Aop: 392

Title

A descriptive title which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Cyclooxygenase inhibition leading to acute kidney injury

Short name
A short name should also be provided that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Cyclooxygenase inhibition leading to acute kidney injury

Graphical Representation

A graphical summary of the AOP listing all the KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs should be provided. This is easily achieved using the standard box and arrow AOP diagram (see this page for example). The graphical summary is prepared and uploaded by the user (templates are available) and is often included as part of the proposal when AOP development projects are submitted to the OECD AOP Development Workplan. The graphical representation or AOP diagram provides a useful and concise overview of the KEs that are included in the AOP, and the sequence in which they are linked together. This can aid both the process of development, as well as review and use of the AOP (for more information please see page 19 of the Users' Handbook).If you already have a graphical representation of your AOP in electronic format, simple save it in a standard image format (e.g. jpeg, png) then click ‘Choose File’ under the “Graphical Representation” heading, which is part of the Summary of the AOP section, to select the file that you have just edited. Files must be in jpeg, jpg, gif, png, or bmp format. Click ‘Upload’ to upload the file. You should see the AOP page with the image displayed under the “Graphical Representation” heading. To remove a graphical representation file, click 'Remove' and then click 'OK.'  Your graphic should no longer be displayed on the AOP page. If you do not have a graphical representation of your AOP in electronic format, a template is available to assist you.  Under “Summary of the AOP”, under the “Graphical Representation” heading click on the link “Click to download template for graphical representation.” A Powerpoint template file should download via the default download mechanism for your browser. Click to open this file; it contains a Powerpoint template for an AOP diagram and instructions for editing and saving the diagram. Be sure to save the diagram as jpeg, jpg, gif, png, or bmp format. Once the diagram is edited to its final state, upload the image file as described above. More help

Authors

List the name and affiliation information of the individual(s)/organisation(s) that created/developed the AOP. In the context of the OECD AOP Development Workplan, this would typically be the individuals and organisation that submitted an AOP development proposal to the EAGMST. Significant contributors to the AOP should also be listed. A corresponding author with contact information may be provided here. This author does not need an account on the AOP-KB and can be distinct from the point of contact below. The list of authors will be included in any snapshot made from an AOP. More help

Nicole Washuck | nwash037@uottawa.ca | University of Ottawa, Department of Biology 

Point of Contact

Indicate the point of contact for the AOP-KB entry itself. This person is responsible for managing the AOP entry in the AOP-KB and controls write access to the page by defining the contributors as described below. Clicking on the name will allow any wiki user to correspond with the point of contact via the email address associated with their user profile in the AOP-KB. This person can be the same as the corresponding author listed in the authors section but isn’t required to be. In cases where the individuals are different, the corresponding author would be the appropriate person to contact for scientific issues whereas the point of contact would be the appropriate person to contact about technical issues with the AOP-KB entry itself. Corresponding authors and the point of contact are encouraged to monitor comments on their AOPs and develop or coordinate responses as appropriate.  More help
Arthur Author   (email point of contact)

Contributors

List user names of all  authors contributing to or revising pages in the AOP-KB that are linked to the AOP description. This information is mainly used to control write access to the AOP page and is controlled by the Point of Contact.  More help
  • Arthur Author

Status

The status section is used to provide AOP-KB users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. “Author Status” is an author defined field that is designated by selecting one of several options from a drop-down menu (Table 3). The “Author Status” field should be changed by the point of contact, as appropriate, as AOP development proceeds. See page 22 of the User Handbook for definitions of selection options. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite
This AOP was last modified on June 27, 2021 18:25
The date the AOP was last modified is automatically tracked by the AOP-KB. The date modified field can be used to evaluate how actively the page is under development and how recently the version within the AOP-Wiki has been updated compared to any snapshots that were generated. More help

