Multifunctional laser-induced graphene circuits and laser-printed nanomaterials toward non-invasive human kidney function monitoring.

Faced with the increasing prevalence of chronic kidney disease (CKD), portable monitoring of CKD-related biomarkers such as potassium ion (K+), creatinine (Cre), and lactic acid (Lac) levels in sweat has shown tremendous potential for early diagnosis. However, a rapidly manufacturable portable device integrating multiple CKD-related biomarker sensors for ease of sweat testing use has yet to be reported. Here, a portable electrochemical sensor integrated with multifunctional laser-induced graphene (LIG) circuits and laser-printed nanomaterials based working electrodes fabricated by fully automatic laser manufacturing is proposed for non-invasive human kidney function monitoring. The sensor comprises a two-electrode LIG circuit for K+ sensing, a three-electrode LIG circuit with a Kelvin compensating connection for Cre and Lac sensing, and a printed circuit board based portable electrochemical workstation. The working electrodes containing Cu and Cu2O nanoparticles fabricated by two-step laser printing show good sensitivity and selectivity toward Cre and Lac sensing. The sensor circuits are fabricated by generating a hydrophilic-hydrophobic interface on a patterned LIG through laser. This sensor recruited rapid laser manufacturing and integrated with multifunctional LIG circuits and laser-printed nanomaterials based working electrodes, which is a potential kidney function monitoring solution for healthy people and kidney disease patients.

Transcutaneous Measurement of Glomerular Filtration Rate in Rodents.

Glomerular filtration rate (GFR) is considered the gold standard to test kidney function. However, the serial blood and/or urine sample collection required for the calculation of the GFR is stressful for the animal and time consuming for the experimenter. Here, we describe a transcutaneous assessment of renal function in conscious animals that does not require plasma or urine sampling and/or deep anesthesia. For the measurement, we use a near-infrared (NIR) device that records the excretion kinetic of the renal marker ABZWCY-HPßCD. ABZWCY-HPßCD is a new hydrophilic, stable, and nontoxic NIR fluorescent agent that can be used as a renal marker as it is filtrated and completely excreted through the kidneys into the urine without reabsorption or secretion and without accumulation in the skin. The data recorded in the device are then analyzed with "GFRmeasure," an open-source, freely downloadable, and user-friendly software.

Isolating Urinary Extracellular Vesicles as Biomarkers for Diabetic Disease.

Extracellular vesicles are lipid bilayer enclosed structures secreted by all cell types. Their cargo includes proteins, lipids, RNAs, and DNA, which reflect the physiological state of their cells of origin. Recently, urinary extracellular vesicles have emerged as a valuable source of biomarkers for kidney and systemic disease.Unfortunately, all existing methods for extracellular vesicle isolation from urine are time consuming and/or expensive. Thus, they are not adaptable to large-scale studies and unsuitable for clinical use without special equipment in the laboratory. Recently, our group has devised a set of new, quick, simple, and inexpensive techniques, based on hydrostatic filtration dialysis (HFD) of urine extremely suitable for diagnostic purposes. This novel approach represents a great potential for new diagnostics and understanding disease biology in general and brings the biomarker detection to the scope of all laboratories.

Transdermal optical renal function monitoring in humans: development, verification, and validation of a prototype device.

A prototype medical device for monitoring kidney function by transdermal measurement of the clearance rate of the exogenous fluorescent tracer agent MB-102 (administered intravenously) was developed. Verification of the device with an in vitro protocol is described. The expected renal clearance of the agent was mimicked by preparing a dilution series of MB-102 in the presence of a scattering agent. The slope of a linear fit to the logarithm of fluorescence intensity as a function of dilution step agreed with predictions within 5%, a level of accuracy that would be adequate in assessment of GFR to prevent misdiagnosis of kidney disease. Transdermal measurement was validated using a rat model. A two-compartment pharmacokinetic dependence was observed, with equilibration of the fluorescent agent between the vascular space into which it was injected and the extracellular space into which it subsequently diffused. The best observed signal-to-noise ratios were about 150, allowing determination of the renal clearance time with 5% precision using a 10-min fitting window. Based on the verification and validation methods for transdermal fluorescence detection described herein, the instrument has been approved by the FDA for a first-in-human clinical study, and a first transdermal clearance curve in a human is presented herein.

