{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T23:16:30Z","timestamp":1793142990983,"version":"4.5.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T00:00:00Z","timestamp":1619568000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T00:00:00Z","timestamp":1619568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["ID1055176"],"award-info":[{"award-number":["ID1055176"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["ID1055176"],"award-info":[{"award-number":["ID1055176"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>MicroRNAs in biofluids are potential biomarkers for detecting kidney and other organ injuries. We profiled microRNAs in\u00a0urine samples from patients with Russell\u2019s viper envenoming or acute self-poisoning following\u00a0paraquat, glyphosate, or oxalic acid [with and without acute kidney injury (AKI)] and on healthy controls. Discovery analysis profiled for 754 microRNAs using TaqMan OpenArray qPCR with three patients per group (12 samples in each toxic agent). From these, 53 microRNAs were selected and validated in a larger cohort of patients\u00a0(Russell\u2019s viper envenoming\u2009=\u200953, paraquat\u2009=\u200951, glyphosate\u2009=\u200951, oxalic acid\u2009=\u200940)\u00a0and 27 healthy controls. Urinary microRNAs had significantly higher expression in patients poisoned\/envenomed by different nephrotoxic agents in both discovery and validation cohorts. Seven microRNAs discriminated\u00a0severe AKI patients from no AKI for all four nephrotoxic agents. Four microRNAs (miR-30a-3p, miR-30a-5p, miR-92a, and miR-204)\u00a0had\u2009&gt;\u200917 fold change (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) and receiver operator characteristics area-under-curve (ROC-AUC)\u2009&gt;\u20090.72.\u00a0Pathway analysis of target mRNAs of these differentially expressed microRNAs showed\u00a0association with the regulation of different nephrotoxic signaling pathways.\u00a0In conclusion, human urinary microRNAs could\u00a0identify toxic AKI early after acute injury. These urinary microRNAs have\u00a0potential clinical application as early\u00a0non-invasive diagnostic AKI biomarkers.<\/jats:p>","DOI":"10.1038\/s41598-021-87918-0","type":"journal-article","created":{"date-parts":[[2021,4,28]],"date-time":"2021-04-28T10:04:55Z","timestamp":1619604295000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Urinary microRNAs as non-invasive biomarkers for toxic acute kidney injury in humans"],"prefix":"10.1038","volume":"11","author":[{"given":"Fathima","family":"Shihana","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wilson K. M.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mugdha V.","family":"Joglekar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fahim","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indika B.","family":"Gawarammana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey K.","family":"Isbister","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anandwardhan A.","family":"Hardikar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devanshi","family":"Seth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas A.","family":"Buckley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,4,28]]},"reference":[{"key":"87918_CR1","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/2045-3701-1-31","volume":"1","author":"Z Yang","year":"2011","unstructured":"Yang, Z. & Wang, L. Regulation of microRNA expression and function by nuclear receptor signaling. Cell Biosci. 1, 31 (2011).","journal-title":"Cell Biosci."},{"key":"87918_CR2","doi-asserted-by":"publisher","first-page":"402","DOI":"10.3389\/fendo.2018.00402","volume":"9","author":"J O\u2019Brien","year":"2018","unstructured":"O\u2019Brien, J., Hayder, H., Zayed, Y. & Peng, C. Overview of microRNA biogenesis, mechanisms of actions, and circulation. Front. Endocrinol. (Lausanne) 9, 402 (2018).","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"87918_CR3","doi-asserted-by":"publisher","first-page":"1528","DOI":"10.2215\/CJN.01170212","volume":"7","author":"JM Lorenzen","year":"2012","unstructured":"Lorenzen, J. M. & Thum, T. Circulating and urinary microRNAs in kidney disease. Clin. J. Am. Soc. Nephrol. 7, 1528\u20131533 (2012).","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"87918_CR4","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.1007\/s00204-020-02679-5","volume":"94","author":"F Shihana","year":"2020","unstructured":"Shihana, F. et al. Circulating human microRNA biomarkers of oxalic acid-induced acute kidney injury. Arch. Toxicol. 