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Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury.

ABSTRACT: 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.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.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 <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2]·[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.Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI.ClinicalTrials.gov number NCT01209169.

SUBMITTER: Kashani K

PROVIDER: S-EPMC4057242 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury.

Kashani Kianoush K Al-Khafaji Ali A Ardiles Thomas T Artigas Antonio A Bagshaw Sean M SM Bell Max M Bihorac Azra A Birkhahn Robert R Cely Cynthia M CM Chawla Lakhmir S LS Davison Danielle L DL Feldkamp Thorsten T Forni Lui G LG Gong Michelle Ng MN Gunnerson Kyle J KJ Haase Michael M Hackett James J Honore Patrick M PM Hoste Eric A J EA Joannes-Boyau Olivier O Joannidis Michael M Kim Patrick P Koyner Jay L JL Laskowitz Daniel T DT Lissauer Matthew E ME Marx Gernot G McCullough Peter A PA Mullaney Scott S Ostermann Marlies M Rimmelé Thomas T Shapiro Nathan I NI Shaw Andrew D AD Shi Jing J Sprague Amy M AM Vincent Jean-Louis JL Vinsonneau Christophe C Wagner Ludwig L Walker Michael G MG Wilkerson R Gentry RG Zacharowski Kai K Kellum John A JA

Critical care (London, England) 20130206 1

<h4>Introduction</h4>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.<h4>Methods</h4>We performed two multicenter observational studies in critically ill patients at ...[more]

PMID: 23388612

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Project description:BackgroundAcute kidney injury (AKI) is a common disease in the intensive care unit (ICU). AKI patients with nonrecovery of renal function have a markedly increased risk of death compared with patients with recovery. The current study aimed to explore and validate the utility of urinary cell cycle arrest biomarkers for predicting nonrecovery in patients who developed AKI after ICU admission.MethodsWe prospectively and consecutively enrolled 379 critically ill patients who developed AKI after admission to the ICU, which were divided into a derivation cohort (194 AKI patients) and a validation cohort (185 AKI patients). The biomarkers of urinary tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) were detected at inclusion immediately after AKI diagnosis (day 0) and 24 h later (day 1). The optimal cut-off values of these biomarkers for predicting nonrecovery were estimated in the derivation cohort, and their predictive accuracy was assessed in the validation cohort. The primary endpoint was nonrecovery from AKI (within 7 days).ResultsOf 379 patients, 159 (41.9%) patients failed to recover from AKI onset, with 79 in the derivation cohort and 80 in the validation cohort. Urinary [TIMP-2]*[IGFBP7] on day 0 showed a better prediction ability for nonrecovery than TIMP-2 and IGFBP7 alone, with an area under the reciever operating characteristic curve (AUC) of 0.751 [95% confidence interval (CI) 0.701-0.852, p < 0.001] and an optimal cut-off value of 1.05 ((ng/mL)2/1000). When [TIMP-2]*[IGFBP7] was combined with the clinical factors of AKI diagnosed by the urine output (UO) criteria, AKI stage 2-3 and nonrenal SOFA score for predicting nonrecovery, the AUC was significantly improved to 0.852 (95% CI 0.750-0.891, p < 0.001), which achieved a sensitivity and specificity of 88.8% (72.9, 98.7) and 92.6% (80.8, 100.0), respectively. However, urine [TIMP-2]*[IGFBP7], TIMP-2 alone, and IGFBP7 alone on day 1 performed poorly for predicting AKI recovery.ConclusionUrinary [TIMP-2]*[IGFBP7] on day 0 showed a fair performance for predicting nonrecovery from AKI. The predictive accuracy can be improved when urinary [TIMP-2]*[IGFBP7] is combined with the clinical factors of AKI diagnosed by the UO criteria, AKI stage 2-3 and nonrenal SOFA score.

Project description:Acute kidney injury (AKI) is a common complication following transcatheter aortic valve implantation (TAVI) leading to increased mortality and morbidity. Urinary G1 cell cycle arrest proteins TIMP-2 and IGFBP7 have recently been suggested as sensitive biomarkers for early detection of AKI in critically ill patients. However, the precise role of urinary TIMP-2 and IGFBP7 in patients undergoing TAVI is unknown.In a prospective observational trial, 40 patients undergoing TAVI (either transaortic or transapical) were enrolled. Serial measurements of TIMP-2 and IGFBP7 were performed in the early post interventional course. The primary clinical endpoint was the occurrence of AKI stage 2/3 according to the KDIGO classification.Now we show, that ROC analyses of [TIMP-2]*[IGFBP7] on day one after TAVI reveals a sensitivity of 100 % and a specificity of 90 % for predicting AKI 2/3 (AUC 0.971, 95 % CI 0.914-1.0, SE 0.0299, p = 0.001, cut-off 1.03). In contrast, preoperative and postoperative serum creatinine levels as well as glomerular filtration rate (GFR) and perioperative change in GFR did not show any association with the development of AKI. Furthermore, [TIMP-2]*[IGFBP7] remained stable in patients with AKI ≤1, but its levels increased significantly as early as 24 h after TAVI in patients who developed AKI 2/3 in the further course (4.77 ± 3.21 vs. 0.48 ± 0.68, p = 0.022). Mean patients age was 81.2 ± 5.6 years, 16 patients were male (40.0 %). 35 patients underwent transapical and five patients transaortic TAVI. 15 patients (37.5 %) developed any kind of AKI; eight patients (20 %) met the primary endpoint and seven patients required renal replacement therapy (RRT) within 72 h after surgery.Early elevation of urinary cell cycle arrest biomarkers after TAVI is associated with the development of postoperative AKI. [TIMP-2]*[IGFBP7] provides an excellent diagnostic accuracy in the prediction of AKI that is superior to that of serum creatinine.

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Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury.

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Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury.

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