Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury.
Kianoush Kashani,Ali Al-Khafaji,Thomas Ardiles,Antonio Artigas,Sean M. Bagshaw,Max Bell,Azra Bihorac,Robert H. Birkhahn,Cynthia M. Cely,Lakhmir S. Chawla,Danielle Davison,Thorsten Feldkamp,Lui G. Forni,Michelle N. Gong,Kyle J. Gunnerson,Michael Haase,James Hackett,Patrick M. Honore,Eric Hoste,Olivier Joannes-Boyau,Michael Joannidis,Patrick K. Kim,Jay L. Koyner,Daniel T. Laskowitz,Matthew Lissauer,Gernot Marx,Peter A. McCullough,Scott Mullaney,Marlies Ostermann,Thomas Rimmelé,Nathan I. Shapiro,Andrew D. Shaw,Jing Shi,Amy M Sprague,Jean Louis Vincent,Christophe Vinsonneau,Ludwig Wagner,Michael G. Walker,R. Gentry Wilkerson,Kai Zacharowski,John A. Kellum +40 more
TLDR
Two novel markers for AKI have been identified and validated in independent multicenter cohorts and are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI.Abstract:
Introduction: Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI. Methods: We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection. Results: Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P 0.72. Furthermore, [TIMP2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.read more
Citations
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Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury
Ravindra L. Mehta,John A. Kellum,Sudhir V. Shah,Bruce A. Molitoris,Claudio Ronco,David G. Warnock,Adeera Levin +6 more
TL;DR: An initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI is described.
Journal ArticleDOI
Acute kidney injury
TL;DR: Evidence suggests that patients who have had acute kidney injury are at increased risk of subsequent chronic kidney disease, and new diagnostic techniques (eg, renal biomarkers) might help with early diagnosis.
Journal ArticleDOI
Balanced Crystalloids versus Saline in Critically Ill Adults
Matthew W. Semler,Wesley H. Self,Jonathan P. Wanderer,Jesse M. Ehrenfeld,Li Wang,Daniel W. Byrne,Joanna L. Stollings,Avinash B. Kumar,Christopher G. Hughes,Antonio Hernandez,Oscar D. Guillamondegui,Addison K. May,Liza Weavind,Jonathan D Casey,Edward D. Siew,Andrew D. Shaw,Gordon R. Bernard,Todd W. Rice +17 more
TL;DR: The use of balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite outcome of death from any cause, new renal‐replacement therapy, or persistent renal dysfunction than the use of saline among critically ill adults.
Journal ArticleDOI
A Unified Theory of Sepsis-Induced Acute Kidney Injury: Inflammation, microcirculatory dysfunction, bioenergetics and the tubular cell adaptation to injury
Hernando Gomez,Can Ince,Daniel De Backer,Peter Pickkers,Didier Payen,John Hotchkiss,John A. Kellum +6 more
TL;DR: It is proposed that the interplay between inflammation and oxidative stress, microvascular dysfunction, and the adaptive response of the tubular epithelial cell to the septic insult is mostly adaptive in origin, that it is driven by mitochondria, and that it ultimately results in and explains the clinical phenotype of sepsis-induced AKI.
Journal ArticleDOI
Global epidemiology and outcomes of acute kidney injury
Eric Hoste,John A. Kellum,Nicholas M. Selby,Alexander Zarbock,Paul M. Palevsky,Sean M. Bagshaw,Stuart L. Goldstein,Jorge Cerdá,Lakhmir S. Chawla +8 more
TL;DR: The global epidemiology of acute kidney injury is described and the influence of modifiable and non-modifiable AKI risk factors, delayed diagnosis, variation in diagnostic criteria and disparities in access to health care are also discussed.
References
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TL;DR: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Initiative developed recommendations on what should be included in an accurate and complete report of an observational study, resulting in a checklist of 22 items that relate to the title, abstract, introduction, methods, results, and discussion sections of articles.
Journal ArticleDOI
The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies
E von Elm,Douglas G. Altman,Matthias Egger,Matthias Egger,Stuart J. Pocock,Peter C Gøtzsche,Jan P. Vandenbroucke +6 more
TL;DR: The STROBE Statement is a checklist of items that should be addressed in articles reporting on the 3 main study designs of analytical epidemiology: cohort, casecontrol, and cross-sectional studies; these recommendations are not prescriptions for designing or conducting studies.
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The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine.
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Nonparametric Statistical Methods
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John A. Kellum,Norbert Lameire,Peter Aspelin,Rashad S. Barsoum,Emmanuel A. Burdmann,Stuart L. Goldstein,Charles A. Herzog,Michael Joannidis,Andreas Kribben,Andrew S. Levey,Alison M. MacLeod,Ravindra L. Mehta,Patrick T. Murray,Saraladevi Naicker,Steven M. Opal,Franz Schaefer,Miet Schetz,Shigehiko Uchino +17 more