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Joseph V Bonventre - One of the best experts on this subject based on the ideXlab platform.
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tubular physiology in acute Kidney Injury cell signalling Injury and inflammation
2018Co-Authors: Joseph V Bonventre, David A Ferenbach, Eoin OsullivanAbstract:Acute Kidney Injury in man results from a diverse range of initiating insults including sepsis, drug nephrotoxicity and hypoperfusion, which generate cellular Injury, inflammation and organ dysfunction. This chapter examines components of the tubular physiology of relevance to the initiation, propagation and eventual adaptive or maladaptive recovery of acute Kidney Injury. The effects of changes in cell polarity and cell-to-cell signalling in acute Kidney Injury will both be summarised, along with a discussion of the roles played by the anti-inflammatory enzyme heme oxygenase-1 and cytokine release from growth-arrested, injured or necrotic cells. The roles of leukocyte subsets, activation of toll-like receptors and complement activation in mediating inflammatory activation, tissue damage and eventual repair in the injured Kidney will also be explored.
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cellular pathophysiology of ischemic acute Kidney Injury
Journal of Clinical Investigation, 2011Co-Authors: Joseph V Bonventre, Li YangAbstract:Ischemic Kidney Injury often occurs in the context of multiple organ failure and sepsis. Here, we review the major components of this dynamic process, which involves hemodynamic alterations, inflammation, and endothelial and epithelial cell Injury, followed by repair that can be adaptive and restore epithelial integrity or maladaptive, leading to chronic Kidney disease. Better understanding of the cellular pathophysiological processes underlying Kidney Injury and repair will hopefully result in the design of more targeted therapies to prevent the Injury, hasten repair, and minimize chronic progressive Kidney disease.
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urinary biomarkers in the early diagnosis of acute Kidney Injury
Kidney International, 2008Co-Authors: Won K Han, Sushrut S Waikar, A Johnson, Rebecca A Betensky, Catherine L Dent, Prasad Devarajan, Joseph V BonventreAbstract:A change in the serum creatinine is not sensitive for an early diagnosis of acute Kidney Injury. We evaluated urinary levels of matrix metalloproteinase-9 (MMP-9), N -acetyl-β-D-glucosaminidase (NAG), and Kidney Injury molecule-1 (KIM-1) as biomarkers for the detection of acute Kidney Injury. Urine samples were collected from 44 patients with various acute and chronic Kidney diseases, and from 30 normal subjects in a cross-sectional study. A case–control study of children undergoing cardio-pulmonary bypass surgery included urine specimens from each of 20 patients without and with acute Kidney Injury. Injury was defined as a greater than 50% increase in the serum creatinine within the first 48 h after surgery. The biomarkers were normalized to the urinary creatinine concentration at 12, 24, and 36 h after surgery with the areas under the receiver-operating characteristic curve compared for performance. In the cross-sectional study, the area under the curve for MMP-9 was least sensitive followed by KIM-1 and NAG. Combining all three biomarkers achieved a perfect score diagnosing acute Kidney Injury. In the case–control study, KIM-1 was better than NAG at all time points, but combining both was no better than KIM-1 alone. Urinary MMP-9 was not a sensitive marker in the case–control study. Our results suggest that urinary biomarkers allow diagnosis of acute Kidney Injury earlier than a rise in serum creatinine.
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biomarkers of nephrotoxic acute Kidney Injury
Toxicology, 2008Co-Authors: Michael A. Ferguson, Vishal S. Vaidya, Joseph V BonventreAbstract:Acute Kidney Injury (AKI) is a common condition with significant associated morbidity and mortality. Epidemiologic data suggest that a significant proportion of AKI cases is at least partially attributable to nephrotoxin exposure. This is not surprising given intrinsic renal susceptibility to toxicant-induced Injury, a consequence of the unique physiologic and biochemical properties of the normally functioning Kidney. A number of pathophysiologic mechanisms have been identified that mediate toxic effects on the Kidney, resulting in a variety of clinical syndromes ranging from subtle changes in tubular function to fulminant renal failure. Unfortunately, standard metrics used to diagnose and monitor Kidney Injury, such as blood urea nitrogen and serum creatinine, are insensitive and nonspecific, resulting in delayed diagnosis and intervention. Considerable effort has been made to identify biomarkers that will allow the earlier diagnosis of AKI. Further characterization of these candidate biomarkers will clarify their utility in the setting of acute nephrotoxicity, define new diagnostic and prognostic paradigms for Kidney Injury, facilitate clinical trials, and lead to novel effective therapies.
