Abstract
Our objective was to identify microRNA (miRNA) biomarkers of drug-induced liver and kidney injury by profiling the circulating miRNome in patients with acetaminophen overdose. Plasma miRNAs were quantified in age- and sex-matched overdose patients with (N = 27) and without (N = 27) organ injury (APAP-TOX and APAP-no TOX, respectively). Classifier miRNAs were tested in a separate cohort (N = 81). miRNA specificity was determined in non-acetaminophen liver injury and murine models. Sensitivity was tested by stratification of patients at hospital presentation (N = 67). From 1809 miRNAs, 75 were 3-fold or more increased and 46 were 3-fold or more decreased with APAP-TOX. A 16 miRNA classifier model accurately diagnosed APAP-TOX in the test cohort. In humans, the miRNAs with the largest increase (miR-122-5p, miR-885-5p, miR-151a-3p) and the highest rank in the classifier model (miR-382-5p) accurately reported non-acetaminophen liver injury and were unaffected by kidney injury. miR-122-5p was more sensitive than ALT for reporting liver injury at hospital presentation, especially combined with miR-483-3p. A miRNA panel was associated with human kidney dysfunction. In mice, miR-122-5p, miR-151a-3p and miR-382-5p specifically reported APAP toxicity - being unaffected by drug-induced kidney injury. Profiling of acetaminophen toxicity identified multiple miRNAs that report acute liver injury and potential biomarkers of drug-induced kidney injury.
Highlights
Acetaminophen is a safe analgesic drug when taken at therapeutic doses
The phase II PCR profiling results: 75 miRNAs were 3-fold or more increased in the APAP-TOX patient group compared to the age- and sex-matched APAP-no TOX group. 46 miRNAs were 3-fold or more decreased in the APAP-TOX patient group
The largest fold increase miRNAs were highly correlated across patients in the training set (Fig. 3A). miR-122-5p has been reported to circulate in a protein fraction of plasma rather than in extra-cellular vesicles this has not been characterized in humans
Summary
Acetaminophen (paracetamol) is a safe analgesic drug when taken at therapeutic doses. In patients with acetaminophen-induced liver injury circulating miR-122-5p has been reported to be increased around 100-fold compared to controls[15,16] It is not known whether other miRNAs can out-perform miR-122-5p with regard to patient stratification. In rodent models of acetaminophen toxicity there have been profiling studies of relatively small numbers of circulating miRNAs - these studies demonstrate that multiple miRNA species change with liver injury[17,18]. Changes in circulating miRNAs have been reported in small numbers of hepatotoxicity patients analysed by high-throughput sequencing[18,19] These studies did not address the unmet clinical need for improved patient stratification, back translate to pre-clinical models or identify signals of kidney toxicity. Selected miRNA candidate biomarkers were tested for liver and kidney specificity in humans and mice, and sensitivity with regard to patient stratification at first presentation to hospital
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