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

• Published in: Nephrology, dialysis, transplantation Vol. 29; no. 11; pp. 2054 - 2061
• Main Authors: Hoste, Eric A.J., McCullough, Peter A., Kashani, Kianoush, Chawla, Lakhmir S., Joannidis, Michael, Shaw, Andrew D., Feldkamp, Thorsten, Uettwiller-Geiger, Denise L., McCarthy, Paul, Shi, Jing, Walker, Michael G., Kellum, John A.
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.11.2014
• Subjects: Acute Kidney Injury - pathology; Acute Kidney Injury - urine; Aged; Biomarkers - urine; Cell Cycle Checkpoints - physiology; CLINICAL SCIENCE; Female; Follow-Up Studies; Humans; Insulin-Like Growth Factor Binding Proteins - urine; Male; Middle Aged; Predictive Value of Tests; ROC Curve; Tissue Inhibitor of Metalloproteinase-2 - urine; insulin-like growth factor binding protein (IGFBP)7 and tissue inhibitor of metalloproteinases (TIMP)-2; acute kidney injury; acute renal failure; sensitivity and specificity (MeSH); biomarkers
• ISSN: 0931-0509; 1460-2385; 1460-2385
• DOI: 10.1093/ndt/gfu292

Acute 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. We 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. One 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%. Urinary [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. Clintrials.gov # NCT01209169 (Sapphire) and NCT01846884 (Opal).