94, 1725\u20131737 (2020).","journal-title":"Arch. Toxicol."},{"key":"87918_CR5","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1159\/000446551","volume":"134","author":"Z Liu","year":"2016","unstructured":"Liu, Z., Wang, S., Mi, Q. S. & Dong, Z. MicroRNAs in pathogenesis of acute kidney injury. Nephron 134, 149\u2013153 (2016).","journal-title":"Nephron"},{"key":"87918_CR6","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1007\/978-1-4939-7046-9_4","volume":"1617","author":"W Huang","year":"2017","unstructured":"Huang, W. MicroRNAs: biomarkers, diagnostics, and therapeutics. Methods Mol. Biol. 1617, 57\u201367 (2017).","journal-title":"Methods Mol. Biol."},{"key":"87918_CR7","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1002\/iub.1174","volume":"65","author":"Q Wei","year":"2013","unstructured":"Wei, Q., Mi, Q. S. & Dong, Z. The regulation and function of microRNAs in kidney diseases. IUBMB Life 65, 602\u2013614 (2013).","journal-title":"IUBMB Life"},{"key":"87918_CR8","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/j.gene.2019.05.009","volume":"707","author":"DI Mohamed","year":"2019","unstructured":"Mohamed, D. I., Khairy, E., Saad, S. S. T., Habib, E. K. & Hamouda, M. A. Potential protective effects of Dapagliflozin in gentamicin induced nephrotoxicity rat model via modulation of apoptosis associated miRNAs. Gene 707, 198\u2013204 (2019).","journal-title":"Gene"},{"key":"87918_CR9","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/j.yexcr.2017.09.019","volume":"360","author":"W Liao","year":"2017","unstructured":"Liao, W. et al. MicroRNA-140-5p attenuated oxidative stress in Cisplatin induced acute kidney injury by activating Nrf2\/ARE pathway through a Keap1-independent mechanism. Exp. Cell Res. 360, 292\u2013302 (2017).","journal-title":"Exp. Cell Res."},{"key":"87918_CR10","doi-asserted-by":"publisher","first-page":"409","DOI":"10.2119\/molmed.2010.00002","volume":"16","author":"K Bhatt","year":"2010","unstructured":"Bhatt, K. et al. MicroRNA-34a is induced via p53 during cisplatin nephrotoxicity and contributes to cell survival. Mol. Med. 16, 409\u2013416 (2010).","journal-title":"Mol. Med."},{"key":"87918_CR11","first-page":"523","volume":"125","author":"HY Zhu","year":"2012","unstructured":"Zhu, H. Y. et al. Role of microRNA-181a in the apoptosis of tubular epithelial cell induced by cisplatin. Chin. Med. J. (Engl.) 125, 523\u2013526 (2012).","journal-title":"Chin. Med. J. (Engl.)"},{"key":"87918_CR12","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1097\/MOP.0b013e328343f4dd","volume":"23","author":"P Devarajan","year":"2011","unstructured":"Devarajan, P. Biomarkers for the early detection of acute kidney injury. Curr. Opin. Pediatr. 23, 194\u2013200 (2011).","journal-title":"Curr. Opin. Pediatr."},{"key":"87918_CR13","doi-asserted-by":"publisher","first-page":"481","DOI":"10.2215\/CJN.03520807","volume":"3","author":"SG Coca","year":"2008","unstructured":"Coca, S. G. & Parikh, C. R. Urinary biomarkers for acute kidney injury: perspectives on translation. Clin. J. Am. Soc. Nephrol. 3, 481\u2013490 (2008).","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"87918_CR14","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.toxlet.2015.06.008","volume":"237","author":"F Mohamed","year":"2015","unstructured":"Mohamed, F. et al. Kidney damage biomarkers detect acute kidney injury but only functional markers predict mortality after paraquat ingestion. Toxicol. Lett. 237, 140\u2013150 (2015).","journal-title":"Toxicol. Lett."},{"key":"87918_CR15","doi-asserted-by":"publisher","first-page":"970","DOI":"10.1080\/15563650.2017.1326607","volume":"55","author":"TM Wijerathna","year":"2017","unstructured":"Wijerathna, T. M. et al. Serum creatinine and cystatin C provide conflicting evidence of acute kidney injury following acute ingestion of potassium permanganate and oxalic acid. Clin. Toxicol. (Phila) 55, 970\u2013976 (2017).","journal-title":"Clin. Toxicol. (Phila)"},{"key":"87918_CR16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.toxlet.2016.06.001","volume":"258","author":"F Mohamed","year":"2016","unstructured":"Mohamed, F. et al. Mechanism-specific injury biomarkers predict nephrotoxicity early following glyphosate surfactant herbicide (GPSH) poisoning. Toxicol. Lett. 258, 1\u201310 (2016).","journal-title":"Toxicol. Lett."