Serial Urinary Tissue Inhibitor of Metalloproteinase-2 and Insulin-Like Growth Factor-Binding Protein 7 and the Prognosis for Acute Kidney Injury over the Course of Critical Illness
Authors: McCullough Peter A. , Ostermann Marlies , Forni Lui G. , Bihorac Azra , Koyner Jay L. , Chawla Lakhmir S. , Shi Jing , Kampf J. Patrick , McPherson Paul , Kellum John A. ,   the Sapphire Investigators
Published: October 2019

<b><i>Introduction:</i></b> Over the course of critical illness, there is a risk of acute kidney injury (AKI), and when it occurs, it is associated with increased length of stay, morbidity, and mortality. The urinary cell-cycle arrest markers tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) have been utilized to predict the risk of AKI over the next 12 h from the time of sampling. The aim of this analysis was to evaluate the utility of [TIMP-2] × [IGFBP7] measured serially to anticipate the occurrence of AKI over the first 7 days of critical illness. <b><i>Methods:</i></b> This analysis is from a prospective, blinded, observational, international study of patients admitted to intensive care units. We designed the analysis to emulate a clinician-driven serial testing strategy. Urine samples collected every 12 h up to 3 days from 530 patients were considered for analysis. We evaluated [TIMP-2] × [IGFBP7] results for the first 3 measurements (baseline, 12 and 24 h) and continued to evaluate additional results if any of the first 3 were positive &#x3e;0.3 (ng/mL)<sup>2</sup>/1,000. Patients were stratified by number of [TIMP-2] × [IGFBP7] results &#x3e;0.3 (ng/mL)<sup>2</sup>/1,000 and number of results &#x3e;2.0 (ng/mL)<sup>2</sup>/1,000. The primary endpoint was AKI stage 2–3 defined by the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. <b><i>Results:</i></b> The median (interquartile range) age was 64 (53–74) years, 61% were men, and 79% were Caucasian. The median APACHE III score was 71 (51–93), and 82% required mechanical ventilation. Baseline serum creatinine was 0.8 mg/dL and 164/530 (31%) developed the primary endpoint by day 7 with a median time from baseline to stage 2/3 AKI of 26 (8–56) h. In patients with negative values for the first 3 tests (≤0.3 (ng/mL)<sup>2</sup>/1,000), the cumulative incidence of the primary endpoint at 7 days was 13.0%. Conversely, for those with one, two, or three strongly positive values (&#x3e;2.0 (ng/mL)<sup>2</sup>/1,000), the cumulative incidence for the primary endpoint at 7 days was 57.7, 75.0, and 94.4%, respectively, <i>p</i> &#x3c; 0.001 for trend. There were 3.4% with test results between 0.3 and 2.0 (ng/mL)<sup>2</sup>/1,000 at all measurements; one third of those patients developed the primary endpoint. We observed a graded increase in the primary endpoint in Kaplan-Meier plots for successively positive test results over time. <b><i>Conclusion:</i></b> Serial urinary [TIMP-2] × [IGFBP7] at baseline, 12 and 24 h, and up through 3 days are prognostic for the occurrence of stage 2/3 AKI over the course of critical illness. Three consecutive negative values (≤0.3 (ng/mL)<sup>2</sup>/1,000) are associated with very low (13.0%) incidence of stage 2/3 AKI over the course of 7 days. Conversely, emerging or persistent, strongly positive results [&#x3e;2.0 [ng/mL]<sup>2</sup>/1,000] predict very high incidence rates (up to 94.4%) of stage 2/3 AKI. There was a low rate of test results between 0.3 and 2.0 (ng/mL)<sup>2</sup>/1,000, where the primary endpoint was observed in a third of cases.