REPEATABILITY AND RELIABILITY OF GLOMERULAR FILTRATION RATE DETERMINATION VIA GAMMA CAMERA UPTAKE OF TC-99M-DTPA IN CATS WITH CHRONIC KIDNEY DISEASE.

Measurement of glomerular filtration rate (GFR) via gamma camera uptake of 99mTc-diethylenetriaminepentaacetic acid is a standard method for quantifying renal function. Aims of this retrospective, observer agreement study were to determine intra- and interobserver variation in GFR values for cats with chronic kidney disease and to determine whether renal insufficiency classification changed between observers. Guideline cut-points were established for the difference in repeated GFRs to differentiate changes caused by therapeutic effect vs. inherent variation. Included cats had a diagnosis of chronic kidney disease and had undergone GFR examinations between the years of 2010 and 2013. Twenty-nine GFR studies were sampled. Each study was read twice, 6 months apart, by two veterinary radiologists and one radiology resident. Modified Bland-Altman plots were used to investigate differences between readings 1 and 2 by observer and between pairs of observers by reading. Reliability of clinical classification was assessed through comparisons between readings and observers. Measurements were not systematically different between readings for the experienced observers but were higher in reading 1 than reading 2 for the inexperienced observer. Measurements were not systematically different between the experienced observers in reading 1 or between any two observers in reading 2. Reliability for GFR measurements was high among experienced observers; variations in GFR measurements rarely led to differences in clinical classification. Results suggested that, for experienced observers, changes in GFR values following treatment in cats with chronic kidney disease between -0.4 and 0.4 mL/min/kg may be due to inherent variability rather than treatment effect.

Avaliação da função renal em pacientes admitidos em um hospital universitário de Recife-PE / Assessment of renal function in adult patients admitted to an university hospital in Recife-PE

Introdução: A doença renal crônica é um problema de saúde pública mundial. Recomenda-se o monitoramento da taxa de filtração glomerular (TFG) para avaliação da função renal (FR), pois sua redução precede a sintomatologia. Método: Estudo transversal, realizado com pacientes admitidos no Hospital das Clínicas de Pernambuco, no período de março a agosto de 2015. Foram consideradas variáveis demográficas, clínicas, bioquímicas e antropométricas. A TFG foi estimada pelas fórmulas Modification of Diet in Renal Disease (MDRD) e Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI). Para verificar as possíveis associações entre as variá- veis, foi utilizada a TFG pelo CKD-EPI, considerando alteração da FR TFG<60 mLmin/1,73m². Resultados: Foram avaliados 272 pacientes, 53,3% do sexo masculino, 48,5% de pardos, 62% não apresentavam afecções associadas. Quanto à antropometria, 9,9% possuíam índice de massa corporal <18,5 kg/m² e 28,3%, >24,9 kg/m². A idade média foi de 50±16,4 anos e 4% com TFG <60 ml/min/1,73m2 com a MDRD e 11,4% pela CKD-EPI. A idade avançada e comorbidades associaram-se positivamente com a redução da TFG (p=0,000). Conclusão: O CKD-EPI mostrou pacientes com déficit da FR, o que se torna um alerta, pois são indivíduos sem diagnóstico prévio.(AU)

Introduction: Chronic kidney disease is a worldwide public health problem. It is recommended to monitor the glomerular filtration rate (GFR) for assessment of renal function (RF), because its reduction precedes symptoms. Objective: To identify the frequency of change in GFR and associated factors. Methods: Cross-sectional study on patients admitted to the Hospital das Clínicas de Pernambuco from March to August 2015. Demographic, clinical, biochemical and anthropometric variables were considered. The GFR was estimated by formulas Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and to verify the possible associations among variables was used the GFR by CKD-EPI considering FR changing GFR < 60 mLmin /1.73 m². Results: We evaluated 272 patients, 53.3% male, 48.5% brown-skinned, 62% had no associated pathologies. Regarding the anthropometry, 9.9% had a body mass index <18.5 kg / m² and 28.3%, > 24.9kg / m². The average age was 50±16.4 years and 4% with GFR <60 ml/min/1.73m2 with MDRD and 11.4% for CKD-EPI. Advanced comorbidities age was positively associated with the GFR reduction (p=0.000). Conclusion: The CKD-EPI found patients with FR deficit, which becomes an alert, for being individuals without previous diagnosis.(AU)

Fluorescently Labeled Cyclodextrin Derivatives as Exogenous Markers for Real-Time Transcutaneous Measurement of Renal Function.