Revision dates for related pages

Page Revision Date/Time
Inhibition, Cyclooxygenase activity September 16, 2017 10:14
Reduction, Prostaglandin E2 concentration June 28, 2021 09:51
Acute kidney injury (AKI) June 28, 2021 09:53
Occurrence, renal proximal tubular necrosis June 27, 2021 19:05
Decreased, Renal plasma flow September 16, 2017 10:16
Inhibition, Cyclooxygenase activity leads to Reduction, Prostaglandin E2 concentration June 28, 2021 09:46
Decreased, Renal plasma flow leads to Acute kidney injury (AKI) June 23, 2021 09:21
Reduction, Prostaglandin E2 concentration leads to Decreased, Renal plasma flow June 13, 2021 16:17
Decreased, Renal plasma flow leads to Occurrence, renal proximal tubular necrosis June 13, 2021 16:20
Occurrence, renal proximal tubular necrosis leads to Acute kidney injury (AKI) June 13, 2021 16:20
NonSteroidal Anti-Inflammatory Drugs (NSAID) April 17, 2017 10:12
Celecoxib November 29, 2016 18:42
Valdecoxib June 26, 2021 11:12
Rofecoxib June 26, 2021 11:12
Diclofenac June 26, 2021 11:13
Stressor:188 Diflunisal June 26, 2021 11:13
Etodolac June 26, 2021 11:14
Fenoprofen June 26, 2021 11:14
Indomethacin November 29, 2016 18:42
Ketorolac June 26, 2021 11:15
Mefenamic acid November 29, 2016 18:42
Meloxicam November 29, 2016 18:42
Nabumetone June 26, 2021 11:16
Oxaprozin November 29, 2016 18:42
Piroxicam June 26, 2021 11:17
Sulindac March 07, 2019 06:15
Tolmetin June 26, 2021 11:18
Aspirin March 07, 2019 06:15
Ibuprofen November 29, 2016 18:42
Naproxen November 29, 2016 18:42
Ketoprofen November 29, 2016 18:42
Bisphenol A December 29, 2019 18:38
Dibutyl phthalate November 29, 2016 18:42
4-Nonylphenol November 29, 2016 18:42
Di(2-ethylhexyl) phthalate November 29, 2016 18:42
2-Phenylphenol June 26, 2021 11:26
Cypermethrin November 29, 2016 18:42
Cyprodinil June 26, 2021 11:27
Imazalil June 26, 2021 11:27
Linuron May 18, 2020 12:53

Abstract

In the abstract section, authors should provide a concise and informative summation of the AOP under development that can stand-alone from the AOP page. Abstracts should typically be 200-400 words in length (similar to an abstract for a journal article). Suggested content for the abstract includes the following: The background/purpose for initiation of the AOP’s development (if there was a specific intent) A brief description of the MIE, AO, and/or major KEs that define the pathway A short summation of the overall WoE supporting the AOP and identification of major knowledge gaps (if any) If a brief statement about how the AOP may be applied (optional). The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance More help

Acute kidney injury (AKI) is one of the most common renal impairments, increasing morbidity and mortality rates globally. The rapid onset and recovery from AKI often goes undiagnosed and in implicated in the progression of more detrimental diseases including chronic kidney disease, renal failure, cardiovascular issues, and diabetes, all of which are of regulatory concern. AKI has been studied as an endpoint in many risk assessments conducted by agencies including the United States Food and Drug Administration (FDA), Health Canada, United States Enviornmental Protection Agency (EPA), and Enviornment and Climate Change Canada (ECCC). Moreover, early intervention and monitoring of AKI risk factors is of great interest in hospital and clinical settings. The purpose of this AOP Is to provide evidence for the regulation of nephrotoxic agents capable of inducing AKI while highlighting the methods that can be used to detect their nephrotoxicity.

For this AOP the effect of cyclooxygenase (COX) inhibition leading to AKI will be examined. Compounds capable of binding COX and sterically hindering the arachidonic acid binding site are implicated in COX inactivation. COX inactivation hinders the production of prostanoids (thromboxane and prostaglandins (PG)) from their arachidonic acid precursor resulting in impaired downstream signaling. The most prominent PG produced by COX is prostaglandin E2 (PGE2) which is an important mediator of the inflammatory response, tightly regulating blood flow by inducing vasodilation. A reduction in tissue PGE2 will result in vasoconstriction and reduced renal blood/plasma flow, a highly desirable trait for anti-inflammatory agents but one that can be detrimental to kidney health. Inadequate renal perfusion can rapidly lead to Ischemic injury and subsequent tubular necrosis which is the most common cause of AKI in humans. The key events in this AOP highlight areas of intervention and early detection prior to development of AKI. There is a significant amount of biological plausibility for this AOP and various KERs as COX are one of the most well studied groups of enzymes due to their therapeutic implications. There was only moderate empirical evidence used to construct this AOP as certain factors including direct COX expression are rarely measured. Despite some research gaps existing in various AOP components, this AOP has extensive regulatory application as it is relevant at all life stages, for all sexes, and in many species with similar renal physiology.