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Biomarkers of Acute Kidney Injury
Annual Review of Pharmacology and Toxicology, 2008Co-Authors: Vishal S. Vaidya, Michael A. Ferguson, Joseph V BonventreAbstract:Acute Kidney Injury (AKI) is a common condition with a high risk of death. The standard metrics used to define and monitor the progression of AKI, such as serum creatinine and blood urea nitrogen levels, are insensitive, nonspecific, and change significantly only after significant Kidney Injury and then with a substantial time delay. This delay in diagnosis not only prevents timely patient management decisions, including administration of putative therapeutic agents, but also significantly affects the preclinical evaluation of toxicity thereby allowing potentially nephrotoxic drug candidates to pass the preclinical safety criteria only to be found to be clinically nephrotoxic with great human costs. Studies to establish effective therapies for AKI will be greatly facilitated by two factors: (a) development of sensitive, specific, and reliable biomarkers for early diagnosis/prognosis of AKI in preclinical and clinical studies, and (b) development and validation of high-throughput innovative technologies that allow rapid multiplexed detection of multiple markers at the bedside.
Stuart L Goldstein - One of the best experts on this subject based on the ideXlab platform.
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furosemide response predicts acute Kidney Injury in children after cardiac surgery
The Journal of Thoracic and Cardiovascular Surgery, 2019Co-Authors: Jamie Penk, Stuart L Goldstein, Katja M Gist, Eric L Wald, Laura Kitzmiller, Tennille N Webb, David S Cooper, Rajit K BasuAbstract:Abstract Objective A standardized assessment of response to furosemide is predictive of acute Kidney Injury progression in adults, but a paucity of data exists in pediatric patients. We evaluate furosemide responsiveness in a multicenter cohort of pediatric patients after cardiac surgery. Methods Children who underwent cardiac surgery with a Society of Thoracic Surgeons-European Association for Cardiothoracic Surgery score of 3 or greater were retrospectively identified. The first dose of furosemide after surgery was recorded, and hourly urine output for 6 hours was recorded after the index dose. Urine flow rate calculated as urine output per hour was used to predict development of acute Kidney Injury. Results A total of 166 patients from 4 institutions (median age, 6.3 months; interquartile range, 0.4-27.7) were included. Acute Kidney Injury occurred in 54 patients (33%). Compared with those without acute Kidney Injury, the 2- and 6-hour urine flow rates were significantly lower in patients in whom acute Kidney Injury developed: 2.9 (0.9-6.5) versus 5.0 (2.5-9.0) mL/kg/h for 2-hour urine flow rate, P = .004, and 2.4 (1.2-4.0) versus 4.0 (2.3-5.9) mL/kg/h for 6-hour flow rate, P = .001. In multivariable regression analysis, 2-hour (odds ratio, 1.2, P = .002) and 6-hour (odds ratio, 1.40, P Conclusions Lower urine flow rate after furosemide administration, when evaluated in a heterogeneous cohort of children from multiple institutions after pediatric cardiac surgery, was independently associated with subsequent acute Kidney Injury and longer length of stay. Future prospective studies are needed to validate furosemide responsiveness as a predictor of acute Kidney Injury.
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epidemiology of acute Kidney Injury in critically ill children and young adults
The New England Journal of Medicine, 2017Co-Authors: Ahmad Kaddourah, Rajit K Basu, Sean M Bagshaw, Stuart L GoldsteinAbstract:BackgroundThe epidemiologic characteristics of children and young adults with acute Kidney Injury have been described in single-center and retrospective studies. We conducted a multinational, prospective study involving patients admitted to pediatric intensive care units to define the incremental risk of death and complications associated with severe acute Kidney Injury. MethodsWe used the Kidney Disease: Improving Global Outcomes criteria to define acute Kidney Injury. Severe acute Kidney Injury was defined as stage 2 or 3 acute Kidney Injury (plasma creatinine level ≥2 times the baseline level or urine output <0.5 ml per kilogram of body weight per hour for ≥12 hours) and was assessed for the first 7 days of intensive care. All patients 3 months to 25 years of age who were admitted to 1 of 32 participating units were screened during 3 consecutive months. The primary outcome was 28-day mortality. ResultsA total of 4683 patients were evaluated; acute Kidney Injury developed in 1261 patients (26.9%; 95% co...
