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Randomized Controlled Trial
. 2014 Nov;29(11):2054-61.
doi: 10.1093/ndt/gfu292. Epub 2014 Sep 18.

Derivation and Validation of Cutoffs for Clinical Use of Cell Cycle Arrest Biomarkers

Affiliations
Free PMC article
Randomized Controlled Trial

Derivation and Validation of Cutoffs for Clinical Use of Cell Cycle Arrest Biomarkers

Eric A J Hoste et al. Nephrol Dial Transplant. .
Free PMC article

Abstract

Background: 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.

Methods: 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.

Results: 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%.

Conclusions: 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.

Clinical trials registration: Clintrials.gov # NCT01209169 (Sapphire) and NCT01846884 (Opal).

Keywords: acute kidney injury; acute renal failure; biomarkers; insulin-like growth factor binding protein (IGFBP)7 and tissue inhibitor of metalloproteinases (TIMP)-2; sensitivity and specificity (MeSH).

Figures

FIGURE 1:
FIGURE 1:
Study design (Opal) and number of subjects.
FIGURE 2:
FIGURE 2:
[TIMP-2]•[IGFBP7] ROC curves and operating characteristics for the Sapphire (solid) and Opal (dash) cohorts. Closed triangles and circles indicate [TIMP-2]•[IGFBP7] cutoffs of 0.3 and 2.0, respectively. End point was AKI Stages 2 or 3 within 12 h of sample collection. Area under the ROC curve [95% confidence interval (CI)] = 0.80 (0.74–0.84) and 0.79 (0.69–0.88) for Sapphire and Opal, respectively. NPV and PPVs are presented in Supplementary Data Figure S4 of the supplement.
FIGURE 3:
FIGURE 3:
Relative risk of AKI Stage 2 or 3 within 12 h in the Opal (light gray), Sapphire (medium gray) and combined Opal and Sapphire (dark gray) cohort. Samples were collected within 18 h of enrollment. Risk for each [TIMP-2]•[IGFBP7] range is shown relative to the lowest [TIMP-2]•[IGFBP7] range (≤0.3). Raw risk in lowest stratum = 4.3, 2.7 and 2.9%, respectively, for the Opal, Sapphire and combined cohorts. Error bars indicate the 95% CI. For both cohorts together 700 (46%) of patients had values ≤0.3; 675 (44%) had values between 0.3 and 2 (raw risk of AKI 12.6%); and 154 (10%) had values >2.0 (raw risk of AKI 49%). Cochran–Armitage test for significant trend: P < 0.001 for all three cohorts. Relative risk P < 0.001 for both the second and third stratum relative to the first stratum for all cohorts, except the second stratum of Opal for which relative risk P < 0.01.
FIGURE 4:
FIGURE 4:
Relative risk of MAKE30 in the Sapphire cohort. Samples were collected within 18 h of enrollment. Risk for each [TIMP-2]•[IGFBP7] range is shown relative to the lowest [TIMP-2]•[IGFBP7] range (≤0.3). Raw risk in lowest stratum = 18%. Error bars indicate the 95% CI. Cochran–Armitage test for significant trend: P < 0.001. *P = 0.036; **P < 0.001.
FIGURE 5:
FIGURE 5:
Prevalence adjusted PPV (A) and NPV (B) for [TIMP-2]•[IGFBP7] cutoff values of 0.3 and 2.0 in the Opal (light gray), Sapphire (medium gray) and combined Opal and Sapphire (dark gray) cohort. Samples were collected within 18 h of enrollment. End point is AKI Stage 2 or 3 within the time window for prediction of AKI indicated along the abscissa (zero time = time of sample collection). Prevalence was adjusted to match the AKI distribution from Joannidis et al. [13] as described in the text [13]. Error bars indicate the 95% CI. Median time from a positive test result to a positive end point was 12.5 h [interquartile range (IQR) 2.7–26] for the Sapphire study and 8 h (IQR 0–15.5) for Opal.

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