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Find video protocols related to scientific articles indexed in Pubmed.
Therapeutic strategies for clinical trials targeting renal recovery.
Nephron Clin Pract
PUBLISHED: 09-24-2014
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Although at present we have developed consensus definitions for acute kidney injury (AKI) and there is a major focus on the treatment and prevention of AKI in high-risk populations, little is known about renal recovery per se and the impact of therapies on renal recovery. Here, we will focus on the specifics of clinical trial design relevant to studies of AKI recovery. While certain design considerations will be common to all trials, others elements will be more specific for studies focused on best practice or novel therapeutics. We will first discuss clinical trial considerations for all studies followed by specific proposals for best practice trials and therapy trials. Other presentations during this round table have focused on other aspects that are highly important for clinical trial design, including definitions for recovery, the potential use of biomarkers, as well as clinical trial endpoints, so we will not address these issues here. © 2014 S. Karger AG, Basel.
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Silencing Bruton's tyrosine kinase in alveolar neutrophils protects mice from LPS/immune complex-induced acute lung injury.
Am. J. Physiol. Lung Cell Mol. Physiol.
PUBLISHED: 08-01-2014
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Previous observations made by our laboratory indicate that Bruton's tyrosine kinase (Btk) may play an important role in the pathophysiology of local inflammation in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). We have shown that there is cross talk between Fc?RIIa and TLR4 in alveolar neutrophils from patients with ALI/ARDS and that Btk mediates the molecular cooperation between these two receptors. To study the function of Btk in vivo we have developed a unique two-hit model of ALI: LPS/immune complex (IC)-induced ALI. Furthermore, we conjugated F(ab)2 fragments of anti-neutrophil antibodies (Ly6G1A8) with specific siRNA for Btk to silence Btk specifically in alveolar neutrophils. It should be stressed that we are the first group to perform noninvasive transfections of neutrophils, both in vitro and in vivo. Importantly, our present findings indicate that silencing Btk in alveolar neutrophils has a dramatic protective effect in mice with LPS/IC-induced ALI, and that Btk regulates neutrophil survival and clearance of apoptotic neutrophils in this model. In conclusion, we put forward a hypothesis that Btk-targeted neutrophil specific therapy is a valid goal of research geared toward restoring homeostasis in lungs of patients with ALI/ARDS.
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Propofol as a panacea for acute kidney injury?
Kidney Int.
PUBLISHED: 08-01-2014
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Yoo and colleagues report a small but provocative randomized clinical trial to prevent acute kidney injury in the setting of cardiopulmonary bypass surgery. Their article describes a trial of 112 patients undergoing valvular surgery with cardiopulmonary bypass who were randomized to receive sevoflurane (an inhaled anesthetic) or propofol for general anesthesia. The use of propofol was associated with a significant decrease in the rate of postoperative acute kidney injury.
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Association of urinary KIM-1, L-FABP, NAG and NGAL with incident end-stage renal disease and mortality in American Indians with type 2 diabetes mellitus.
Diabetologia
PUBLISHED: 07-29-2014
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Kidney injury molecule 1 (KIM-1), liver fatty acid-binding protein (L-FABP), N-acetyl-?-D-glucosaminidase (NAG) and neutrophil gelatinase-associated lipocalin (NGAL) are urinary biomarkers of renal tubular injury. We examined their association with incident end-stage renal disease (ESRD) and all-cause mortality in American Indians with type 2 diabetes.
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Prevalence and impact of active and passive cigarette smoking in acute respiratory distress syndrome.
Crit. Care Med.
PUBLISHED: 06-20-2014
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Cigarette smoke exposure has recently been found to be associated with increased susceptibility to trauma- and transfusion-associated acute respiratory distress syndrome. We sought to determine 1) the incidence of cigarette smoke exposure in a diverse multicenter sample of acute respiratory distress syndrome patients and 2) whether cigarette smoke exposure is associated with severity of lung injury and mortality in acute respiratory distress syndrome.
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Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia.
Thorax
PUBLISHED: 06-02-2014
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Human bone marrow-derived mesenchymal stem (stromal) cells (hMSCs) improve survival in mouse models of acute respiratory distress syndrome (ARDS) and reduce pulmonary oedema in a perfused human lung preparation injured with Escherichia coli bacteria. We hypothesised that clinical grade hMSCs would reduce the severity of acute lung injury (ALI) and would be safe in a sheep model of ARDS.
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Rosuvastatin for sepsis-associated acute respiratory distress syndrome.
N. Engl. J. Med.
PUBLISHED: 05-18-2014
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In the acute respiratory distress syndrome (ARDS), inflammation in the lungs and other organs can cause life-threatening organ failure. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) can modulate inflammatory responses. Previous observational studies suggested that statins improved clinical outcomes in patients with sepsis. We hypothesized that rosuvastatin therapy would improve clinical outcomes in critically ill patients with sepsis-associated ARDS.
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The daily burden of acute kidney injury: a survey of U.S. nephrologists on World Kidney Day.
Am. J. Kidney Dis.
