Kinetics of Urinary Cell Cycle Arrest Markers for Acute Kidney Injury Following Exposure to Potential Renal Insults

Abstract

Objectives: Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 predict the development of acute kidney injury following renal insults of varied aetiology. To aid clinical interpretation, we describe the kinetics of biomarker elevations around an exposure.

Design: In an ancillary analysis of the multicenter SAPPHIRE study, we examined the kinetics of the urinary [tissue inhibitor of metalloproteinase-2]•[insulin-like growth factor binding protein 7] in association with exposure to common renal insults (major surgery, IV radiocontrast, vancomycin, nonsteroidal anti-inflammatory drugs, and piperacillin/tazobactam).

Setting: Thirty-five sites in North America and Europe between September 2010 and June 2012.

Patients: Seven hundred twenty-three critically ill adult patients admitted to the ICU.

Interventions: None.

Measurements and main results: We compared the urinary [tissue metalloproteinase-2]•[insulin growth factor binding protein 7] kinetics from the day prior to exposure up to 5 days after exposure in patients developing acute kidney injury stage 2-3, stage 1, or no acute kidney injury by Kidney Disease Improving Global Outcome criteria. Among the 723 patients, 679 (94%) had at least one, 70% had more than one, and 35% had three or more exposures to a known renal insult. There was a significant association between cumulative number of exposures up to study day 3 and risk of acute kidney injury (p = 0.02) but no association between the specific type of exposure and acute kidney injury (p = 0.22). With the exception of radiocontrast, patients who developed acute kidney injury stage 2-3 after one of the five exposures, had a clear rise and fall of urinary [tissue inhibitor of metalloproteinase-2]•[insulin-like growth factor binding protein 7] from the day of exposure to 24-48 hours later. In patients without acute kidney injury, there was no significant elevation in urinary [tissue inhibitor of metalloproteinase-2]•[insulin-like growth factor binding protein 7].

Conclusions: Exposure to potential renal insults is common. In patients developing acute kidney injury stage 2-3, the kinetics of urinary [tissue inhibitor of metalloproteinase-2]•[insulin-like growth factor binding protein 7] matched the exposure except in the case of radiocontrast.

Figure 1.

Patient flow diagram. AKI = acute kidney injury, NSAID = nonsteroidal anti-inflammatory drug. *Exposures occurred in hospital between 5 days prior to enrollment through 7 days after enrollment.

Figure 2.

Biomarker kinetics in association with specific exposures. Time course of urinary tissue inhibition of metalloproteinase [TIMP-2]•insulin-like growth factor binding protein [IGFBP7] concentrations relative to the time or day of exposure by acute kidney injury (AKI) stage for patients exposed to major surgery (A), IV contrast (B), vancomycin (C), NSAIDs (D), or piperacillin/tazobactam (E). Symbols show median urinary [TIMP-2]•[IGFBP7] concentrations for patients who had no AKI (circles), AKI stage 1 (squares), and AKI stage 2–3 (triangles) within 3 days postexposure. Vertical and horizontal lines through the symbols show the interquartile range of bootstrap medians for the [TIMP-2]•[IGFBP7] concentrations and the time from exposure, respectively. Median urinary [TIMP-2]•[IGFBP7] concentrations are shown by day for drug exposures because only the day and not the time of exposure was recorded. The width of the shaded area indicates the day of the first dose of each drug.