},{"key":"87918_CR17","doi-asserted-by":"publisher","first-page":"e0007486","DOI":"10.1371\/journal.pntd.0007486","volume":"13","author":"I Ratnayake","year":"2019","unstructured":"Ratnayake, I. et al. Early identification of acute kidney injury in Russell\u2019s viper (Daboia russelii) envenoming using renal biomarkers. PLoS Negl. Trop. Dis. 13, e0007486 (2019).","journal-title":"PLoS Negl. Trop. Dis."},{"key":"87918_CR18","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.toxlet.2018.10.002","volume":"299","author":"TM Wijerathna","year":"2018","unstructured":"Wijerathna, T. M. et al. Albuminuria and other renal damage biomarkers detect acute kidney injury soon after acute ingestion of oxalic acid and potassium permanganate. Toxicol. Lett. 299, 182\u2013190 (2018).","journal-title":"Toxicol. Lett."},{"key":"87918_CR19","first-page":"409","volume":"166","author":"SF Glineur","year":"2018","unstructured":"Glineur, S. F. et al. Assessment of a urinary kidney microRNA panel as potential nephron segment-specific biomarkers of subacute renal toxicity in preclinical rat models. Toxicol. Sci. Off. J. Soc. Toxicol. 166, 409\u2013419 (2018).","journal-title":"Toxicol. Sci. Off. J. Soc. Toxicol."},{"key":"87918_CR20","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.tox.2014.05.004","volume":"324","author":"M Kanki","year":"2014","unstructured":"Kanki, M. et al. Identification of urinary miRNA biomarkers for detecting cisplatin-induced proximal tubular injury in rats. Toxicology 324, 158\u2013168 (2014).","journal-title":"Toxicology"},{"key":"87918_CR21","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1093\/toxsci\/kfw077","volume":"152","author":"M Pavkovic","year":"2016","unstructured":"Pavkovic, M. et al. Detection of drug-induced acute kidney injury in humans using urinary KIM-1, miR-21, -200c, and -423. Toxicol. Sci. 152, 205\u2013213 (2016).","journal-title":"Toxicol. Sci."},{"key":"87918_CR22","doi-asserted-by":"publisher","first-page":"1742","DOI":"10.1373\/clinchem.2013.210245","volume":"59","author":"K Ramachandran","year":"2013","unstructured":"Ramachandran, K. et al. Human miRNome profiling identifies microRNAs differentially present in the urine after kidney injury. Clin. Chem. 59, 1742\u20131752 (2013).","journal-title":"Clin. Chem."},{"key":"87918_CR23","doi-asserted-by":"publisher","first-page":"1545","DOI":"10.2215\/CJN.11561113","volume":"9","author":"W Zhang","year":"2014","unstructured":"Zhang, W. et al. Evaluation of microRNAs miR-196a, miR-30a-5P, and miR-490 as biomarkers of disease activity among patients with FSGS. Clin. J. Am. Soc. Nephrol. 9, 1545\u20131552 (2014).","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"87918_CR24","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1373\/clinchem.2012.195297","volume":"59","author":"Y Luo","year":"2013","unstructured":"Luo, Y. et al. Increased serum and urinary microRNAs in children with idiopathic nephrotic syndrome. Clin. Chem. 59, 658\u2013666 (2013).","journal-title":"Clin. Chem."},{"key":"87918_CR25","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1373\/clinchem.2013.202671","volume":"59","author":"JM Lorenzen","year":"2013","unstructured":"Lorenzen, J. M. & Thum, T. MicroRNAs in idiopathic childhood nephrotic syndrome. Clin. Chem. 59, 595\u2013597 (2013).","journal-title":"Clin. Chem."},{"key":"87918_CR26","doi-asserted-by":"publisher","first-page":"2110","DOI":"10.1111\/j.1600-6143.2011.03666.x","volume":"11","author":"MJ Scian","year":"2011","unstructured":"Scian, M. J. et al. MicroRNA profiles in allograft tissues and paired urines associate with chronic allograft dysfunction with IF\/TA. Am. J. Transplant. 11, 2110\u20132122 (2011).","journal-title":"Am. J. Transplant."},{"key":"87918_CR27","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/bcp.12601","volume":"80","author":"F Mohamed","year":"2015","unstructured":"Mohamed, F., Endre, Z. H. & Buckley, N. A. Role of biomarkers of nephrotoxic acute kidney injury in deliberate poisoning and envenomation in less developed countries. Br. J. Clin. Pharmacol. 80, 3\u201319 (2015).","journal-title":"Br. J. Clin. Pharmacol."},{"key":"87918_CR28","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1089\/ars.2016.6665","volume":"25","author":"BB Ratliff","year":"2016","unstructured":"Ratliff, B. B., Abdulmahdi, W., Pawar, R. & Wolin, M. S. Oxidant mechanisms in renal injury and disease. Antioxid. Redox Signal. 