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.
Toxicological sciences an official journal of the Society of Toxicology