Evaluation of renal function is crucial for a number of clinical situations. Here, we reported a novel exogenous fluorescent marker (FITC-HPßCD) to real-time assess renal function by using a transcutaneous fluorescent detection technique. FITC-HPßCD was designed based on the principle of renal clearance of designed drugs. It displays favorable fluorescent properties, high hydrophilicity, low plasma protein binding, and high stability in porcine liver esterase as well as in plasma and nontoxicity. More importantly, FITC-HPßCD can be efficiently and rapidly filtered by glomerulus and completely excreted into urine without proximal tubular reabsorption or secretion in rat models. Additionally, the marker was well-tolerated, with nearly 100% urinary recovery of the given doses, and no metabolism were found. Relying on this novel kidney function marker and transcutaneous devices, we demonstrate a rapid, robust, and convenient approach for real-time assessing renal function without the need of time-consuming blood and urine sample preparation. Our work provides a promising tool for noninvasive real-time monitoring of renal function in vivo.

Population-based estimated reference creatinine values: a novel method of a robust electronic acute kidney injury alert system.

BACKGROUND: Acute kidney injury (AKI) is common in hospitalized patients. Despite the progress that has been made in the last decade, early identification of AKI cases remains a challenge. In recent years, electronic AKI alert (e-AKI alert) systems have been tested and are usually based on changes in serum creatinine (Cr) values. However, these methods do not include one of the common scenarios, i.e. when there is no available preadmission Cr value available for a patient to compare and hence an e-AKI alert cannot be issued. Therefore, it is essential to have an alternative algorithm to produce e-AKI alerts in such scenarios. METHOD: We have developed e-AKI alert algorithms which compare serum Cr values at presentation with previous results, within KDIGO AKI guideline-specified classifications. However, where a comparator is not available, we have produced a 'population-based reference Cr value' age and sex matched from 137,000 serum Cr values extracted from blood tests in general practice from our Telepath system. RESULTS: Cr results were split by gender, and then within each group the Cr were stratified according to year of age. The median Cr for each individual year of age was identified and plotted versus age to give separate graphs for males and females that gave excellent fits (R(2)) to cubic regressions. CONCLUSION: Population-based estimated reference Cr measurements from community blood test results is a more robust method of baseline Cr value estimation in generating potential e-AKI alerts to help early recognition and treatment of AKI cases leading to improved outcome.

Technology innovation for patients with kidney disease.

The loss of kidney function is a life-changing event leading to life-long dependence on healthcare. Around 5000 people are diagnosed with kidney failure every year. Historically, technology in renal medicine has been employed for replacement therapies. Recently, a lot of emphasis has been placed on technologies that aid early identification and prevent progression of kidney disease, while at the same time empowering affected individuals to gain control over their chronic illness. There is a shift in diversity of technology development, driven by collaborative innovation initiatives such the National Institute's for Health Research Healthcare Technology Co-operative for Devices for Dignity. This has seen the emergence of the patient as a key figure in designing technologies that are fit for purpose, while business involvement has ensured uptake and sustainability of these developments. An embodiment of this approach is the first successful Small Business Research Initiative in the field of renal medicine in the UK.

Recent trends in performance and current state of creatinine assays.

CONTEXT: Measured plasma or serum creatinine concentration is a primary component of equations used to calculate estimated glomerular filtration rate (eGFR). In recent years, most assay manufacturers have adopted creatinine calibration procedures that are traceable to the National Institute of Standards and Technology's Standard Reference Material 967. OBJECTIVES: To examine the current performance of creatinine assays, to compare changes in assay performance since 2003, and to examine the reliability of laboratory eGFR calculations. DESIGN: Serum samples spiked with different concentrations of creatinine were analyzed by participating laboratories in the College of American Pathologists' LN24 survey. Participants' reported values were compared against values measured by liquid chromatography-isotope dilution mass spectrometry. Participants were asked to calculate the eGFR for certain samples, and results were compared with those obtained from the 4-parameter Modification of Diet in Renal Disease equation. RESULTS: Biases among current creatinine methods are in the range of -5% to 10%, compared with -7% to 34% seen in a 2003 study. This degree of bias in eGFR calculations is of clinical significance only for concentrations near the cut points used to stage chronic kidney disease. Approximately 20% of laboratories report eGFR values that exceed ±1 mL/min per 1.73 m(2) from the expected eGFR using the 4-parameter Modification of Diet in Renal Disease equation. CONCLUSIONS: Since 2003, there have been improvements in the performance of creatinine assays, which appear to be related to the adoption of standard reference materials for calibration. The effect of the observed method biases in clinical practice now appears minimal. Laboratories should continue to monitor the accuracy of eGFR calculations.

