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Curr Drug Metab. 2019;20(8):656-664. doi: 10.2174/1389200220666190711114504.

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

Da Y1,2, Akalya K1,2, Murali T1,2, Vathsala A1,2, Tan CS3, Low S1,2, Lim HN4, Teo BW1,2, Lau T1,2, Ong L5, Chua HR1,2.

Author information

1
Division of Nephrology, University Medicine Cluster, National University Hospital, Singapore 119074, Singapore.
2
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore.
3
Saw Swee Hock School of Public Health, National University of Singapore, Singapore 119077, Singapore.
4
Department of Pharmacy, National University Hospital, Singapore 119074, Singapore.
5
Department of Laboratory Medicine, National University Hospital, Singapore 119074, Singapore.

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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