PUBLISHED: 03-18-2014
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World Kidney Day 2013 focused on raising awareness of the impact and consequences of acute kidney injury (AKI). Although many studies have examined rates of AKI in hospitalized patients, we were interested in the impact of AKI on the workload of nephrologists.
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Urine Neutrophil Gelatinase-Associated Lipocalin and Risk of Cardiovascular Disease and Death in CKD: Results From the Chronic Renal Insufficiency Cohort (CRIC) Study.
Am. J. Kidney Dis.
PUBLISHED: 02-08-2014
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Chronic kidney disease is common and is associated with increased cardiovascular disease risk. Currently, markers of renal tubular injury are not used routinely to describe kidney health and little is known about the risk of cardiovascular events and death associated with these biomarkers independent of glomerular filtration-based markers (such as serum creatinine or albuminuria).
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Reperfusion pulmonary edema in children with tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collateral arteries undergoing unifocalization procedures: A pilot study examining potential pathophysiologic mechanisms and clinical significance.
J. Thorac. Cardiovasc. Surg.
PUBLISHED: 01-20-2014
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Children with tetralogy of Fallot (TOF), pulmonary atresia (PA), and major aortopulmonary collateral arteries (MAPCAs) are at risk for reperfusion pulmonary edema (RPE) after unifocalization procedures to reconstruct the central pulmonary arteries. The purpose of this study was to determine the incidence of RPE, describe the clinical course of patients with RPE, and explore the mechanism of RPE in this population by measuring plasma biomarkers of alveolar epithelial and endothelial injury and lung inflammation.
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Performance of interleukin-27 as a sepsis diagnostic biomarker in critically ill adults.
J Crit Care
PUBLISHED: 01-15-2014
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We recently identified interleukin-27 (IL-27) as a sepsis diagnostic biomarker in children. Here we assess IL-27 as a sepsis diagnostic biomarker in critically ill adults with systemic inflammatory response syndrome and sepsis.
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An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS): protocol for a randomized controlled trial.
Trials
PUBLISHED: 01-11-2014
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Organ dysfunction consequent to infection ('severe sepsis') is the leading cause of admission to an intensive care unit (ICU). In both animal models and early clinical studies the calcium channel sensitizer levosimendan has been demonstrated to have potentially beneficial effects on organ function. The aims of the Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS) trial are to identify whether a 24-hour infusion of levosimendan will improve organ dysfunction in adults who have septic shock and to establish the safety profile of levosimendan in this group of patients.
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Intercellular transfer of GPRC5B via exosomes drives HGF-mediated outward growth.
Curr. Biol.
PUBLISHED: 01-09-2014
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How cells communicate during development and regeneration is a critical question. One mechanism of intercellular communication is via exosomes, extracellular vesicles that originate by the fusion of multivesicular endosomes with the plasma membrane [1-8]. To model exosome-based intercellular communication, we used Madin-Darby canine kidney (MDCK) cell cysts grown in 3D gels of extracellular matrix, which form tubules in response to hepatocyte growth factor (HGF). We report that GPRC5B, an orphan G protein coupled receptor, is in exosomes produced by HGF-treated cysts and released into the cyst lumen. Exosomal GPRC5B is taken up by nearby cells and together with HGF promotes extracellular signal-regulated kinase 1/2 (ERK1/2) activation and tubulogenesis, even under conditions where tubulogenesis would otherwise not occur. Recovery from injury, such as acute kidney injury (AKI), often recapitulates developmental processes. Here, we show that GPRC5B is elevated in urinary exosomes from patients with AKI. Our results elucidate how GPRC5B is carried by exosomes and augments HGF-induced morphogenesis. The unexpected role of exosomes in transporting GPRC5B between cells during morphogenesis and the ability of GPRC5B to predict the disease state of AKI elucidate a novel mechanism for intercellular communication during development and repair.
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The Association Between Physiologic Dead-Space Fraction and Mortality in Subjects With ARDS Enrolled in a Prospective Multi-Center Clinical Trial.
Respir Care
PUBLISHED: 01-02-2014
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We tested the association between pulmonary dead-space fraction (ratio of dead space to tidal volume [VD/VT]) and mortality in subjects with ARDS (Berlin definition, PaO2 /FIO2 ? 300 mm Hg; PEEP ? 5 cm H2O) enrolled into a clinical trial incorporating lung-protective ventilation.
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Evolving practices in critical care and their influence on acute kidney injury.
Curr Opin Crit Care
PUBLISHED: 11-19-2013
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This review highlights the principal advances in critical care over the past year, and discusses the impact of these advances on the diagnosis and management of acute kidney injury (AKI).
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AKI: a path forward.
Clin J Am Soc Nephrol
PUBLISHED: 07-18-2013
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The Kidney Research National Dialogue, supported by the National Institute of Diabetes and Digestive and Kidney Diseases, asked the scientific community to formulate and prioritize research objectives that would improve our understanding of kidney function and disease. High-priority objectives for AKI were identified, including enhancing training and collaborative opportunities, improving phenotyping and development of clinical tools, expanding our understanding of the pathophysiology and interaction between injury and reparative processes, and identifying determinants of long-term outcomes. Research in animal models must be translated to improve diagnosis and treatment of patients. The objectives identified by the Kidney Research National Dialogue provide the research community with future opportunities for improving the prevention, diagnosis, and treatment of people with AKI.
