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Event: 1097

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Occurrence, renal proximal tubular necrosis

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Occurrence, renal proximal tubular necrosis

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Organ term
renal tubule

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help
Process Object Action
necrotic cell death kidney tubule cell occurrence

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
OAT1 inhibition KeyEvent Brendan Ferreri-Hanberry (send email) Under Development: Contributions and Comments Welcome
Cox1 inhibition renal failure KeyEvent Agnes Aggy (send email) Under Development: Contributions and Comments Welcome
unknown MIE renal failure KeyEvent Cataia Ives (send email) Under Development: Contributions and Comments Welcome
Cyclooxygenase inhibition leading to acute kidney injury KeyEvent Arthur Author (send email) Under development: Not open for comment. Do not cite

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
cow Bos taurus Moderate NCBI
mice Mus sp. High NCBI
rat Rattus norvegicus High NCBI
dogs Canis lupus familiaris High NCBI
zebra fish Danio rerio High NCBI
duck Anas platyrhynchos Low NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
All life stages High

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Term Evidence
Unspecific High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Renal proximal tubular necrosis also known as acute tubular necrosis (ATN) is the result of inadequate renal perfusion leading to a reduction in glomerular filtration rate (GFR) while still maintaining tubular integrity (Gill et al., 2005).The cell injury that defines ATN is damage to renal tubular cells and subsequent cell death. There are still inconsistencies regarding the histopathological findings associated with ATN as most cases of ATN have very limited actual necrosis and damage may not be exclusive to the renal tubules. Decreased GFR can lead to three mechanisms capable of damaging tubular epithelial cells (1) arteriolar vasoconstriction (2) back leak of glomerular filtrate and (3) tubular obstruction (Hanif et al., 2021). Some morphological changes noted during ATN include swelling of the tubular epithelium, detachment of tubular cells, loss of the PAS-positive bush boarder, thinning of the epithelium, interstitial edema and casts collecting in the distal tubules (Silva, 2004). Clinically, ATN can be divided into four phases: initiating, extension, maintenance, and recovery phases. The Initiating phase may last hours, or days depending on the cause of ATN. Extension can occur if the injury is worsened by ongoing hypoxia or a secondary inflammatory response. The maintenance phase is characterized by a decrease in GFR causing the retention of substances typically cleared by the kidneys (urea, sulfate, potassium, and creatinine). Although ATN is associated with increased morbidity and mortality, the injury is often reversible. Recovery depends on whether necrotic cells and casts are removed allowing for adequate tissue regeneration. The repair of renal tissue takes place during the recovery period (Pathophysiology review: Acute tubular necrosis, 2010).

ATN can occur following ischemia, sepsis, or exposure to nephrotoxins. Any factors capable of causing prerenal azotemia, which is the rise in blood urea nitrogen and serum creatinine levels may lead to ischemic ATN. Conditions including vomiting, bleeding, dehydration, third fluid sequestration and renal losses via osmotic diuresis and diuretics may lead to a hypovolemic state limiting renal perfusion (Hanif et al., 2021). Nephrotoxic induced ATN may be brought on by drugs such as aminoglycoside, rapamycin, mTOR inhibitors, cisplatin, calcineurin inhibitors, acyclovir, and heavy metals such as lead and mercury (Hanif et al., 2021; Silva, 2004). Heme pigment-containing proteins are also able to exert toxic effects leading to ATN by causing proximal tubular injury, vasoconstriction, and tubular obstruction (Hanif et al., 2021).

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

Urine Microscopy (urinalysis)

The presence of renal tubular epithelial cells and cell casts and/or granular casts in urine sediment has shown to be a promising method of noninvasive ATN diagnosis. Urinalysis requires the examination of urine samples by an experienced nephrologist and can provide important histological insight into the health status of the kidneys (Kanbay et al., 2010). The employment of a urinary scoring system has also been used to differentiate ATN from pre-renal acute kidney injury (AKI), with a microscopy score >2  associated with a 74-fold increase in the odds of a final ATN diagnosis (Perazella et al., 2008). Additionally, measurement of proteinuria and enzymuria including elevated cystatin C and α1-microglobulin had high accuracy in predicting severe ATN (Herget-Rosenthal et al., 2004).

