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

Mira Pavkovic, Cassianne Robinson-Cohen, Alicia S Chua, Oana Nicoara, Mariana Cárdenas-González, Vanesa Bijol, Krithika Ramachandran, Lucy Hampson, Munir Pirmohamed, Daniel J Antoine, Gyorgy Frendl, Jonathan Himmelfarb, Sushrut S Waikar, Vishal S Vaidya

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)205-13
Number of pages9
JournalToxicological Sciences
Volume152
Issue number1
Early online date27 Apr 2016
DOIs
Publication statusPublished - Jul 2016

Keywords

  • Acetaminophen
  • Acute Kidney Injury
  • Adult
  • Biomarkers
  • Case-Control Studies
  • Cells, Cultured
  • Cisplatin
  • Cross-Sectional Studies
  • Dose-Response Relationship, Drug
  • Drug Overdose
  • Epithelial Cells
  • Female
  • Hepatitis A Virus Cellular Receptor 1
  • Humans
  • Kidney Tubules, Proximal
  • Longitudinal Studies
  • Male
  • MicroRNAs
  • Middle Aged
  • Predictive Value of Tests
  • Time Factors
  • Urinalysis
  • Young Adult
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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