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congenital heart surgery in infants effects of acute Kidney Injury on outcomes
The Journal of Thoracic and Cardiovascular Surgery, 2012Co-Authors: Joshua J Blinder, Stuart L Goldstein, Veivei Lee, Alixandra Baycroft, Charles D Fraser, David L Nelson, John L JefferiesAbstract:Objectives We sought to characterize factors and outcomes associated with postoperative acute Kidney Injury in infants undergoing cardiac surgery. Methods We retrospectively studied 430 infants ( Results Postoperative acute Kidney Injury occurred in 225 patients (52%): 135 patients (31%) reached maximum acute Kidney Injury stage I, 59 (14%) reached stage II, and 31 (7%) reached stage III. On multivariable analysis, single-ventricle status (odds ratio, 1.6; 95% confidence interval, 1.08–2.37; P = .02), cardiopulmonary bypass (odds ratio, 1.2; 95% confidence interval 1.01–1.47; P = .04), and higher reference serum creatinine (odds ratio, 5.1; 95% confidence interval, 1.94–13.2; P = .0009) were associated with postoperative acute Kidney Injury. Thirty-two (7%) patients died in the hospital. Multivariable logistic regression showed that more severe acute Kidney Injury was associated with in-hospital mortality (maximum acute Kidney Injury stage II odds ratio, 5.1; 95% confidence interval, 1.7–15.2; P = .004; maximum acute Kidney Injury stage III odds ratio, 9.46; 95% confidence interval, 2.91–30.7; P = .0002) and longer mechanical ventilation and inotropic support. All acute Kidney Injury stages were associated with longer intensive care durations. Stage III acute Kidney Injury was associated with systemic ventricular dysfunction at hospital discharge. Conclusions Perioperative acute Kidney Injury is common in infant heart surgery and portends a poor clinical outcome.
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modified rifle criteria in critically ill children with acute Kidney Injury
Kidney International, 2007Co-Authors: Ayse Akcanarikan, Michael Zappitelli, Laura Loftis, Kimberly K Washburn, Larry S Jefferson, Stuart L GoldsteinAbstract:A classification system has been proposed to standardize the definition of acute Kidney Injury in adults. These criteria of risk, Injury, failure, loss, and end-stage renal disease were given the acronym of RIFLE. We have modified the criteria based on 150 critically ill pediatric RIFLE (pRIFLE) patients to assess acute Kidney Injury incidence and course along with renal and/or non-renal comorbidities. Of these children, 11 required dialysis and 24 died. Patients without acute Kidney Injury in the first week of intensive care admission were less likely to subsequently develop renal Injury or Failure; however, 82% of acute Kidney Injury occurred in this initial week. Within this group of 123 children, 60 reached pRIFLEmax for Risk, 32 reached Injury, and 31 reached Failure. Acute Kidney Injury during admission was an independent predictor of intensive care; hospital length of stay and an increased risk of death independent of the Pediatric Risk of Mortality (PRISM II) score (odds ratio 3.0). Our results show that a majority of critically ill children develop acute Kidney Injury by pRIFLE criteria and do so early in the course of intensive care. Acute Kidney Injury is associated with mortality and may lead to increased hospital costs. We suggest that the pRIFLE criteria serves to characterize the pattern of acute Kidney Injury in critically ill children.
Rinaldo Bellomo - One of the best experts on this subject based on the ideXlab platform.
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histopathology of septic acute Kidney Injury a systematic review of experimental data
Critical Care Medicine, 2016Co-Authors: Junko Kosaka, Clive N May, Yugeesh R Lankadeva, Rinaldo BellomoAbstract:Objective:The histopathologic changes associated with septic acute Kidney Injury are poorly understood, in part, because of the lack of biopsy data in humans. Animal models of septic acute Kidney Injury may help define such changes. Therefore, we performed a systematic review of the histopathologic
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renal histopathology during experimental septic acute Kidney Injury and recovery
Critical Care Medicine, 2014Co-Authors: Christoph Langenberg, Glenda C Gobe, Sally G Hood, Clive N May, Rinaldo BellomoAbstract:Objectives: Our understanding of septic acute Kidney Injury is limited. We therefore assessed renal histopathological changes induced by septic acute Kidney Injury and their evolution during recovery.
