Derivation and validation of cutoffs for clinical use of cell cycle arrest biomarkers

Abstract

BackgroundAcute kidney injury (AKI) remains a deadly condition. Tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein (IGFBP)7 are two recently discovered urinary biomarkers for AKI. We now report on the development, and diagnostic accuracy of two clinical cutoffs for a test using these markers.MethodsWe derived cutoffs based on sensitivity and specificity for prediction of Kidney Disease: Improving Global Outcomes Stages 2–3 AKI within 12 h using data from a previously published multicenter cohort (Sapphire). Next, we verified these cutoffs in a new study (Opal) enrolling 154 critically ill adults from six sites in the USA.ResultsOne hundred subjects (14%) in Sapphire and 27 (18%) in Opal met the primary end point. The results of the Opal study replicated those of Sapphire. Relative risk (95% CI) in both studies for subjects testing at ≤0.3 versus >0.3–2 were 4.7 (1.5–16) and 4.4 (2.5–8.7), or 12 (4.2–40) and 18 (10–37) for ≤0.3 versus >2. For the 0.3 cutoff, sensitivity was 89% in both studies, and specificity 50 and 53%. For 2.0, sensitivity was 42 and 44%, and specificity 95 and 90%.ConclusionsUrinary [TIMP-2]•[IGFBP7] values of 0.3 or greater identify patients at high risk and those >2 at highest risk for AKI and provide new information to support clinical decision-making.Clinical Trials RegistrationClintrials.gov # NCT01209169 (Sapphire) and NCT01846884 (Opal).

Biomarkers for AKI improve clinical practice: no

“…Consequently, research in the last decade has focussed on the discovery and validation of more specific and sensitive markers of tubular damage/functional impairment. The most advanced biomarkers promise to identify patients at risk of AKI, diagnose AKI earlier than conventional tests and prognosticate risk of progression, including need for (RRT) renal replacement therapy [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. The hope is that, with such an approach and more timely and relevant interventions, the outcome of patients with AKI can be improved.…”

Biomarkers in critical illness: have we made progress?

“…The SAPPHIRE study 6,7 showed that two novel cell cycle arrest biomarkers, tissue inhibitor of metalloproteinase-2 and urinary insulin-like growth factor binding protein 7, largely outperformed existing markers. Whether these markers can predict the need for or duration of renal replacement therapy is currently under investigation.…”

Urinary TIMP2·IGFBP7 for the prediction of platinum-induced acute renal injury

“…Many studies have shown that the product of the concentration of these proteins TIMP2·IGFBP7 in urine (Astute Medical, San Diego, CA, USA) is an early indicator of risk for AKI. [23][24][25][26][27][28] As the first available AKI biomarker test in the USA, urinary TIMP2·IGFBP7 was cleared in 2014 by the US FDA. 29 In this study, we tested the hypothesis that urinary TIMP2·IGFBP7 collected directly prior and after PBC administration can predict the development of AKI.…”