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Acute kidney injury: an increasing global concern.
Lancet
PUBLISHED: 05-31-2013
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Despite an increasing incidence of acute kidney injury in both high-income and low-income countries and growing insight into the causes and mechanisms of disease, few preventive and therapeutic options exist. Even small acute changes in kidney function can result in short-term and long-term complications, including chronic kidney disease, end-stage renal disease, and death. Presence of more than one comorbidity results in high severity of illness scores in all medical settings. Development or progression of chronic kidney disease after one or more episode of acute kidney injury could have striking socioeconomic and public health outcomes for all countries. Concerted international action encompassing many medical disciplines is needed to aid early recognition and management of acute kidney injury.
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Urine Stability Studies for Novel Biomarkers of Acute Kidney Injury.
Am. J. Kidney Dis.
PUBLISHED: 05-27-2013
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The study of novel urinary biomarkers of acute kidney injury has expanded exponentially. Effective interpretation of data and meaningful comparisons between studies require awareness of factors that can adversely affect measurement. We examined how variations in short-term storage and processing might affect the measurement of urine biomarkers.
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Urine Biomarkers Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Injury Molecule-1 (KIM-1) Have Different Patterns in Heart Failure Exacerbation.
Biomark Insights
PUBLISHED: 03-11-2013
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Individuals with acute heart failure exacerbation often experience a deterioration in renal function. We sought to determine whether this deterioration is ischemic in nature and detectable by sensitive urine biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). We measured serial biomarker levels and evaluated the associations of these biomarkers with renal recovery in a cohort of hospitalized patients with acute heart failure exacerbation.
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KDOQI US commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury.
Am. J. Kidney Dis.
PUBLISHED: 02-12-2013
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In response to the recently released 2012 KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline for acute kidney injury (AKI), the National Kidney Foundation organized a group of US experts in adult and pediatric AKI and critical care nephrology to review the recommendations and comment on their relevancy in the context of current US clinical practice and concerns. The first portion of the KDIGO guideline attempts to harmonize earlier consensus definitions and staging criteria for AKI. While the expert panel thought that the KDIGO definition and staging criteria are appropriate for defining the epidemiology of AKI and in the design of clinical trials, the panel concluded that there is insufficient evidence to support their widespread application to clinical care in the United States. The panel generally concurred with the remainder of the KDIGO guidelines that are focused on the prevention and pharmacologic and dialytic management of AKI, although noting the dearth of clinical trial evidence to provide strong evidence-based recommendations and the continued absence of effective therapies beyond hemodynamic optimization and avoidance of nephrotoxins for the prevention and treatment of AKI.
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Urine neutrophil gelatinase-associated lipocalin levels do not improve risk prediction of progressive chronic kidney disease.
Kidney Int.
PUBLISHED: 01-23-2013
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Novel biomarkers may improve our ability to predict which patients with chronic kidney disease (CKD) are at higher risk for progressive loss of renal function. Here, we assessed the performance of urine neutrophil gelatinase-associated lipocalin (NGAL) for outcome prediction in a diverse cohort of 3386 patients with CKD in the Chronic Renal Insufficiency Cohort study. In this cohort, the baseline mean estimated glomerular filtration rate (eGFR) was 42.4 ml/min per 1.73 m(2), the median 24-h urine protein was 0.2 g/day, and the median urine NGAL concentration was 17.2 ng/ml. Over an average follow-up of 3.2 years, there were 689 cases in which the eGFR was decreased by half or incident end-stage renal disease developed. Even after accounting for eGFR, proteinuria, and other known CKD progression risk factors, urine NGAL remained a significant independent risk factor (Cox model hazard ratio 1.70 highest to lowest quartile). The association between baseline urine NGAL levels and risk of CKD progression was strongest in the first 2 years of biomarker measurement. Within this time frame, adding urine NGAL to a model that included eGFR, proteinuria, and other CKD progression risk factors led to net reclassification improvement of 24.7%, but the C-statistic remained nearly identical. Thus, while urine NGAL was an independent risk factor of progression among patients with established CKD of diverse etiology, it did not substantially improve prediction of outcome events.
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Plasma angiopoietin-2 predicts the onset of acute lung injury in critically ill patients.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 01-19-2013
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Current clinical prediction scores for acute lung injury (ALI) have limited positive predictive value. No studies have evaluated predictive plasma biomarkers in a broad population of critically ill patients or as an adjunct to clinical prediction scores.
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The association between a Darc gene polymorphism and clinical outcomes in African American patients with acute lung injury.