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acute Kidney Injury
The Lancet, 2012Co-Authors: Rinaldo Bellomo, John A Kellum, Claudio RoncoAbstract:Acute Kidney Injury (formerly known as acute renal failure) is a syndrome characterised by the rapid loss of the Kidney's excretory function and is typically diagnosed by the accumulation of end products of nitrogen metabolism (urea and creatinine) or decreased urine output, or both. It is the clinical manifestation of several disorders that affect the Kidney acutely. Acute Kidney Injury is common in hospital patients and very common in critically ill patients. In these patients, it is most often secondary to extrarenal events. How such events cause acute Kidney Injury is controversial. No specific therapies have emerged that can attenuate acute Kidney Injury or expedite recovery; thus, treatment is supportive. New diagnostic techniques (eg, renal biomarkers) might help with early diagnosis. Patients are given renal replacement therapy if acute Kidney Injury is severe and biochemical or volume-related, or if uraemic-toxaemia-related complications are of concern. If patients survive their illness and do not have premorbid chronic Kidney disease, they typically recover to dialysis independence. However, evidence suggests that patients who have had acute Kidney Injury are at increased risk of subsequent chronic Kidney disease.
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a comparison of the rifle and acute Kidney Injury network classifications for cardiac surgery associated acute Kidney Injury a prospective cohort study
The Journal of Thoracic and Cardiovascular Surgery, 2009Co-Authors: Michael Haase, Rinaldo Bellomo, George Matalanis, Paolo Calzavacca, Duska Dragun, Anja HaasefielitzAbstract:Objectives There is an intense debate on whether the RIFLE (R–renal risk, I–Injury, F–failure, L–loss of Kidney function, E–end-stage renal disease) classification or its recent modification, the Acute Kidney Injury Network definition and classification system should be used to standardize research on acute Kidney Injury. In this study we compared these classifications with regard to (1) the detection of acute Kidney Injury, (2) their agreement according to the grading of acute Kidney Injury across classes, and (3) their prognostic value. Methods We prospectively enrolled 282 cardiac surgery patients undergoing cardiopulmonary bypass and assigned a RIFLE and Acute Kidney Injury Network class to each patient. The incidence of acute Kidney Injury and in-hospital mortality across classes was compared by using the χ 2 test, and their prognostic value was compared by using the area under the curve receiver-operating characteristic for in-hospital mortality. Results According to the RIFLE (45.8%) or Acute Kidney Injury Network (44.7%) classification, a similar proportion of patients had acute Kidney Injury. There was large agreement between classifications according to patients graded as having nonacute Kidney Injury; however, there was some disagreement across classes for staging the severity of acute Kidney Injury. The area under the curve for in-hospital mortality was similar for all classifications: 0.91 for the RIFLE classification (95% confidence interval, 0.82–0.99) and 0.94 for the Acute Kidney Injury Network classification (95% confidence interval, 0.81–0.97; P = .6 for area under the curve comparison). Conclusions In patients undergoing cardiac surgery, modifications of the RIFLE classification for acute Kidney Injury do not materially improve the clinical usefulness of the definition. Other factors, such as the applicability of the acute Kidney Injury definition and classification system to be applied, need to be considered.
Vishal S. Vaidya - One of the best experts on this subject based on the ideXlab platform.
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Kidney Injury molecule 1 outperforms traditional biomarkers of Kidney Injury in preclinical biomarker qualification studies
Nature Biotechnology, 2010Co-Authors: Vishal S. Vaidya, Josef S Ozer, Frank Dieterle, Fitz B Collings, Victoria Ramirez, Sean P Troth, Nagaraja Muniappa, Douglas Thudium, David GerholdAbstract:Kidney toxicity accounts both for the failure of many drug candidates as well as considerable patient morbidity. Whereas histopathology remains the gold standard for nephrotoxicity in animal systems, serum creatinine (SCr) and blood urea nitrogen (BUN) are the primary options for monitoring Kidney dysfunction in humans. The transmembrane tubular protein Kidney Injury molecule-1 (Kim-1) was previously reported to be markedly induced in response to renal Injury. Owing to the poor sensitivity and specificity of SCr and BUN, we used rat toxicology studies to compare the diagnostic performance of urinary Kim-1 to BUN, SCr and urinary N-acetyl-beta-D-glucosaminidase (NAG) as predictors of Kidney tubular damage scored by histopathology. Kim-1 outperforms SCr, BUN and urinary NAG in multiple rat models of Kidney Injury. Urinary Kim-1 measurements may facilitate sensitive, specific and accurate prediction of human nephrotoxicity in preclinical drug screens. This should enable early identification and elimination of compounds that are potentially nephrotoxic.