25, 119\u2013146 (2016).","journal-title":"Antioxid. Redox Signal."},{"key":"87918_CR29","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1093\/toxsci\/kfv167","volume":"148","author":"R Nassirpour","year":"2015","unstructured":"Nassirpour, R. et al. Identification of promising urinary microRNA biomarkers in two rat models of glomerular injury. Toxicol. Sci. 148, 35\u201347 (2015).","journal-title":"Toxicol. Sci."},{"key":"87918_CR30","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1186\/1471-2164-15-485","volume":"15","author":"R Nassirpour","year":"2014","unstructured":"Nassirpour, R. et al. Identification of tubular injury microRNA biomarkers in urine: comparison of next-generation sequencing and qPCR-based profiling platforms. BMC Genomics 15, 485 (2014).","journal-title":"BMC Genomics"},{"key":"87918_CR31","doi-asserted-by":"publisher","first-page":"5330","DOI":"10.1073\/pnas.0813121106","volume":"106","author":"D Anglicheau","year":"2009","unstructured":"Anglicheau, D. et al. MicroRNA expression profiles predictive of human renal allograft status. Proc. Natl. Acad. Sci. U. S. A. 106, 5330\u20135335 (2009).","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"87918_CR32","doi-asserted-by":"publisher","first-page":"e188","DOI":"10.1093\/nar\/gnh186","volume":"32","author":"Y Sun","year":"2004","unstructured":"Sun, Y. et al. Development of a micro-array to detect human and mouse microRNAs and characterization of expression in human organs. Nucleic Acids Res. 32, e188 (2004).","journal-title":"Nucleic Acids Res."},{"key":"87918_CR33","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1038\/ki.2011.448","volume":"81","author":"K Chandrasekaran","year":"2012","unstructured":"Chandrasekaran, K. et al. Role of microRNAs in kidney homeostasis and disease. Kidney Int. 81, 617\u2013627 (2012).","journal-title":"Kidney Int."},{"key":"87918_CR34","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.3892\/or.2016.5294","volume":"37","author":"SJ Chen","year":"2017","unstructured":"Chen, S. J. et al. miR-204 regulates epithelial-mesenchymal transition by targeting SP1 in the tubular epithelial cells after acute kidney injury induced by ischemia-reperfusion. Oncol. Rep. 37, 1148\u20131158 (2017).","journal-title":"Oncol. Rep."},{"key":"87918_CR35","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.intimp.2018.03.023","volume":"59","author":"Y Chen","year":"2018","unstructured":"Chen, Y. et al. Long non-coding RNA NEAT1 plays an important role in sepsis-induced acute kidney injury by targeting miR-204 and modulating the NF-kappaB pathway. Int. Immunopharmacol. 59, 252\u2013260 (2018).","journal-title":"Int. Immunopharmacol."},{"key":"87918_CR36","doi-asserted-by":"publisher","first-page":"e0122357","DOI":"10.1371\/journal.pone.0122357","volume":"10","author":"F Mohamed","year":"2015","unstructured":"Mohamed, F. et al. Mechanisms underlying early rapid increases in creatinine in paraquat poisoning. PLoS ONE 10, e0122357 (2015).","journal-title":"PLoS ONE"},{"key":"87918_CR37","doi-asserted-by":"publisher","first-page":"R31","DOI":"10.1186\/cc5713","volume":"11","author":"RL Mehta","year":"2007","unstructured":"Mehta, R. L. et al. Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit. Care 11, R31 (2007).","journal-title":"Crit. Care"},{"key":"87918_CR38","first-page":"e52586","volume":"98","author":"W Wong","year":"2015","unstructured":"Wong, W., Farr, R., Joglekar, M., Januszewski, A. & Hardikar, A. Probe-based real-time PCR approaches for quantitative measurement of microRNAs. J. Vis. Exp. 98, e52586 (2015).","journal-title":"J. Vis. Exp."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-87918-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-87918-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-87918-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T07:24:26Z","timestamp":1670052266000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-87918-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,28]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["87918"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-87918-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,28]]},"assertion":[{"value":"3 August 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 April 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 April 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"9165"}}