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

By K. Kashani, A. Al-Khafaji, T. Ardiles, A. Artigas, Sean M. Bagshaw, M. Bell, Azra Bihorac, R. Birkhahn, Cynthia M Cely, L. Chawla and 31 more. Critical Care, 2013

1,231 citations recorded by the source corpus.

IntroductionAcute 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.MethodsWe 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.ResultsModerate 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.ConclusionsTwo 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.Trial registrationClinicalTrials.gov number NCT01209169.

Subfields: Critical Care and Intensive Care Medicine, Nephrology

View Paper: https://www.semanticscholar.org/paper/760db1bb94386d432d0c5bd197697527bcf06f1a

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In Critical Care and Intensive Care Medicine

1. R. Bellomo
2. John A. Kellum

In Nephrology

1. John A. Kellum
2. R. Bellomo
3. Claudio Ronco
4. Sean M. Bagshaw
5. M. Ostermann
6. R. Chang

Citations in the corpus

• Acute kidney injury in sepsis (2017, background): “of critically ill patients, including many with septic AKI [12], found an area under the receiver operating characteristic curve (AUC) of 0.”
• A Unified Theory of Sepsis-Induced Acute Kidney Injury: Inflammation, microcirculatory dysfunction, bioenergetics and the tubular cell adaptation to injury (2014, neutral): “These findings have become even more clinically relevant as tissue inhibitor of metalloproteinases 2 (TIMP-2) and insulinlike growth factorYbinding protein 7 (IGFBP-7), two markers involved in G1-S cycle arrest, have been identified as the most sensitive and specific markers to predict risk of devel”
• Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: the PrevAKI randomized controlled trial (2017, methodology): “The two new renal biomarkers, insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), are involved in G1 cell cycle arrest and are able to identify patients at high risk for AKI [9].”