Chest
PUBLISHED: 12-29-2011
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Acute lung injury (ALI) mortality is increased among African Americans compared with Americans of European descent, and genetic factors may be involved. A functional T-46C polymorphism (rs2814778) in the promoter region of Duffy antigen/receptor for chemokines (Darc) gene, present almost exclusively in people of African descent, results in isolated erythrocyte DARC deficiency and has been implicated in ALI pathogenesis in preclinical and murine models, possibly because of an increase in circulating Duffy-binding, proinflammatory chemokines like IL-8. We sought to determine the effect of the functional rs2814778 polymorphism, C/C genotype (Duffy null state), on clinical outcomes in African Americans with acute lung injury.
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Acute kidney injury in patients with acute lung injury: impact of fluid accumulation on classification of acute kidney injury and associated outcomes.
Crit. Care Med.
PUBLISHED: 07-26-2011
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It has been suggested that fluid accumulation may delay recognition of acute kidney injury. We sought to determine the impact of fluid balance on the incidence of nondialysis requiring acute kidney injury in patients with acute lung injury and to describe associated outcomes, including mortality.
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Single-nucleotide polymorphisms in the ?-adrenergic receptor genes are associated with lung allograft utilization.
J. Heart Lung Transplant.
PUBLISHED: 05-25-2011
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Pulmonary edema and associated impaired oxygenation are a major reason for rejection of donor lung allografts offered for transplantation. Clearance of pulmonary edema can be upregulated by stimulation of ?-adrenergic receptors (?ARs). Single-nucleotide polymorphisms (SNPs) in ?AR genes have functional effects in vitro and in vivo. We hypothesized that SNPs in ?AR genes would be associated with rates of utilization of donor lung allografts offered for transplantation.
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Randomized, placebo-controlled clinical trial of an aerosolized ??-agonist for treatment of acute lung injury.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 05-13-2011
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??-Adrenergic receptor agonists accelerate resolution of pulmonary edema in experimental and clinical studies.
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The value of positive end-expiratory pressure and Fio? criteria in the definition of the acute respiratory distress syndrome.
Crit. Care Med.
PUBLISHED: 05-03-2011
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The criteria that define acute lung injury and the acute respiratory distress syndrome include PaO?/Fio? but not positive end-expiratory pressure or Fio2. PaO2/Fio2 ratios of some patients increase substantially after mechanical ventilation with positive end-expiratory pressure of 5-10 cm H?O, and the mortality of these patients may be lower than those whose PaO?/Fio?ratios remain <200. Also, PaO?/Fio? may increase when Fio2 is raised from moderate to high levels, suggesting that patients with similar PaO?/Fio? ratios but different Fio? levels have different risks of mortality. The primary purpose of this study was to assess the value of adding baseline positive end-expiratory pressure and Fio? to PaO?/Fio? for predicting mortality of acute lung injury/acute respiratory distress syndrome patients enrolled in Acute Respiratory Distress Syndrome Network clinical trials. We also assessed effects of two study interventions on clinical outcomes in subsets of patients with mild and severe hypoxemia as defined by PaO?/Fio?.
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Positive fluid balance is associated with higher mortality and prolonged mechanical ventilation in pediatric patients with acute lung injury.
Crit Care Res Pract
PUBLISHED: 04-01-2011
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Introduction. We analyzed a database of 320 pediatric patients with acute lung injury (ALI), to test the hypothesis that positive fluid balance is associated with worse clinical outcomes in children with ALI. Methods. This is a post-hoc analysis of previously collected data. Cumulative fluid balance was analyzed in ml per kilogram per day for the first 72?hours after ALI while in the PICU. The primary outcome was mortality; the secondary outcome was ventilator-free days. Results. Positive fluid balance (in increments of 10?mL/kg/24?h) was associated with a significant increase in both mortality and prolonged duration of mechanical ventilation, independent of the presence of multiple organ system failure and the extent of oxygenation defect. These relationships remained unchanged when the subgroup of patients with septic shock (n = 39) were excluded. Conclusions. Persistently positive fluid balance may be deleterious to pediatric patients with ALI. A confirmatory, prospective randomized controlled trial of fluid management in pediatric patients with ALI is warranted.
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Fluid balance, diuretic use, and mortality in acute kidney injury.
Clin J Am Soc Nephrol
PUBLISHED: 03-10-2011
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Management of volume status in patients with acute kidney injury (AKI) is complex, and the role of diuretics is controversial. The primary objective was to elucidate the association between fluid balance, diuretic use, and short-term mortality after AKI in critically ill patients.
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FGF-23 and PTH levels in patients with acute kidney injury: A cross-sectional case series study.
Ann Intensive Care
PUBLISHED: 03-08-2011
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Fibroblast growth factor-23 (FGF-23), a novel regulator of mineral metabolism, is markedly elevated in chronic kidney disease and has been associated with poor long-term outcomes. However, whether FGF-23 has an analogous role in acute kidney injury is unknown. The goal of this study was to measure FGF-23 levels in critically ill patients with acute kidney injury to determine whether FGF-23 levels were elevated, as in chronic kidney disease.
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Clinical significance of elevated B-type natriuretic peptide in patients with acute lung injury with or without right ventricular dilatation: an observational cohort study.