Urine sodium concentration:

This test can be used to differentiate ATN from prerenal disease as the kidneys will try to conserve plasma sodium levels during prerenal disease and will lose sodium during tubular injury. Therefore, a urine sodium concentration of more than 40-50 milliequivalents per litre (mEq/L) is indicative of ATN whereas a concentration less then 20 mEq/L suggests prerenal disease (Hanif et al., 2021). Urine sodium measurements may also be coupled with other measures of renal concentrating ability such as creatine levels to better differentiate between these two conditions (Winter & Gabow, 1981).

Blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI)

BOLD-MRI allows for a non-invasive measurement of tissue oxygenation, which is commonly used following surgery to assess renal dysfunction (Lal et al., 2018). BOLD MRI uses the transverse relaxation rate (R2*) as a measure of deoxygenated hemoglobin. Kidneys with ATN display lower R2* values then those with normal oxygenation. The drawback of this technique is that MRIs are expensive and require highly specialized equipment and staff to run (Bauer et al., 2017).

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

ATN is not age or sex specific as it has been observed in adults and hospitalized children of both sexes (Perazella & Wilson, 2016 ; Perazella et al., 2008). Old age however is often associated with increased risk of ATN and delayed recovery (Abdel-Kader & Palevsky, 2009). ATN is most readily observed in humans however it can occur in a variety of species all of which rely on adequate renal perfusion (Gill et al., 2005; Perazella et al., 2008). Rats (BI et al., 2015) and mice (Perin et al., 2010) are typically used as models for ATN in humans. Adult and larval zebrafish have also been well defined as models to augment mammalian disease in kidney injury studies (Cirio et al., 2015; Kim et al., 2020; Wen et al., 2018). ATN has been diagnosed in many mammals including sheep (Ashrafihelan et al., 2014), cows (Collett et al., 2011) and dogs (Pozniak et al., 1992). ATN following nephrotoxin exposure has also been reported in birds including penguins, parrots, and waterfowl (Schmidt, 2006).

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

Abdel-Kader, K., & Palevsky, P. M. (2009). Acute kidney injury in the elderly. Clinics in Geriatric Medicine, 25(3), 331–358. https://doi.org/10.1016/j.cger.2009.04.001

Ashrafihelan, J., Eisapour, H., Erfani, A. M., Kalantary, A. A., Amoli, J. S., & Mozafari, M. (2014). High mortality due to accidental salinomycin intoxication in sheep. Interdisciplinary Toxicology, 7(3), 173–176. https://doi.org/10.2478/intox-2014-0024

Bauer, F., Wald, J., Bauer, F. J., Dahlkamp, L. M., Seibert, F. S., Pagonas, N., … Westhoff, T. H. (2017). Detection of Acute Tubular Necrosis Using Blood Oxygenation Level-Dependent (BOLD) MRI. Kidney and Blood Pressure Research, 42(6), 1078–1089. https://doi.org/10.1159/000485600

Bi, L., Wang, G., Yang, D., Li, S., Liang, B. I. N., & Han, Z. (2015). Effects of autologous bone marrow-derived stem cell mobilization on acute tubular necrosis and cell apoptosis in rats. Experimental and Therapeutic Medicine, 10(3), 851–856. https://doi.org/10.3892/etm.2015.2592

Cirio, M. C., de Caestecker, M. P., & Hukriede, N. A. (2015). Zebrafish Models of Kidney Damage and Repair. Current Pathobiology Reports, 3(2), 163–170. https://doi.org/10.1007/s40139-015-0080-4

Collett, M. G., Thompson, K. G., & Christie, R. J. (2011). Photosensitisation, crystal-associated cholangiohepatopathy, and acute renal tubular necrosis in calves following ingestion of Phytolacca octandra (inkweed). New Zealand Veterinary Journal, 59(3), 147–152. https://doi.org/10.1080/00480169.2011.567966

Gill, N., Nally, J. V, & Fatica, R. A. (2005). Renal Failure Secondary to Acute Tubular Necrosis: Epidemiology, Diagnosis, and Management. Chest, 128(4), 2847–2863. https://doi.org/https://doi.org/10.1378/chest.128.4.2847

