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Toxicol Sci. 2016 Jul;152(1):205-13. doi: 10.1093/toxsci/kfw077. Epub 2016 Apr 27.

Detection of Drug-Induced Acute Kidney Injury in Humans Using Urinary KIM-1, miR-21, -200c, and -423.

Author information

1
*Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts 02115 Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115 vvaidya@bwh.harvard.edu.
2
Kidney Research Institute, University of Washington, Seattle, Washington 98195.
3
Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts 02115.
4
Boston Children's Hospital, Nephrology, Boston, Massachusetts 02115.
5
*Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
6
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115.
7
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115.
8
Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, L69 3BX, UK.
9
Department of Anesthesiology, Brigham and Women's Hospital, Boston, Massachusetts 02115.
10
*Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts 02115 Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115 Harvard School of Public Health, Environmental Health, Boston, MA, 02115 vvaidya@bwh.harvard.edu.

Abstract

Drug-induced acute kidney injury (AKI) is often encountered in hospitalized patients. Although serum creatinine (SCr) is still routinely used for assessing AKI, it is known to be insensitive and nonspecific. Therefore, our objective was to evaluate kidney injury molecule 1 (KIM-1) in conjunction with microRNA (miR)-21, -200c, and -423 as urinary biomarkers for drug-induced AKI in humans. In a cross-sectional cohort of patients (n = 135) with acetaminophen (APAP) overdose, all 4 biomarkers were significantly (P < .004) higher not only in APAP-overdosed (OD) patients with AKI (based on SCr increase) but also in APAP-OD patients without clinical diagnosis of AKI compared with healthy volunteers. In a longitudinal cohort of patients with malignant mesothelioma receiving intraoperative cisplatin (Cp) therapy (n = 108) the 4 biomarkers increased significantly (P < .0014) over time after Cp administration, but could not be used to distinguish patients with or without AKI. Evidence for human proximal tubular epithelial cells (HPTECs) being the source of miRNAs in urine was obtained first, by in situ hybridization based confirmation of increase in miR-21 expression in the kidney sections of AKI patients and second, by increased levels of miR-21, -200c, and -423 in the medium of cultured HPTECs treated with Cp and 4-aminophenol (APAP degradation product). Target prediction analysis revealed 1102 mRNA targets of miR-21, -200c, and -423 that are associated with pathways perturbed in diverse pathological kidney conditions. In summary, we report noninvasive detection of AKI in humans by combining the sensitivity of KIM-1 along with mechanistic potentials of miR-21, -200c, and -423.

KEYWORDS:

KIM-1; acute kidney injury; biomarker; microRNAs; nephrotoxicity in patients

PMID:
27122240
PMCID:
PMC5009468
DOI:
10.1093/toxsci/kfw077
[Indexed for MEDLINE]
Free PMC Article

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