Ann Intensive Care
PUBLISHED: 02-28-2011
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The primary objective of this study was to examine levels of B-type natriuretic peptide (BNP) in mechanically ventilated patients with acute lung injury and to test whether the level of BNP would be higher in patients with right ventricular dilatation and would predict mortality.
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Therapeutic potential of mesenchymal stem cells for severe acute lung injury.
Chest
PUBLISHED: 10-07-2010
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Preclinical studies indicate that allogeneic human mesenchymal stem cells (MSC) may be useful for the treatment of several clinical disorders, including sepsis, acute renal failure, acute myocardial infarction, and more recently, acute lung injury (ALI). This article provides a brief review of the biologic qualities of MSC that make them suitable for the treatment of human diseases, as well as the experimental data that provide support for their potential efficacy for critically ill patients with acute respiratory failure from ALI. The article then discusses which patients with ALI might be the best candidates for cell-based therapy and provides a template for the regulatory and practical steps that will be required to test allogeneic human MSC in patients with severe ALI. There is a dual focus on how to design trials for testing both safety and efficacy.
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Acute kidney injury: is acute kidney injury a risk factor for long-term mortality?
Nat Rev Nephrol
PUBLISHED: 06-30-2010
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Acute kidney injury seems to have sequelae long beyond the index hospitalization. A new study suggests that even after adjusting for the impact of subsequent chronic kidney disease, acute kidney injury is associated with an increased risk of death.
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Ratio of angiopoietin-2 to angiopoietin-1 as a predictor of mortality in acute lung injury patients.
Crit. Care Med.
PUBLISHED: 06-29-2010
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To test the hypothesis that the concentration of angiopoietin-2 relative to angiopoietin-1 may be a useful biological marker of mortality in acute lung injury patients. We also tested the association of concentration of angiopoietin-2 relative to angiopoietin-1 with physiologic and biological markers of activated endothelium.
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The assessment, serial evaluation, and subsequent sequelae of acute kidney injury (ASSESS-AKI) study: design and methods.
BMC Nephrol
PUBLISHED: 06-09-2010
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The incidence of acute kidney injury (AKI) has been increasing over time and is associated with a high risk of short-term death. Previous studies on hospital-acquired AKI have important methodological limitations, especially their retrospective study designs and limited ability to control for potential confounding factors.
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Clinical trials for acute kidney injury: design challenges and possible solutions.
Curr Drug Targets
PUBLISHED: 07-20-2009
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Acute kidney injury is associated with significant morbidity and mortality in hospitalized patients. Clinical trials for acute kidney injury have been hampered not only by a paucity of appropriate potential therapeutic agents, but also by several clinical trial design challenges. First, for novel therapies to have the best chance at efficacy, early patient identification is critical. Second, for certain novel therapies with a mechanism of action directed at the underlying disease state (e.g., sepsis) or a specific pathogenic process, careful disease phenotyping may be required. Third, even among patients with AKI, risk stratification may be required to select a higher-risk subset for clinical trials. Finally, clinical endpoints for clinical trials must be considered carefully, as patients may die for reasons unrelated to AKI, including withdrawal of support. However, these challenges are not unique to AKI; some possible solutions including alternative endpoints used in other clinical trial settings are reviewed here.
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Measurement of extravascular lung water using the single indicator method in patients: research and potential clinical value.
Am. J. Physiol. Lung Cell Mol. Physiol.
PUBLISHED: 07-17-2009
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Extravascular lung water includes all of the fluid within the lung but outside of the vasculature. Lung water increases as a result of increased hydrostatic vascular pressure or from an increase in lung endothelial and epithelial permeability or both. Experimentally, extravascular lung water has been measured gravimetrically. Clinically, the chest radiograph is used to determine whether extravascular lung water is present but is an insensitive instrument for determining the quantity of lung water. Bedside measurement of extravascular lung water in patients is now possible using a single indicator thermodilution method. This review critically evaluates the experimental and clinical evidence supporting the potential value of measuring extravascular lung water in patients using the single indicator method.
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Inhaled activated protein C: a novel therapy for acute lung injury?
Crit Care
PUBLISHED: 05-21-2009
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Acute lung injury (ALI) is characterized by the presence of dysregulated coagulation and inflammation. Therefore, Waerhaug and colleagues hypothesized that administration of activated protein C (APC) via the inhaled route would be a novel and effective treatment for ALI. They demonstrated that inhaled APC improved oxygenation and lung aeration in a sheep model of lipopolysaccharide-induced ALI, but did not alter lung water or hemodynamics. Future studies are needed to determine plasma and airspace APC levels when administered by the inhaled route, and to determine if inhaled APC has a similar effect in other models of ALI.
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Protective mechanisms of activated protein C in severe inflammatory disorders.
Br. J. Pharmacol.
