Urinary TIMP-2*IGFBP-7 to diagnose acute kidney injury in children receiving cisplatin

Abstract

Background: Cisplatin is associated with acute kidney injury (AKI) and electrolyte abnormalities. Urine tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP-7) may be early cisplatin-AKI biomarkers.

Methods: We conducted a 12-site prospective cohort study with pediatric patients treated with cisplatin (May 2013-December 2017). Blood and urine (measured for TIMP-2, IGFBP-7) were collected pre-cisplatin, 24-h post-cisplatin, and near hospital discharge during the first or second cisplatin cycle (early visit (EV)) and during second-to-last or last cisplatin cycle (late visit (LV)).

Primary outcome: serum creatinine (SCr)-defined AKI (≥ stage 1).

Results: At EV (median (interquartile (IQR)) age: 6 (2-12) years; 78 (50%) female), 46/156 (29%) developed AKI; at LV, 22/127 (17%) experienced AKI. At EV, TIMP-2, IGFBP-7, and TIMP-2*IGFBP-7 pre-cisplatin infusion concentrations were significantly higher in participants with vs. those without AKI. At EV and LV, biomarker concentrations were significantly lower in participants with vs. those without AKI at post-infusion and near-hospital discharge. Biomarker values normalized to urine creatinine were higher in patients with AKI compared to without (LV post-infusion, median (IQR): TIMP-2*IGFBP-7: 0.28 (0.08-0.56) vs. 0.04 (0.02-0.12) (ng/mg creatinine)²/1000; P < .001). At EV, pre-infusion biomarker concentrations had the highest area under the curves (AUC) (range: 0.61-0.62) for AKI diagnosis; at LV, biomarkers measured post-infusion and near discharge yielded the highest AUCs (range: 0.64-0.70).

Conclusions: TIMP-2*IGFBP-7 were poor to modest at detecting AKI post-cisplatin. Additional studies are needed to determine whether raw biomarker values or biomarker values normalized to urinary creatinine are more strongly associated with patient outcomes. A higher resolution version of the Graphical abstract is available as Supplementary information.

Keywords: Acute kidney injury; Cisplatin nephrotoxicity; Insulin-like growth factor binding protein; Pediatrics; Tissue inhibitor of metalloproteinase-2; Urine biomarkers.