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

Our plain-English summary of Detection of Drug-Induced Acute Kidney Injury in Humans Using Urinary KIM-1, miR-21, -200c, and -423, by M. Pavkovic, C. Robinson-Cohen, A.S. Chua, et al (Toxicological Sciences, 2016).

The study

• Authors: M. Pavkovic, C. Robinson-Cohen, A.S. Chua, O. Nicoara, M. Cárdenas-González, V. Bijol, K. Ramachandran, L. Hampson, M. Pirmohamed, D.J. Antoine, G. Frendl, J. Himmelfarb, S.S. Waikar, V.S. Vaidya
• Journal: Toxicological Sciences
• Published: 2016;152(1):205-13
• Cited by: 59 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

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In plain English

This study tested whether four substances in urine, the protein KIM-1 and three microRNAs (miR-21, miR-200c and miR-423), could detect kidney injury caused by drugs. It compared 70 people who had overdosed on acetaminophen with 65 healthy volunteers. All four markers were significantly higher in overdosed patients than in healthy volunteers, both in those with diagnosed acute kidney injury and in those without. Among the overdosed patients, KIM-1 best distinguished those with clinically diagnosed kidney injury (area under the curve 0.84, 95% CI 0.74 to 0.94). A second group of 106 patients with malignant mesothelioma received heated cisplatin chemotherapy during surgery. In this group all four markers rose after treatment, but none differed significantly between patients who did and did not develop kidney injury. Before treatment, the microRNAs were already high in these patients compared with the healthy volunteers from the acetaminophen study. Kidney biopsies, cultured kidney cells and a computer analysis explored where the microRNAs come from and what they may do. The authors concluded that the markers can detect drug-induced kidney injury. They noted that the cancer itself may have affected microRNA levels. The study did not examine asbestos exposure.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Two human biomarker studies: a cross-sectional study of acetaminophen overdose patients and a longitudinal study of mesothelioma patients given cisplatin. These were supplemented by in situ hybridization on kidney biopsies, cell-culture experiments, and computer-based target prediction.
• Who was studied: Participants were recruited at Brigham and Women's Hospital, Boston, and the MRC Centre for Drug Safety Science, University of Liverpool, UK. The acetaminophen study had 65 healthy volunteers and 70 overdose patients (43 with acute kidney injury, 27 without). The cisplatin study enrolled 108 patients with malignant mesothelioma; 2 were excluded for incomplete data, leaving 61 without clinical kidney injury, 30 with AKI Stage 1 and 15 with AKI Stage 2&3. The biopsy work used kidney samples from 3 patients with acute tubular necrosis after allograft rejection and 3 normal samples. Study dates were not given.
• Exposure: The exposures were drugs that injure the kidney: acetaminophen overdose, and heated cisplatin chemotherapy given during cytoreductive surgery for malignant mesothelioma. In the laboratory, kidney cells were treated with 85 µM cisplatin or 100 µM 4-aminophenol (an acetaminophen degradation product). Asbestos exposure was not studied.
• Main results:
  • In the acetaminophen study, urinary KIM-1, miR-21, miR-200c and miR-423 were significantly higher (adjusted cutoff p less than 0.004) than in healthy controls. This held both for overdose patients with acute kidney injury and for overdose patients without a kidney injury diagnosis.
  • Among acetaminophen overdose patients, after adjustment for age and sex, each doubling of a marker was linked to higher odds of acute kidney injury. For KIM-1 the odds ratio was 3.18 (95% CI 1.74, 5.82; given as 3.2 in the text). For miR-21 it was 1.31 (1.07, 1.60), for miR-200c 1.27 (1.04, 1.57), and for miR-423 1.29 (1.07, 1.56).
  • Among acetaminophen overdose patients, KIM-1 had the highest area under the ROC curve for clinically diagnosed acute kidney injury: 0.84 (95% CI 0.74, 0.94). The three microRNAs ranged from 0.64 to 0.71. Combining the microRNAs with KIM-1 did not substantively improve prediction.
  • In the mesothelioma patients, the three microRNAs were already high before cisplatin treatment compared with healthy non-cancer participants from the acetaminophen study.
  • In the cisplatin cohort, all four markers increased significantly after treatment (adjusted cutoff p less than 0.0014). They were high both in patients diagnosed with acute kidney injury and in patients without clinically proven injury.
  • In the cisplatin cohort, no marker differed significantly between patients with and without acute kidney injury at any time point. Marker concentrations were not associated with the odds of injury.
  • In kidney biopsies, miR-21 was not detectable in normal tissue but increased and co-localized with injured areas in acute tubular necrosis. miR-200c was not seen in either group, and miR-423 was strongly expressed in both.
  • In cultured human proximal tubular kidney cells, 85 µM cisplatin and 100 µM 4-aminophenol reduced cell viability by about 50%. All three microRNAs rose significantly (p less than 0.05) in the culture medium.
  • Computer analysis identified 1102 possible gene targets of the three microRNAs, mostly linked to pathways disturbed in kidney diseases. The top pathway was MYC-mediated apoptosis signaling, and the top associated condition was renal necrosis/cell death.
• The authors' conclusion: The authors concluded that KIM-1 together with miR-21, miR-200c and miR-423 can serve as non-invasive and specific urinary markers for detecting drug-induced acute kidney injury in patients. They added that the microRNAs could give information about the molecular pathways affected in the kidney.
• Limitations the authors state:
  • Because the longitudinal cohort had malignant mesothelioma, the authors could not exclude that the cancer, rather than cisplatin, affected the urinary microRNA profile.
  • The microRNA candidates had been chosen from an earlier comparison of healthy volunteers with intensive care unit patients whose kidney injury had various causes, not specifically drug-induced injury.
  • The authors suggested the markers' poor performance at predicting kidney injury may reflect the inadequacy of defining kidney injury by serum creatinine.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Malignant Mesothelioma, Cisplatin.

Related studies

• Acute kidney injury after cytoreductive surgery and hyperthermic intraoperative cisplatin chemotherapy for malignant pleural mesothelioma — T. Hod, K.J. Freedberg, et al. (2021)
• Pemetrexed induced acute kidney injury in patients with non-small cell lung cancer: reversible and chronic renal damage — G. Rombolà, F. Vaira, et al. (2015)
• Commentary: Acute kidney injury after intrapleural cisplatin: Minimizing collateral damage — M.I. Ebright (2021)
• Use of postoperative creatinine to predict sustained kidney injury in patients undergoing mesothelioma surgery — K.A. Mizuguchi, A. Mitani, et al. (2012)
• Malignant pleural mesothelioma with associated minimal change disease and acute renal failure — J.Y. Li, T.Y. Yong, et al. (2010)
• Commentary: Cisplatin-induced nephrotoxicity following cytoreductive surgery and heated intraoperative chemotherapy for malignant pleural mesothelioma — S.S. Groth, R.T. Ripley (2021)

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