Bilateral kidney sodium-MRI: Enabling accurate quantification of renal sodium concentration through a two-element phased array system.

PURPOSE: To develop a sodium-MRI ((23) Na-MRI) method for bilateral renal sodium concentration (RSC) measurements in rat kidneys at 9.4 Tesla (T). MATERIALS AND METHODS: To simultaneously achieve high B1 -field homogeneity and high receive sensitivity a dual resonator system composed of a double-tuned linearly polarized (1) H/(23) Na volume resonator and a newly developed two-element (23) Na receive array was used. In conjunction with three-dimensional (3D) ultra-short Time-to-Echo sequence a quantification accuracy of ± 10% was achieved for a nominal spatial resolution of (1 × 1 × 4) mm(3) in 10 min acquisition time. The technique was applied to study the RSC in six kidneys before and after furosemide-induced diuresis. RESULTS: The loop diuretic agent induced an increase of cortical RSC by 22% from 86 ± 16 mM to 105 ± 18 mM (P = 0.02), whereas the RSC in the inner medulla decreased by 38% from 213 ± 24 mM to 132 ± 25 mM (P = 0.8×10(-4) ). The RSC changes measured in this study agreed well with the qualitative sodium signal intensity variations reported elsewhere. CONCLUSION: Furosemide-induced diuresis has been investigated accurately with herein presented quantitative (23) Na-MRI technique. In the future, RSC quantification could allow for defining pathological and nonpathological RSC ranges to assess sodium concentration changes, e.g., induced by drugs.

Determination of kidney function with 99mTc-DTPA renography using a dual-head camera.

OBJECTIVE: Single-head gamma camera renography has been used for decades to estimate kidney function. An estimate of the glomerular filtration rate (GFR) can be obtained using Tc-diethylenetriaminepentaacetic acid (Tc-DTPA). However, because of differing attenuation, an error is introduced when the kidney depth or kidney size is unequal. This error can be reduced using geometric mean data obtained from dual-head renography. The aim of this study was to compare single-head versus dual-head assessment of single kidney function. METHODS: Thirty-four patients were examined with (a) single-head renography, acquiring counts from the left ventricle and kidneys from a posterior projection, and simultaneously with (b) dual-head renography, acquiring counts from the left ventricle from an anterior projection and kidneys from both anterior and posterior projections using geometric mean values. Single kidney GFR from both models was estimated (GFRcam1 and GFRcam2, respectively) and compared with GFR determined with plasma samples of Tc-DTPA (GFRps). RESULTS: The prediction intervals of GFRcam1 and GFRcam2 compared with GFRps did not differ significantly (SD of GFRcam1-GFRps=17.6 ml/min and SD of GFR2-GFRps=15.5 ml/min; P=0.48). The corresponding coefficients of variation were 16.5 and 14.7%, respectively. CONCLUSION: There is no difference in variance between GFR estimated from single-head renography and that estimated using dual-head renography. Hence, dual-head camera renography might be useful in daily practice with the potential to provide a better estimate of absolute function in each kidney and the relative kidney function in patients with differing kidney depths and/or malformed kidneys.

Evaluation of the analytical performance of the nova StatSensor creatinine meter for blood testing.

