution and blood, respectively. Mass balance analysis reported a rapid adsorption of LZD onto a polysulfone membrane followed by its release: a rebound phenomenon occurred. Conclusions: Although further studies are necessary to clarify this phenomenon, LZD level variations observed in our study should be considered to avoid antimicrobial underexposure. Several strategies are available for adjusting the dosage regimen of LZD, but therapeutic drug monitoring is highly recommended when it is used.

Antibiotic Adjustment in Continuous Renal Replacement Therapy

Abstract The management of infection in the intensive care unit represents an imperative challenge for critical care clinicians. At present, antibiotic dosing regimens are derived from studies on healthy volunteers and do not account for these major differences in drug prescriptions. The chapter summarizes the pharmacokinetic/pharmacodynamics relationship changes in antimicrobial agents resulting from the typical homeostatic disturbance or altered end-organ function of the critical illness. The focus is on how the renal clearance alterations or continuous renal replacement therapy may affect individual antimicrobial dosage and dosing interval of the antimicrobial agents.

Discontinuation of Continuous Renal Replacement Therapy and Dialysis Dependence

Renal replacement therapy (RRT) is a form of extracorporeal support for critical patients, especially for those with acute kidney injury. This therapy enables to gain adequate control over the great metabolic and fluids demand when kidneys are not able to do so; this condition is habitually present in patients who are admitted to intensive care units. However, it is also clear that these patients present a higher mortality rate and, in some cases, complications associated with the therapy. Therefore, it is fundamental to optimize and customize different aspects of RRT that range from the ideal timing including the modality and the dose until its suspension or ending. There currently is a great deal of controversy in all of these RRT-related topics. Although different predictive models have been proposed to determine the optimal timing of therapy discontinuation, nowadays urine output, serum and urine creatinine levels are perhaps the only variables associated with effective discontinuation. Future studies should focus on more accurately predicting renal recovery. This review provides an approach based on current evidence regarding effective discontinuation.

Predicting Acute Kidney Injury in Intensive Care Unit Patients: The Role of Tissue Inhibitor of Metalloproteinases-2 and Insulin-Like Growth Factor-Binding Protein-7 Biomarkers

Background: Acute kidney injury (AKI) diagnosis is based on a rise in serum creatinine and/or fall in urine output. It has been shown that there are patients that fulfill AKI definition but do not have AKI, and there are also patients with evidence of renal injury who do not meet any criteria for AKI. Recently the innovative and emerging proteomic technology has enabled the identification of novel biomarkers that allow improved risk stratification. Methods: Tissue inhibitor of metalloproteinases-2 (TIMP-2), insulin-like growth factor-binding protein 7 (IGFBP7) were measured to a cohort of 719 consecutive patients admitted to Intensive Care Unit (ICU). The primary endpoint was the evaluation of clinical performances of the biomarkers focusing on the probability do develop AKI in the first 7 days. Results: The Kaplan-Meier analysis considering the first 7 days of ICU stay suggested a lower risk of developing AKI (p < 0.0001) for patients with a negative (<0.3; TIMP-2*IGFBP7) test. Conclusion: (TIMP-2*IGFBP7) at ICU admission has a good performance in predicting AKI, especially in the first 4 days in ICU.

Development of the New Kibou® Equipment for Continuous Renal Replacement Therapy from Scratch to the Final Configuration

A new technology has recently appeared in the area of extracorporeal therapies for critically ill patients with acute kidney injury. The International Renal Research Institute of Vicenza was involved from the beginning in the development of a new continuous renal replacement therapy (CRRT) equipment with peculiar characteristics. We report the overall experience from design of the new machine to its in vitro and in vivo testing. Kibou® (Asahi Kasei Kuraray Medical Co., Ltd., Tokyo, Japan) is a new multifunctional machine designed for delivering RRT. Kibou® carries out many features of the fourth generation CRRT machines including the possibility of a dynamic prescription and reduction of nursing workload. We describe our first experience with this new device, focusing on several usability and performance parameters. A specific in vitro protocol was designed to analyze the various characteristics and accuracy of performance of the machine. Furthermore, a preliminary in vivo alpha trial with 12 CRRT sessions was performed to test, characterize and evaluate the machine in terms of usability, flexibility and reliability. The in vitro evaluation confirmed an adequate design and a good usability of the machine with accurate delivery of prescribed parameters. No adverse events were observed during the in vivo test that confirmed usability and safety together with accuracy of treatment delivery in different modalities. In general, the machine was rated by physicians and nurses involved in the evaluation as practical and easy to use, although a specific training is required to familiarize with the equipment. A large-scale multicenter beta trial is required to confirm the results reported in this preliminary evaluation in terms of safety, accuracy and performance of Kibou®.