Detection of Drug-Induced Acute Kidney Injury in Humans Using Urinary KIM-1, miR-21, -200c, and -423.
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.
*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.
Mira
M
Pavkovic
Kidney Research Institute, University of Washington, Seattle, Washington 98195.
Cassianne
C
Robinson-Cohen
Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Alicia S
AS
Chua
Boston Children's Hospital, Nephrology, Boston, Massachusetts 02115.
Oana
O
Nicoara
*Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
Mariana
M
Cárdenas-González
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Vanesa
V
Bijol
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Krithika
K
Ramachandran
Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, L69 3BX, UK.
Lucy
L
Hampson
Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, L69 3BX, UK.
Munir
M
Pirmohamed
Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, L69 3BX, UK.
Daniel J
DJ
Antoine
Department of Anesthesiology, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Gyorgy
G
Frendl
Kidney Research Institute, University of Washington, Seattle, Washington 98195.
Jonathan
J
Himmelfarb
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Sushrut S
SS
Waikar
*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.
Vishal S
VS
Vaidya
D000082:Acetaminophen / Q000009:adverse effects*; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000175:diagnosis* / Q000235:genetics / Q000652:urine; D000328:Adult; D015415:Biomarkers / Q000652:urine; D016022:Case-Control Studies; D002478:Cells, Cultured; D002945:Cisplatin / Q000009:adverse effects*; D003430:Cross-Sectional Studies; D004305:Dose-Response Relationship, Drug; D062787:Drug Overdose; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D000072596:Hepatitis A Virus Cellular Receptor 1 / Q000032:analysis*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008137:Longitudinal Studies; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000652:urine*; D008875:Middle Aged; D011237:Predictive Value of Tests; D013997:Time Factors; D016482:Urinalysis; D055815:Young Adult
D015415:Biomarkers; C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; C533896:MIRN200 microRNA, human; C524940:MIRN21 microRNA, human; C548900:MIRN423 microRNA, human; D035683:MicroRNAs; D000082:Acetaminophen; D002945:Cisplatin
KIM-1; acute kidney injury; biomarker; microRNAs; nephrotoxicity in patients