Background (optional)

This optional subsection should be used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development. The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. Examples of potential uses of the optional background section are listed on pages 24-25 of the User Handbook. More help

The kidneys are the major organ for drug excretion and waste filtration across all vertebrates, requiring 25% of all cardiac output in humans. This makes the kidneys especially vulnerable to toxic agents and conditions capable of reducing renal blood flow (Dixit et al., 2010). Acute kidney injury (AKI) may also be referred to as acute renal failure (ARF) and is characterized as the abrupt reduction in kidney function which includes both structural and functional impairments (Makris & Spanou, 2016). Between 2005 to 2014 In the United States, hospitalization from AKI as the principal diagnosis jumped from 281,500 to 504,600 and from 1,034,900 to 3,225,200 for secondary diagnosis (Moore et al., 2017). AKI disproportionately affects hospitalized patients, with 50% of intensive care unit patients developing AKI and 4-15% requiring renal replacement therapy (Shiao et al., 2020). This increased risk is primarily associated with over prescription of nephrotoxic drugs and other co-morbidities (Makris & Spanou, 2016). Recovery from AKI can take up to seven days before normal function is returned but in cases of maladaptive repair or repeated insults AKI may lead to other diseases (Forni et al., 2017). Recent evidence suggests that AKI may lead to more detrimental downstream effects including chronic kidney disease (CKD) and end stage kidney disease (EDKD) (Coca et al., 2012; See et al., 2019), increased risk of cardiovascular events (Coca et al., 2012; Odutayo et al., 2017) and increased long-term mortality (Coca et al., 2012; See et al., 2019). AKI is primarily caused by insufficient renal perfusion which can occur due to a physical obstruction, surgery, community acquired disease (eg. Diarrhea, dehydration, infection) or following exposure to nephrotoxic agents. Cyclooxygenase (COX) enzymes also known as prostaglandin-endoperoxide synthase (PTGS) tightly regulate renal perfusion by catalyzing the production of molecules important in vasodilation and anticoagulation. The present AOP examines how inhibition of COX can lead to AKI and highlights the regulatory significance and methods of quantifying the key events in this AOP. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the largest group of COX inhibitors and may be prescribed or bought over the counter globally. NSAIDs account for 21% of adverse drug events (ADEs) in the United States and 21% in the United Kingdom (Zhang et al., 2017). A number of commonly applied pesticides and select endocrine distrupting chemicals (EDCs) have also displayed COX inhibiting activity, adding concern surrounding environmental exposure (Kugathas et al., 2016; Kristensen et al., 2011).

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a stressor and the biological system) of an AOP. More help
Key Events (KE)
This table summarises all of the KEs of the AOP. This table is populated in the AOP-Wiki as KEs are added to the AOP. Each table entry acts as a link to the individual KE description page.  More help
Adverse Outcomes (AO)
An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP.  More help
Sequence Type Event ID Title Short name
1 MIE 79 Inhibition, Cyclooxygenase activity Inhibition, Cyclooxygenase activity
2 KE 243 Reduction, Prostaglandin E2 concentration Reduction, Prostaglandin E2 concentration
4 KE 820 Decreased, Renal plasma flow Decreased, Renal plasma flow
5 KE 1097 Occurrence, renal proximal tubular necrosis Occurrence, renal proximal tubular necrosis
6 AO 1865 Acute kidney injury (AKI) Acute kidney injury (AKI)

Relationships Between Two Key Events (Including MIEs and AOs)

