Title:Elevated Urinary Tissue Inhibitor of Metalloproteinase-2 and Insulin-Like Growth
Factor Binding Protein-7 Predict Drug-Induced Acute Kidney Injury
Volume: 23
Issue: 3
Author(s): K Akalya, Tanusya Murali Murali, Anantharaman Vathsala, Boon-Wee Teo, Sanmay Low, Dharmini Dharmasegaran, Liang-Piu Koh, Glenn Kunnath Bonney, Wei-Zhen Hong, Yi Da and Horng-Ruey Chua*
Affiliation:
- Division of Nephrology, University Medicine Cluster, National University Hospital, Singapore, Singapore
- Department of Medicine,
Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Keywords:
Acute kidney injury, antimicrobials, biomarkers, calcineurin inhibitors, drug-related side effects and adverse reactions, Insulinlike growth factor binding proteins, nephrotoxicity, tissue inhibitor of metalloproteinase-2, urinalysis, vancomycin.
Abstract:
Background: Urinary tissue inhibitor of metalloproteinase-2 (TIMP2) and insulin-like growth factor binding
protein-7 (IGFBP7) predict severe acute kidney injury (AKI) in critical illness. Earlier but subtle elevation of
either biomarker from nephrotoxicity may predict drug-induced AKI.
Methods: A prospective study involving serial urine collection in patients treated with vancomycin, aminoglycosides,
amphotericin, foscarnet, or calcineurin inhibitors was performed. Urinary TIMP2 and IGFBP7, both absolute
levels and those normalized with urine creatinine, were examined in days leading to AKI onset by KDIGO criteria in
cases or at final day of nephrotoxic therapy in non-AKI controls, who were matched for age, baseline kidney function,
and nephrotoxic exposure.
Results: Urinary biomarker analyses were performed in 21 AKI patients and 28 non-AKI matched-controls; both
groups had comparable baseline kidney function and duration of nephrotoxic drug therapy. Significantly higher absolute,
normalized, and composite levels of TIMP2 and IGFBP7 were observed in AKI cases versus controls as early as
2-3 days before AKI onset (all P<0.05); >70% of patients with corresponding levels above 75th percentile developed
AKI. Normalized TIMP2 at 2-3 days pre-AKI predicted AKI with the highest average AUROC of 0.81, followed by
that of composite [TIMP2]x[IGFBP7] (0.78) after cross-validation. [TIMP2]x[IGFBP7] >0.01 (ng/mL)2/1000 predicted
AKI with a sensitivity of 79% and specificity of 60%.
Conclusion: Elevated urinary TIMP2 or IGFBP7 predicts drug-induced AKI with a lead-time of 2-3 days; an opportune
time for interventions to reduce nephrotoxicity.