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biomarkers of nephrotoxic acute Kidney Injury
Toxicology, 2008Co-Authors: Michael A. Ferguson, Vishal S. Vaidya, Joseph V BonventreAbstract:Acute Kidney Injury (AKI) is a common condition with significant associated morbidity and mortality. Epidemiologic data suggest that a significant proportion of AKI cases is at least partially attributable to nephrotoxin exposure. This is not surprising given intrinsic renal susceptibility to toxicant-induced Injury, a consequence of the unique physiologic and biochemical properties of the normally functioning Kidney. A number of pathophysiologic mechanisms have been identified that mediate toxic effects on the Kidney, resulting in a variety of clinical syndromes ranging from subtle changes in tubular function to fulminant renal failure. Unfortunately, standard metrics used to diagnose and monitor Kidney Injury, such as blood urea nitrogen and serum creatinine, are insensitive and nonspecific, resulting in delayed diagnosis and intervention. Considerable effort has been made to identify biomarkers that will allow the earlier diagnosis of AKI. Further characterization of these candidate biomarkers will clarify their utility in the setting of acute nephrotoxicity, define new diagnostic and prognostic paradigms for Kidney Injury, facilitate clinical trials, and lead to novel effective therapies.
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Biomarkers of Acute Kidney Injury
Annual Review of Pharmacology and Toxicology, 2008Co-Authors: Vishal S. Vaidya, Michael A. Ferguson, Joseph V BonventreAbstract:Acute Kidney Injury (AKI) is a common condition with a high risk of death. The standard metrics used to define and monitor the progression of AKI, such as serum creatinine and blood urea nitrogen levels, are insensitive, nonspecific, and change significantly only after significant Kidney Injury and then with a substantial time delay. This delay in diagnosis not only prevents timely patient management decisions, including administration of putative therapeutic agents, but also significantly affects the preclinical evaluation of toxicity thereby allowing potentially nephrotoxic drug candidates to pass the preclinical safety criteria only to be found to be clinically nephrotoxic with great human costs. Studies to establish effective therapies for AKI will be greatly facilitated by two factors: (a) development of sensitive, specific, and reliable biomarkers for early diagnosis/prognosis of AKI in preclinical and clinical studies, and (b) development and validation of high-throughput innovative technologies that allow rapid multiplexed detection of multiple markers at the bedside.
Michael A. Ferguson - One of the best experts on this subject based on the ideXlab platform.
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biomarkers of nephrotoxic acute Kidney Injury
Toxicology, 2008Co-Authors: Michael A. Ferguson, Vishal S. Vaidya, Joseph V BonventreAbstract:Acute Kidney Injury (AKI) is a common condition with significant associated morbidity and mortality. Epidemiologic data suggest that a significant proportion of AKI cases is at least partially attributable to nephrotoxin exposure. This is not surprising given intrinsic renal susceptibility to toxicant-induced Injury, a consequence of the unique physiologic and biochemical properties of the normally functioning Kidney. A number of pathophysiologic mechanisms have been identified that mediate toxic effects on the Kidney, resulting in a variety of clinical syndromes ranging from subtle changes in tubular function to fulminant renal failure. Unfortunately, standard metrics used to diagnose and monitor Kidney Injury, such as blood urea nitrogen and serum creatinine, are insensitive and nonspecific, resulting in delayed diagnosis and intervention. Considerable effort has been made to identify biomarkers that will allow the earlier diagnosis of AKI. Further characterization of these candidate biomarkers will clarify their utility in the setting of acute nephrotoxicity, define new diagnostic and prognostic paradigms for Kidney Injury, facilitate clinical trials, and lead to novel effective therapies.
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Biomarkers of Acute Kidney Injury
Annual Review of Pharmacology and Toxicology, 2008Co-Authors: Vishal S. Vaidya, Michael A. Ferguson, Joseph V BonventreAbstract:Acute Kidney Injury (AKI) is a common condition with a high risk of death. The standard metrics used to define and monitor the progression of AKI, such as serum creatinine and blood urea nitrogen levels, are insensitive, nonspecific, and change significantly only after significant Kidney Injury and then with a substantial time delay. This delay in diagnosis not only prevents timely patient management decisions, including administration of putative therapeutic agents, but also significantly affects the preclinical evaluation of toxicity thereby allowing potentially nephrotoxic drug candidates to pass the preclinical safety criteria only to be found to be clinically nephrotoxic with great human costs. Studies to establish effective therapies for AKI will be greatly facilitated by two factors: (a) development of sensitive, specific, and reliable biomarkers for early diagnosis/prognosis of AKI in preclinical and clinical studies, and (b) development and validation of high-throughput innovative technologies that allow rapid multiplexed detection of multiple markers at the bedside.