TESTINGThis table summarises all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP. Each table entry acts as a link to the individual KER description page.To add a key event relationship click on either Add relationship: events adjacent in sequence or Add relationship: events non-adjacent in sequence.For example, if the intended sequence of KEs for the AOP is [KE1 > KE2 > KE3 > KE4]; relationships between KE1 and KE2; KE2 and KE3; and KE3 and KE4 would be defined using the add relationship: events adjacent in sequence button.  Relationships between KE1 and KE3; KE2 and KE4; or KE1 and KE4, for example, should be created using the add relationship: events non-adjacent button. This helps to both organize the table with regard to which KERs define the main sequence of KEs and those that provide additional supporting evidence and aids computational analysis of AOP networks, where non-adjacent KERs can result in artifacts (see Villeneuve et al. 2018; DOI: 10.1002/etc.4124).After clicking either option, the user will be brought to a new page entitled ‘Add Relationship to AOP.’ To create a new relationship, select an upstream event and a downstream event from the drop down menus. The KER will automatically be designated as either adjacent or non-adjacent depending on the button selected. The fields “Evidence” and “Quantitative understanding” can be selected from the drop-down options at the time of creation of the relationship, or can be added later. See the Users Handbook, page 52 (Assess Evidence Supporting All KERs for guiding questions, etc.).  Click ‘Create [adjacent/non-adjacent] relationship.’  The new relationship should be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. To edit a key event relationship, click ‘Edit’ next to the name of the relationship you wish to edit. The user will be directed to an Editing Relationship page where they can edit the Evidence, and Quantitative Understanding fields using the drop down menus. Once finished editing, click ‘Update [adjacent/non-adjacent] relationship’ to update these fields and return to the AOP page.To remove a key event relationship to an AOP page, under Summary of the AOP, next to “Relationships Between Two Key Events (Including MIEs and AOs)” click ‘Remove’ The relationship should no longer be listed on the AOP page under the heading “Relationships Between Two Key Events (Including MIEs and AOs)”. More help

Network View

The AOP-Wiki automatically generates a network view of the AOP. This network graphic is based on the information provided in the MIE, KEs, AO, KERs and WoE summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Stressors

The stressor field is a structured data field that can be used to annotate an AOP with standardised terms identifying stressors known to trigger the MIE/AOP. Most often these are chemical names selected from established chemical ontologies. However, depending on the information available, this could also refer to chemical categories (i.e., groups of chemicals with defined structural features known to trigger the MIE). It can also include non-chemical stressors such as genetic or environmental factors. Although AOPs themselves are not chemical or stressor-specific, linking to stressor terms known to be relevant to different AOPs can aid users in searching for AOPs that may be relevant to a given stressor. More help

Life Stage Applicability

Identify the life stage for which the KE is known to be applicable. More help
Life stage Evidence
All life stages High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected. 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
mice Mus sp. High NCBI
rats Rattus norvegicus High NCBI
dog Canis lupus familiaris Moderate NCBI
cat Felis catus Moderate NCBI
zebra fish Danio rerio Moderate NCBI
chickens Gallus gallus Moderate NCBI
duck Anas platyrhynchos Moderate NCBI

Sex Applicability

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

Overall Assessment of the AOP

This section addresses the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and WoE for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). The goal of the overall assessment is to provide a high level synthesis and overview of the relative confidence in the AOP and where the significant gaps or weaknesses are (if they exist). Users or readers can drill down into the finer details captured in the KE and KER descriptions, and/or associated summary tables, as appropriate to their needs.Assessment of the AOP is organised into a number of steps. Guidance on pages 59-62 of the User Handbook is available to facilitate assignment of categories of high, moderate, or low confidence for each consideration. While it is not necessary to repeat lengthy text that appears elsewhere in the AOP description (or related KE and KER descriptions), a brief explanation or rationale for the selection of high, moderate, or low confidence should be made. More help