Hanif, Muhammad., Bali, Atul., Ramphul, K. (2021). Acute Renal Tubular Necrosis. https://doi.org/10.1001/jama.1967.03120150130036

Herget-Rosenthal, S., Poppen, D., Hüsing, J., Marggraf, G., Pietruck, F., Jakob, H. G., … Kribben, A. (2004). Prognostic Value of Tubular Proteinuria and Enzymuria in Nonoliguric Acute Tubular Necrosis. Clinical Chemistry, 50(3), 552–558. https://doi.org/10.1373/clinchem.2003.027763

Kanbay, M., Kasapoglu, B., & Perazella, M. A. (2010). Acute tubular necrosis and pre-renal acute kidney injury: Utility of urine microscopy in their evaluation - A systematic review. International Urology and Nephrology, 42(2), 425–433. https://doi.org/10.1007/s11255-009-9673-3

Kim, M.-J., Moon, D., Jung, S., Lee, J., & Kim, J. (2020). Cisplatin nephrotoxicity is induced via poly(ADP-ribose) polymerase activation in adult zebrafish and mice. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 318(5), R843–R854. https://doi.org/10.1152/ajpregu.00130.2019

Lal, H., Mohamed, E., Soni, N., Yadav, P., Jain, M., Bhadauria, D., … Sharma, R. K. (2018). Role of Blood Oxygen Level-dependent MRI in Differentiation of Acute Renal Allograft Dysfunction. Indian Journal of Nephrology, 28(6), 441–447. https://doi.org/10.4103/ijn.IJN_43_18

Pathophysiology review: Acute tubular necrosis. (2010). Nursing, 40(4), 46-47. Retrieved from https://journals.lww.com/nursing/Fulltext/2010/04000/Pathophysiology_review__Acute_tubular_necrosis.17.aspx

Perazella, M. A., Coca, S. G., Kanbay, M., Brewster, U. C., & Parikh, C. R. (2008). Diagnostic Value of Urine Microscopy for Differential Diagnosis of Acute Kidney Injury in Hospitalized Patients. Clinical Journal of the American Society of Nephrology, 3(6), 1615–1619. https://doi.org/10.2215/CJN.02860608

Perazella, M. A., & Wilson, F. P. (2016). Acute kidney injury: Preventing acute kidney injury through nephrotoxin management. Nature Reviews Nephrology, 12(9), 511–512. https://doi.org/10.1038/nrneph.2016.95

Perin, L., Sedrakyan, S., Giuliani, S., Da Sacco, S., Carraro, G., Shiri, L., … De Filippo, R. E. (2010). Protective effect of human amniotic fluid stem cells in an immunodeficient mouse model of acute tubular necrosis. PloS One, 5(2), e9357–e9357. https://doi.org/10.1371/journal.pone.0009357

Pozniak, M. A., Kelcz, F., D’Alessandro, A., Oberley, T., & Stratta, R. (1992). Sonography of renal transplants in dogs: the effect of acute tubular necrosis, cyclosporine nephrotoxicity, and acute rejection on resistive index and renal length. American Journal of Roentgenology (1976), 158(4), 791–797. https://doi.org/10.2214/ajr.158.4.1546594

Schmidt, R. E. (2006). Types of renal disease in avian species. The Veterinary Clinics of North America. Exotic Animal Practice, 9(1), 97–106. https://doi.org/10.1016/j.cvex.2005.10.003

Silva, F. G. (2004). Chemical-induced nephropathy: A review of the renal tubulointerstitial lesions in humans. Toxicologic Pathology, 32(SUPPL. 2), 71–84. https://doi.org/10.1080/01926230490457530

Wen, X., Cui, L., Morrisroe, S., Maberry  Donald, J., Emlet, D., Watkins, S., … Kellum, J. A. (2018). A zebrafish model of infection-associated acute kidney injury. American Journal of Physiology. Renal Physiology, 315(2), F291–F299. https://doi.org/10.1152/ajprenal.00328.2017

Winter, S. D., & Gabow, P. A. (1981). Measurement of urine electrolytes: Clinical significance and methods. Critical Reviews in Clinical Laboratory Sciences, 14(3), 163–187. https://doi.org/10.3109/10408368109105863