A New Approach of Assessing Acute Kidney Injury in Patients: urinary microRNAs
Public Health, Healthcare Research, Social and Occupational Medicine
Final Report Abstract
A meta-analysis of clinical data revealed that acute kidney injury (AKI) affects 1 in 5 hospitalized patients worldwide. Drug-induced AKI accounts for a substantial portion of all AKI causes and plays a major role in the high incidence and prevalence of AKI in both hospitalized and nonhospitalized patients. Traditional markers of AKI, e.g. serum creatinine (SCr), lack the sensitivity and/or specificity to adequately detect nephrotoxicity prior to significant loss of renal function. Although new protein biomarkers, like kidney injury molecule 1 (KIM-1), outperformed traditional kidney biomarkers in preclinical rat studies, their translatability, applicability and usefulness in clinical settings has not been qualified, yet. Hence, therre is an urgent need for biomarkers to not only help in the timely and specific diagnosis of AKI in patients but also to enable improved stratification of patients with AKI in clinical trials to facilitate the development of therapies for kidney injury. microRNAs (miRNAs, miRs) are highly conserved in sequence and often also in organ expression across mammals, are present and stable in easily accessible body fluids, thereby having a less- or non-invasive source, are associated with diverse diseases, and finally can be easily measured by PCR. Therefore, the research objective underlying this fellowship was as follows: the evaluation of urinary miRNAs as biomarker candidates for drug-induced AKI in patients. Three previously nominated miRNA biomarker candidates, miR-21, -200c and -423, were measured in a cross-sectional study (patients with acetaminophen overdose; n=135) and even more extraordinary in a longitudinal study (patients enrolled before and during cisplatin treatment; n=108). Although all three miRNAs performed well in the cross-sectional setting, they could not differentiate AKI vs. NoAKI patients in the longitudinal study. However, an overall increase after cisplatin treatment in parallel to an increase of KIM-1 indicated that there might be injury present and that the clinical AKI diagnosis based on SCr might have biased the biomarker performance analysis. To investigate the origin of urinary miRNAs, in situ hybridizations in human kidney biopsies and small RNA sequencing were performed. Additionally, the miRNAs were measured in primary human proximal tubular cells as well as in the medium confirming for the first time a kidney origin for the three miRNAs. Their role in AKI was further investigated by target prediction analyses. Findings converged to the innovative hypothesis of urinary miRNA profiles as mirrors of affected pathways within the injured kidney. In parallel, miR-21, -200c and -423 in connection with KIM-1 were evaluated in the setting of exposure to environmental kidney toxicants (Mexican children; n=83; 5-12 years of age). In the urine of those children, arsenic (45.6ppb) and chromium (61.7ppb) were higher than the biological exposure index, a reference value in occupational settings. Urinary KIM-1 levels were associated with higher arsenic and chromium exposure. An association of miR-200c and -423 with higher chromium exposure was found as well, indicating potentially early maladaptive changes in the kidney due to heavy metal exposure and the usefulness of miRNAs and KIM-1 in detecting those. A new discovery approach could not be finished, but urinary miRNA profiles were heavily and differentially perturbed in AKI patients highlighting once again their potential as biomarkers. In summary, this data added more positive results on miRNA biomarkers in clinical studies contributing to the body of evidence necessary for further evaluation and eventually regulatory qualification and implementation into the clinical routine.
Publications
- (2016). Detection of Drug-Induced Acute Kidney Injury in Humans Using Urinary KIM-1, miR-21, -200c, and -423. Toxicol Sci 152(1):205-213
Pavkovic M., Robinson-Cohen C., Chua A.S., Nicoara O., Cárdenas-González M., Bijol V., Ramachandran K., Hampson L., Pirmohamed M., Antoine D.J., Frendl G., Himmelfarb J., Waikar S.S., Vaidya V.S.
(See online at https://doi.org/10.1093/toxsci/kfw077) - (2016). MicroRNAs and drug-induced kidney injury. Pharmacol Ther 163:48-57
Pavkovic M., Vaidya V.S.
(See online at https://doi.org/10.1016/j.pharmthera.2016.03.016) - (2016). MicroRNAs and drug-induced kidney injury. Pharmacol Ther 163:48-57
Pavkovic M., Vaidya V.S.
(See online at https://doi.org/10.1016/j.pharmthera.2016.03.016)