This AOP is not exclusive to any sex or life stage as COX and PGE2 expression is ubiquitous across all individuals in almost all taxonomic domains with only slight variation. Furthermore, despite some individuals being predisposed to reduced renal plasma flow, renal proximal tubular necrosis (or acute tubular necrosis (ATN)), and AKI these events are not life stage or sex exclusive. Taxonomic applicability is the main limiting domain of this AOP as not all species possess similar renal physiology or have been recorded to experience AKI. Biologically, this AOP should apply to most vertebrates however the taxonomic applicability listed here only extends to those with documented records of renal proximal tubular necrosis and AKI development. There was strong biological evidence supporting the KER1 as COX inhibition and downstream PGE2 expression have been extensively studied and is a staple in most pharmacology and toxicology textbooks. The empirical evidence for this relationship was only moderate. Few studies succeeded in directly measuring COX activity and of those studies included, most focused on COX-2 activity highlighting uncertainty for the role of COX-1 in this relationship. The variety of stressors used strengthened the empirical evidence but provided little opportunity to compare results across studies to address any inconsistencies. Apart from ATN, all the KEs listed in this AOP are easily quantifiable allowing for methods integration into a chemical risk assessment framework. ATN is difficult to measure and is often seen in parallel with AKI making it hard to deduce temporal concordance of these events. Furthermore, some studies use ATN interchangeably with AKI as these conditions share similar biomarkers and pathophysiology. The stressors applicable to this AOP mainly consist of NSAIDs which have the largest effect on humans taking them orally or dermally. NSAIDs have however been detected in waste-water effluent discharged into oceans, lakes and streams highlighting the potential adverse COX inhibitory effects on downstream organisms (Kermia, Fouial-Djebbar, & Trari, 2016). Additionally, select endocrine disrupting chemicals (EDCs) and pesticides have displayed COX inhibitory effects making this AOP applicable to wildlife species. Further research is required to determine the true extent of COX inhibition by these compounds. 

Domain of Applicability

The relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context are defined in this section. Biological domain of applicability is informed by the “Description” and “Biological Domain of Applicability” sections of each KE and KER description (see sections 2G and 3E for details). In essence the taxa/life-stage/sex applicability is defined based on the groups of organisms for which the measurements represented by the KEs can feasibly be measured and the functional and regulatory relationships represented by the KERs are operative.The relevant biological domain of applicability of the AOP as a whole will nearly always be defined based on the most narrowly restricted of its KEs and KERs. For example, if most of the KEs apply to either sex, but one is relevant to females only, the biological domain of applicability of the AOP as a whole would be limited to females. While much of the detail defining the domain of applicability may be found in the individual KE and KER descriptions, the rationale for defining the relevant biological domain of applicability of the overall AOP should be briefly summarised on the AOP page. More help

The AOP has a broad domain of applicability, applying to any vertebrate possessing kidneys and COX enzymes without sex or age exclusion. By this definition the current AOP does not apply to invertebrates who utilize malpighian tubules for filtration and excretion, prokaryotes, plants, and select aquatic species with different renal physiology (e.g. Jelly fish and coral). COX genes have a conserved intron-exon arrangement across all vertebrates and is mostly conserved across all species, resulting in a wide domain of applicability to the MIE (Chandrasekharan & Simmons, 2004). The most limiting evidence for taxonomic applicability existed for the occurrence of ATN and AKI. There was strong evidence for ATN and AKI diagnosis in a variety of mammals, moderate evidence in select bird species and weak evidence available for fish, as zebrafish were the only species cited (Kim ET AL., 2020; Wen et al., 2018).The functional significance of the kidneys and their role in filtration and excretion is not sex or age dependent, allowing for this AOP to apply to both males and females and span infancy to adulthood. The studies cited in the construction of this AOP use both male and female subjects (Morthorst, Lister, Bjerregaard, & Der Kraak, 2013; Shiao et al., 2020). Furthermore a variety of life stages are examined ranging from PGE2 expression in rat embryos (Jawerbaum et al., 2000) and AKI in pediatric patients (Dixit et al., 2010) to ATN and AKI development in elderly hospital patients (Abdel-Kader & Palevsky, 2009). Despite this AOP being widely applicable, certain risk factors can put an individual at an elevated risk of developing AKI. Univariate regression analysis showed that male gender, old age, diabetes hypertension, chronic kidney disease, cardiovascular disease, and chronic obstructive pulmonary disease (COPD) all significantly increase an individual’s risk of developing AKI (Nie et al., 2018).

