Serial Quantification of Urinary Protein Biomarkers to Predict Drug-induced Acute Kidney Injury

Author(s): Yi Da, K. Akalya, Tanusya Murali, Anantharaman Vathsala, Chuen-Seng Tan, Sanmay Low, Hui-Ning Lim, Boon-Wee Teo, Titus Lau, Lizhen Ong, Horng-Ruey Chua*.

Journal Name: Current Drug Metabolism

Volume 20 , Issue 8 , 2019


Graphical Abstract:


Abstract:

Background: Drug-induced Acute Kidney Injury (AKI) develops in 10-15% of patients who receive nephrotoxic medications. Urinary biomarkers of renal tubular dysfunction may detect nephrotoxicity early and predict AKI.

Methods: We prospectively studied patients who received aminoglycosides, vancomycin, amphotericin, or calcineurin inhibitors, and collected their serial urine while on therapy. Patients who developed drug-induced AKI (fulfilling KDIGO criteria) were matched with non-AKI controls in a 1:2 ratio. Their urine samples were batch-analyzed at time-intervals leading up to AKI onset; the latter benchmarked against the final day of nephrotoxic therapy in non- AKI controls. Biomarkers examined include clusterin, beta-2-microglobulin, KIM1, MCP1, cystatin-C, trefoil-factor- 3, NGAL, interleukin-18, GST-Pi, calbindin, and osteopontin; biomarkers were normalized with corresponding urine creatinine.

Results: Nine of 84 (11%) patients developed drug-induced AKI. Biomarkers from 7 AKI cases with pre-AKI samples were compared with those from 14 non-AKI controls. Corresponding mean ages were 55(±17) and 52(±16) years; baseline eGFR were 99(±21) and 101(±24) mL/min/1.73m2 (all p=NS). Most biomarker levels peaked before the onset of AKI. Median levels of 5 biomarkers were significantly higher in AKI cases than controls at 1-3 days before AKI onset (all µg/mmol): clusterin [58(8-411) versus 7(3-17)], beta-2-microglobulin [1632(913-3823) versus 253(61-791)], KIM1 [0.16(0.13-0.76) versus 0.07(0.05-0.15)], MCP1 [0.40(0.16-1.90) versus 0.07(0.04-0.17)], and cystatin-C [33(27-2990) versus 11(7-19)], all p<0.05; their AUROC for AKI prediction were >0.80 (confidence intervals >0.50), with average accuracy highest for clusterin (86%), followed by beta-2-microglobulin, cystatin-C, MCP1, and KIM1 (57%) after cross-validation.

Conclusion: Serial surveillance of these biomarkers could improve the lead time for nephrotoxicity detection by days.

Keywords: Antimicrobials, beta-2-microglobulin, biomarkers, calcineurin inhibitors, clusterin, drug-induced acute kidney injury, nephrotoxicity.

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VOLUME: 20
ISSUE: 8
Year: 2019
Page: [656 - 664]
Pages: 9
DOI: 10.2174/1389200220666190711114504
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