PUBLISHED: 05-14-2009
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The protein C system is an important natural anticoagulant mechanism mediated by activated protein C (APC) that regulates the activity of factors VIIIa and Va. Besides well-defined anticoagulant properties, APC also demonstrates anti-inflammatory, anti-apoptotic and endothelial barrier-stabilizing effects that are collectively referred to as the cytoprotective effects of APC. Many of these beneficial effects are mediated through its co-receptor endothelial protein C receptor, and the protease-activated receptor 1, although exact mechanisms remain unclear and are likely pleiotropic in nature. Increased insight into the structure-function relationships of APC facilitated design of APC variants that conserve cytoprotective effects and reduce anticoagulant features, thereby attenuating the risk of severe bleeding with APC therapy. Impairment of the protein C system plays an important role in acute lung injury/acute respiratory distress syndrome and severe sepsis. The pathophysiology of both diseases states involves uncontrolled inflammation, enhanced coagulation and compromised fibrinolysis. This leads to microvascular thrombosis and organ injury. Administration of recombinant human APC to correct the dysregulated protein C system reduced mortality in severe sepsis patients (PROWESS trial), which stimulated further research into its mechanisms of action. Several other clinical trials evaluating recombinant human APC have been completed, including studies in children and less severely ill adults with sepsis as well as a study in acute lung injury. On the whole, these studies have not supported the use of APC in these populations and challenge the field of APC research to search for additional answers.
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Higher pulmonary dead space may predict prolonged mechanical ventilation after cardiac surgery.
Pediatr. Pulmonol.
PUBLISHED: 04-22-2009
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Children undergoing congenital heart surgery are at risk for prolonged mechanical ventilation and length of hospital stay. We investigated the prognostic value of pulmonary dead space fraction as a non-invasive, physiologic marker in this population. In a prospective, cross-sectional study, we measured pulmonary dead space fraction in 52 intubated, pediatric patients within 24 hr postoperative from congenital heart surgery. Measurements were obtained with a bedside, non-invasive cardiac output (NICO) monitor (Respironics Novametrix, Inc., Wallingford, CT). Median pulmonary dead space fraction was 0.46 (25-75% IQR 0.34-0.55). Pulmonary dead space fraction significantly correlated with duration of mechanical ventilation and length of hospital stay in the entire cohort (r(s) = 0.51, P = 0.0002; r(s) = 0.51, P = 0.0002) and in the subset of patients without residual intracardiac shunting (r(s) = 0.45, P = 0.008; r(s) = 0.49, P = 0.004). In a multivariable logistic regression model, pulmonary dead space fraction remained an independent predictor for prolonged mechanical ventilation in the presence of cardiopulmonary bypass time and ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (OR 2.2; 95% CI 1.14-4.38; P = 0.02). The area under the receiver operator characteristic curve for this model was 0.91. Elevated pulmonary dead space fraction is associated with prolonged mechanical ventilation and hospital stay in pediatric patients who undergo surgery for congenital heart disease and has additive predictive value in identifying those at risk for longer duration of mechanical ventilation. Pulmonary dead space may be a useful prognostic tool for clinicians in patients who undergo congenital heart surgery.
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Some methodological issues in studying the long-term renal sequelae of acute kidney injury.
Curr. Opin. Nephrol. Hypertens.
PUBLISHED: 03-26-2009
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There has been great interest recently in better understanding how an episode of acute kidney injury (AKI) affects risk of development or acceleration of chronic kidney disease. This area of epidemiology research presents several methodological challenges that have not been sufficiently discussed in the literature. These are related to the current consensus definitions of AKI; the determination of baseline renal function before the AKI episode; and the possibility that observed associations between AKI and future adverse events are confounded by differences in the severity of baseline chronic kidney disease. In this study, we discuss several potential solutions to these problems. Concerted efforts to address these methodological issues will propel research in this field to a higher level.
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Blood product transfusions and clinical outcomes in pediatric patients with acute lung injury.
Pediatr Crit Care Med
PUBLISHED: 03-25-2009
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There are data suggesting that blood product transfusions increase the risk of developing acute lung injury (ALI) in adults, and may be associated with increased mortality in adults with ALI. A possible association between transfusions and adverse outcomes of pediatric patients with ALI has not been studied previously. We tested the hypothesis that blood product transfusions to pediatric patients with ALI within the first 72 hours of the diagnosis would be associated with increased mortality and prolonged mechanical ventilation.
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Serum interleukin-6 and interleukin-8 are early biomarkers of acute kidney injury and predict prolonged mechanical ventilation in children undergoing cardiac surgery: a case-control study.
Crit Care
PUBLISHED: 03-06-2009
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Acute kidney injury (AKI) is associated with high mortality rates. New biomarkers that can identify subjects with early AKI (before the increase in serum creatinine) are needed to facilitate appropriate treatment. The purpose of this study was to test the role of serum cytokines as biomarkers for AKI and prolonged mechanical ventilation.
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Nectin proteins are expressed at early stages of nephrogenesis and play a role in renal epithelial cell morphogenesis.
Am. J. Physiol. Renal Physiol.