BACKGROUND AND OBJECTIVE: For reliability of laboratory results, all methods, instruments, and reagents should be evaluated The Nova StatSensor creatinine meter is a hand-held device for determination of creatinine concentration in the whole blood Therefore, the device has to be validated or verified before performing. MATERIAL AND METHOD: Observational analysis method with cross sectional design was used in this evaluation. The commercial reagents and coded samples were prepared for linearity, precision, accuracy, and interference studies. RESULTS: The linear measurement range of 1.3 to 9.5 mg/dL was verified with the recovery results between 91.6 to 105.0%. Total imprecision demonstrated by coefficient of variation (CV) was 6.4 to 8.9 CV%. Linear regression was y = 0.946x + 0.103, r = 0.992, r2 = 0.984. The bias was calculated from our data using regression equation. Our results demonstrated the accuracy was acceptable. Glucose level of 200 mg/dL and 400 mg/dL created the high difference between baseline creatinine (1.2 mg/dL and 2.8 mg/dL) and creatinine measured in the presence of interference was 25.0%, 16.7%, 14.3%, and 19.7% respectively. CONCLUSION: Our results demonstrated that the device provides reliable creatinine measurement and could be used in point-of-care testing. Use of this device in diabetic patients with high glucose level of > or = 200 mg/dL is not recommended

A portable fiberoptic ratiometric fluorescence analyzer provides rapid point-of-care determination of glomerular filtration rate in large animals.

Measurement of the glomerular filtration rate (GFR) is the gold standard for precise assessment of kidney function. A rapid, point-of-care determination of the GFR may provide advantages in the clinical setting over currently available assays. Here we demonstrate a proof of principle for such an approach in a pig and dogs, two species that approximate the vascular access and GFR results expected in humans. In both animal models, a sub-millimeter optical fiber that delivered excitation light and collected fluorescent emissions was inserted into a peripheral vein (dog) or central venous access (pig) by means of commercial intravenous catheters. A mixture of fluorescent chimeras of a small freely filterable reporter and large non-filterable plasma volume marker were infused as a bolus, excited by light-emitting diodes, and the in vivo signals detected and quantified by photomultiplier tubes in both species in less than 60 min. Concurrent standardized 6-h iohexol plasma kidney clearances validated the accuracy of our results for both physiologic and a chronic kidney disease setting. Thus, our ratiometric technique allows for both measurement of plasma vascular volume and highly accurate real-time GFR determinations, enabling clinical decision making in real time.

Multisensor smart system on a chip.

Sensors are becoming of considerable importance in several areas, particularly in health care. Therefore, the development of inexpensive and miniaturized sensors that are highly selective and sensitive, and for which control and analysis is present all on one chip is very desirable. These types of sensors can be implemented with microelectromechanical systems (MEMS), and because they are fabricated on a semiconductor substrate, additional signal processing circuitry can easily be integrated into the chip, thereby readily providing additional functions, such as multiplexing and analog-to-digital conversion. Here, we present a general framework for the design of a multisensor system on a chip, which includes intelligent signal processing, as well as a built-in self-test and parameter adjustment units. Specifically, we outline the system architecture and develop a transistorized bridge biosensor for monitoring changes in the dielectric constant of a fluid, which could be used for in-home monitoring of kidney function of patients with renal failure.

Kidney instant monitoring (K.IN.G): a new analyzer to monitor kidney function.

AIM: The key role of the kidney in the regulation of body fluids and acid-base status is well known. Nonetheless, urine analysis has not received great attention in critically ill patients, likely due to the common practice of only analyzing 24-hour collected specimens. We hypothesized that the kidney may react more rapidly to minimal hemodynamic and acid-base status variations than can be assessed by a 24-hour analysis. Accordingly, we developed and tested a urine analyzer, allowing quasi-continuous urinary analysis. METHODS: A novel analyzer (Kidney INstant monitorinG--K.IN.G) was developed that allows non-invasive, quasi-continuous analysis of urine pH, sodium, chloride, potassium and ammonium levels. Analytic measurement accuracy was calculated for urine samples of patients admitted to ICUs as well as medical staff, using standard techniques as references. For clinical investigation, approximately 200 patients were connected to the analyzer after ICU admission until discharge. Clinically relevant parameters were recorded. Here, three cases are presented. RESULTS: For each analytic parameter, the accuracy of measurements obtained with the K.IN.G analyzer appeared to be acceptable as compared to those of the reference techniques. In case 1, urine analysis revealed increased urinary sodium and chloride excretion strictly in parallel with mean arterial pressure, and increased ammonium excretion which was associated with moderate hypercapnia. Case 2 showed increases in urinary pH and sodium and chloride levels following awakening after sedation suspension. In case 3, urine analysis revealed an impairment of renal concentrative power, which was associated with hypovolemia. CONCLUSION: The K.IN.G analyzer, allowing quasi-continuous monitoring of urinary pH and principal electrolyte levels, may represent a novel tool for clinical and research purposes.