PUBLISHED: 01-01-2009
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Development of the nephron requires conversion of the metanephric mesenchyme into tubular epithelial structures with specifically organized intercellular junctions. The nectin proteins are a family of transmembrane proteins that dimerize to form intercellular junctional complexes between epithelial cells. In this study, we demonstrate that nectin junctions appear during the earliest stages of epithelial cell morphogenesis in the murine nephron concurrently with the transition of mesenchymal cells into epithelial cells. We have defined the role of nectin during epithelial cell morphogenesis by studying nectin in a three-dimensional culture of Madin-Darby canine kidney (MDCK) cells. In a three-dimensional culture of MDCK cells grown in purified type 1 collagen, expression of a dominant negative form of nectin causes disruption of the formation of cell polarity and disruption of tight junction (TJ) formation, as measured by zonula occludens-1 (ZO-1) localization. In MDCK cells cultured in Matrigel, exogenous expression of nectin-1 causes disruption of normal epithelial cell cyst formation and decreased apoptosis. These data demonstrate that nectins play an important role in normal epithelial cell morphogenesis and may play a role in mesenchymal-to-epithelial transition during nephrogenesis by providing an antiapoptotic signal and promoting the formation of TJs and cell polarity.
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Fluid overload in AKI: epiphenomenon or putative effect on mortality?
Curr Opin Crit Care
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The incidence of acute kidney injury (AKI) is increasing dramatically, and despite advances in dialytic therapy and critical care, there has been little improvement in associated morbidity and mortality. Recently, several articles have suggested that fluid overload in patients with AKI is associated with an increased risk of death.
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Pathogenetic and predictive value of biomarkers in patients with ALI and lower severity of illness: results from two clinical trials.
Am. J. Physiol. Lung Cell Mol. Physiol.
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Plasma and bronchoalveolar lavage (BAL) biomarkers related to the pathogenesis of acute lung injury (ALI) have previously been associated with poorer clinical outcomes and increased disease severity among patients with ALI. Whether these biomarkers have predictive value in a less severely ill population that excludes septic patients with high APACHE II scores is currently unknown. We tested the association of plasma and BAL biomarkers with physiological markers of ALI severity or clinically relevant outcomes in a secondary analysis of a clinical trial of activated protein C for the treatment of ALI. Plasma plasminogen activator inhibitor-1 (PAI-1) and mini-BAL protein were both significantly associated with increased oxygenation index (P = 0.02 and 0.01, respectively), whereas there was a trend toward an association between IL-6 and oxygenation index (P = 0.057). High plasma IL-6, thrombomodulin, and mini-BAL protein were all significantly associated with fewer ventilator-free days (VFDs) (P = 0.01, 0.01, and 0.05, respectively); no markers were associated with mortality, but we hypothesized that this was due to the small size of our cohort and the low death rate. To confirm these associations in a larger sample, we identified a restricted cohort of patients from the ARDS Network ALVEOLI study with similar baseline characteristics. We retested the associations of the significant biomarkers with markers of severity and clinical outcomes and studied IL-8 as an additional biomarker given its important predictive value in prior studies. In this restricted cohort, IL-6 was significantly associated with oxygenation index (P = 0.02). Both IL-6 and IL-8 were associated with decreased VFDs and increased 28-day mortality. Future studies should be focused on examining larger numbers of patients with less severe ALI to further test the relative predictive value of plasma and mini-BAL biomarkers for clinically relevant outcomes, including VFDs and mortality, and for their prospective utility in risk stratification for future clinical trials.
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Extracorporeal treatment for thallium poisoning: recommendations from the EXTRIP Workgroup.
Clin J Am Soc Nephrol
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The EXtracorporeal TReatments In Poisoning (EXTRIP) workgroup was formed to provide recommendations on the use of extracorporeal treatment (ECTR) in poisoning. To test and validate its methods, the workgroup reviewed data for thallium (Tl).
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The EXTRIP (EXtracorporeal TReatments In Poisoning) workgroup: guideline methodology.
Clin Toxicol (Phila)
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Extracorporeal treatments (ECTRs), such as hemodialysis and hemoperfusion, are used in poisoning despite a lack of controlled human trials demonstrating efficacy. To provide uniform recommendations, the EXTRIP group was formed as an international collaboration among recognized experts from nephrology, clinical toxicology, critical care, or pharmacology and supported by over 30 professional societies. For every poison, the clinical benefit of ECTR is weighed against associated complications, alternative therapies, and costs. Rigorous methodology, using the AGREE instrument, was developed and ratified. Methods rely on evidence appraisal and, in the absence of robust studies, on a thorough and transparent process of consensus statements. Twenty-four poisons were chosen according to their frequency, available evidence, and relevance. A systematic literature search was performed in order to retrieve all original publications regardless of language. Data were extracted on a standardized instrument. Quality of the evidence was assessed by GRADE as: High = A, Moderate = B, Low = C, Very Low = D. For every poison, dialyzability was assessed and clinical effect of ECTR summarized. All pertinent documents were submitted to the workgroup with a list of statements for vote (general statement, indications, timing, ECTR choice). A modified Delphi method with two voting rounds was used, between which deliberation was required. Each statement was voted on a Likert scale (1-9) to establish the strength of recommendation. This approach will permit the production of the first important practice guidelines on this topic.
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Design of clinical trials in acute kidney injury: a report from an NIDDK workshop--prevention trials.
Clin J Am Soc Nephrol
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AKI is an important clinical problem that has become increasingly more common. Mortality rates associated with AKI remain high despite advances in supportive care. Patients surviving AKI have increased long-term mortality and appear to be at increased risk of developing CKD and progressing to ESRD. No proven effective pharmacologic therapies are currently available for the prevention or treatment of AKI. Advances in addressing this unmet need will require the development of novel therapeutic agents based on precise understanding of key pathophysiological events and the implementation of well designed clinical trials. To address this need, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored the "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers" workshop in December 2010. The event brought together representatives from academia, industry, the National Institutes of Health, and the US Food and Drug Administration. We report the discussions of workgroups that developed outlines of clinical trials for the prevention of AKI in two patient populations: patients undergoing elective surgery who are at risk for or who develop AKI, and patients who are at risk for contrast-induced AKI. In both of these populations, primary prevention or secondary therapy can be delivered at an optimal time relative to kidney injury. The workgroups detailed primary and secondary endpoints for studies in these groups, and explored the use of adaptive clinical trial designs for trials of novel preventive strategies to improve outcomes of patients with AKI.
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Design of clinical trials in AKI: a report from an NIDDK workshop. Trials of patients with sepsis and in selected hospital settings.
Clin J Am Soc Nephrol
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AKI remains an important clinical problem, with a high mortality rate, increasing incidence, and no Food and Drug Administration-approved therapeutics. Advances in addressing this clinical need require approaches for rapid diagnosis and stratification of injury, development of therapeutic agents based on precise understanding of key pathophysiological events, and implementation of well designed clinical trials. In the near future, AKI biomarkers may facilitate trial design. To address these issues, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a meeting, "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers," in December of 2010 that brought together academic investigators, industry partners, and representatives from the National Institutes of Health and the Food and Drug Administration. Important issues in the design of clinical trials for interventions in AKI in patients with sepsis or AKI in the setting of critical illness after surgery or trauma were discussed. The sepsis working group discussed use of severity of illness scores and focus on patients with specific etiologies to enhance homogeneity of trial participants. The group also discussed endpoints congruent with those endpoints used in critical care studies. The second workgroup emphasized difficulties in obtaining consent before admission and collaboration among interdisciplinary healthcare groups. Despite the difficult trial design issues, these clinical situations represent a clinical opportunity because of the high event rates, severity of AKI, and poor outcomes. The groups considered trial design issues and discussed advantages and disadvantages of several short- and long-term primary endpoints in these patients.
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Ongoing clinical trials in AKI.
Clin J Am Soc Nephrol
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AKI is an important public health issue. AKI is a common hospital complication associated with increased in-hospital and long-term mortality, extensive morbidity (including prolonged hospital length of stay), and an estimated annual cost of at least $10 billion in the United States. At present, no specific therapy has been developed to prevent AKI, hasten recovery of kidney function, or abrogate the deleterious systemic effects of AKI. However, recent progress includes establishing a consensus definition of AKI and discovery of novel biomarkers that may allow early detection of AKI. Furthermore, significant insights into the pathophysiology of AKI and its deleterious systemic effects have been gleaned from animal studies. Urgently needed are large, definitive randomized clinical trials testing interventions to prevent and/or treat AKI. This review summarizes and analyzes current ongoing clinical trials registered with clinicaltrials.gov that address prevention or management of AKI. The purpose of this review is to provide a resource for people interested in potential prophylactic and therapeutic approaches to patient care and investigators hoping to plan and execute the next round of randomized clinical trials. Finally, this review discusses research needs that are not addressed by the current clinical trials portfolio and suggests key areas for future research in AKI.
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Design of clinical trials in acute kidney injury: report from an NIDDK workshop on trial methodology.
Clin J Am Soc Nephrol
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Acute kidney injury (AKI) remains a complex clinical problem associated with significant short-term morbidity and mortality and lacking effective pharmacologic interventions. Patients with AKI experience longer-term risks for progressive chronic ESRD, which diminish patients health-related quality of life and create a larger burden on the healthcare system. Although experimental models have yielded numerous promising agents, translation into clinical practice has been unsuccessful, possibly because of issues in clinical trial design, such as delayed drug administration, masking of therapeutic benefit by adverse events, and inadequate sample size. To address issues of clinical trial design, the National Institute of Diabetes and Digestive and Kidney Diseases sponsored a workshop titled "Clinical Trials in Acute Kidney Injury: Current Opportunities and Barriers" in December 2010. Workshop participants included representatives from academia, industry, and government agencies whose areas of expertise spanned basic science, clinical nephrology, critical care medicine, biostatistics, pharmacology, and drug development. This document summarizes the discussions of collaborative workgroups that addressed issues related to patient selection, study endpoints, the role of novel biomarkers, sample size and power calculations, and adverse events and pilot/feasibility studies in prevention and treatment of AKI. Companion articles outline the discussions of workgroups for model trials related to prevention or treatment of established AKI in different clinical settings, such as in patients with sepsis.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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