Avaliação de técnicas de biópsia renal em ovinos / Evaluation of renal biopsy techniques in sheep

Devido à escassez de trabalhos sobre biópsias renais em ovinos foi desenvolvido um estudo comparativo entre três técnicas de biópsia renal nesta espécie. Neste estudo foram utilizadas nove ovelhas (26,64 kg ±4,86) mestiças (Santa Inês) em procedimentos seriados, com intervalos consecutivos de uma semana. Foram avaliados os aspectos clínicos, achados de patologia clínica, o peso das amostras renais, a qualidade histológica, o número de glomérulos e a presença de artefatos no corte histológico da técnica de biópsia percutânea cega, da biópsia guiada por ultrassonografia e do procedimento videolaparoscópico. Não foram observadas alterações hematológicas ou bioquímicas relevantes nos animais submetidos às biópsias renais e as manifestações clínicas detectadas foram leves e transitórias, exceto por um caso de obstrução uretral por coágulo sangüíneo. A técnica percutânea cega foi relacionada à maior ocorrência e gravidade de hematúria, com danos mais graves ao tecido renal e com o único caso de obstrução do fluxo urinário. Na técnica videolaparoscópica, o peso médio das amostras foi superior e a hematúria discreta e transitória. Verificou-se relação direta entre a ocorrência de hematúria grave e a presença de epitélio de transição nas amostras e o número de tentativas utilizado para a obtenção dos fragmentos.

Due to lack of studies about renal biopsies in sheep, a comparative study was performed for three renal biopsy techniques in this species. In this study, nine crossbred (Santa Inês) ewe lamb (26.64 kg ±4,86) were used in serial procedures with one week consecutive intervals. The clinical aspects, clinical pathological findings, renal sample weights, histology quality, number of glomeruli, and the presence of artifacts in the histology slices were evaluated using the techniques of percutaneous blind biopsy, ultrasound guided biopsies and of videolaparoscopic procedure. No relevant hematological or biochemical alterations were observed in the animals subjected to renal biopsies and the clinical manifestations detected were slight and transitory, except for one case of urethral obstruction by blood clot. The blind technique was related to more frequent and severe cases of hematuria, with more severe damage to the renal tissue and to the only case of obstruction of the urinary flow. In the videolaparocopic technique, the average weight of the samples was superior and hematuria was slight and transitory. A direct relation was seen between occurrence of severe hematuria and presence of transitional epithelium in the samples and the number of trials used for obtainment of fragments.

Renal viability evaluated by the multiprobe assembly: a unique tool for the assessment of renal ischemic injury.

BACKGROUND: One of the major causes of transplanted organs' dysfunction is ischemia-reperfusion injury, where mitochondrial dysfunction is the primary contributor to cell damage. Mitochondrial NADH fluorescence reliably describes intracellular oxygen deficiency and mitochondrial function. Therefore, its monitoring at the tissue level, together with other physiological parameters, can serve to evaluate tissue vitality. METHODS: The multiprobe assembly (MPA) enabled the assessment of renal blood flow (RBF) using laser Doppler flowmetry, mitochondrial NADH redox state using the fluorometric technique, and ionic homeostasis using specific mini-electrodes (K(+) and H(+)). The MPA was utilized in two rat groups in which ischemia was induced for a period of 25-30 min (group 1) or for 60 min (group 2), and RBF and NADH were also monitored in a group of rats that underwent a complete kidney ischemia 24 h before the monitoring - a well-known model of acute renal failure. RESULTS: During ischemia, the RBF was completely abolished, NADH and extracellular potassium levels increased, and extracellular pH decreased. Immediately after the reperfusion, full recovery was observed; however, in the rats undergoing 60-min ischemia followed by 24-hour reperfusion, the tissue hemodynamic and mitochondrial functions were significantly impaired. CONCLUSION: This study demonstrates the advantage of using the MPA for real-time evaluation of kidney physiological state, which may serve as a practical instrument for the evaluation of graft viability during transplantation procedures.