Stressors (*added due to non-original MIE page*) 

Non-steroidal anti-inflammatory drugs (NASIDs) are the largest class of COX inhibitors and are typically used for their anti-inflammatory, antipyretic, and analgesic effects. NSAIDs are competitive inhibitors of COX and may be non-selective or selective for just COX-2 inhibition. COX inhibitors bind to the COX active site which is a long hydrophobic channel. The difference of three amino acids between isoenzymes results in COX-2 having a more accessible active site which forms the basis for COX-2 selective binding (Zarghi & Arfaei, 2011). Selective COX-2 inhibitors are taken to minimize some of the adverse gastric effects including gastritis and ulcers that are linked to COX-1 inhibition. Most NSAIDS inhibit COX reversibly except for acetyl salicylate (aspirin) which inhibits COX-1 and COX-2 irreversibly (FDA, 2006). FDA approved COX-2 selective NSAIDs include celecoxib, valdecoxib, and rofecoxib all of which are available by prescription only. FDA approve prescription non-selective NSAIDs include diclofenac, diflunisal, etodolac, fenoprofen, indomethacin, ketorolac, mefenamic acid, meloxicam, nabumetone, oxaprozin, piroxicam, sulindac and tolmetin. FDA approve non-selective NSAIDs that are available over the counter include acetyl salicylate, ibuprofen, ketoprofen, and naproxen (FDA, 2018). Besides those drugs directly synthesized to inhibit COX, other chemicals including endocrine disrupting chemicals (EDCs) and pesticides have been found to bind to the COX active site resulting in enzyme inhibition. EDCs are often associated with decreasing PG synthesis and recent studies have shown that this may be impart through inhibition of COX-2. A study by Kristensen et al., found that the point of PG inhibition by parabens and phalates is upstream of PGD2 and PGE2 synthase implying COX binding. Predicted pKi scores from computer modeling showed that select EDCs (Dibutyl phthalate, oxybenzone and bisphenol A (BPA)) have the potential to bind COX-2 at a higher affinity then estimates for random binding. Modeling also showed that Di(2-ethylhexyl)phalate (DEHP), and more so its metabolites (f-OH-MEHP, 5-OXO-MEHP, and 5-CX-MEPP) have high affinity for COX-2 binding (Kristensen et al., 2011). Another study measuring direct inhibition of COX by EDCs found that nonylphenol not BPA was capable of inhibiting COX-1 at concentrations of 100 microM (Fujimoto et al., 2002). Other studies however have found that BPA is capable of inducing COX-2 expression at environmentally relevant doses, adding uncertainty surrounding the role EDCs play in COX inhibition (Wang et al., 2013). Lastly, measurement of PGD2 secretion in mouse sertoli cells accompanied with binding affinity modeling showed that select pesticides may be capable of inhibiting COX enzymes through active site binding. Compounds including 2-phenylphenol, cypermethrin, cyprodinil, imazail, and linuron showed similar potencies of PDG2 inhibition to that of NSAIDs tested. Moreover, in silico models displayed that these compounds are capable of binding to the COX-2 active site (Kugathas et al., 2016). Data for pesticide inhibition of COX was only available from one source, providing weak evidence of inhibition but highlighting a potential gap in research needed to better apply this AOP in risk assessment and management.

Essentiality of the Key Events

An important aspect of assessing an AOP is evaluating the essentiality of its KEs. The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence.The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs.When assembling the support for essentiality of the KEs, authors should organise relevant data in a tabular format. The objective is to summarise briefly the nature and numbers of investigations in which the essentiality of KEs has been experimentally explored either directly or indirectly. See pages 50-51 in the User Handbook for further definitions and clarifications.  More help

Essentiality of the MIE (COX inhibition) for the AO (Acute Kidney Injury) is MODERATE:

Direct evidence of essentiality of the MIE for the AO

COX-2 knockout mice display elevated blood urea nitrogen and serum creatinine levels, consistent with the diagnosis of AKI. Furthermore, these mice displayed a significant decline in PGE2 production accompanied by a rise in tissue necrosis in comparison to wild-type mice. These changes provide strong essentiality for the role of COX in multiple modules of the AOP (Dinchuk et al., 1995). In another study, eight-week-old COX-2 deficient mice showed signs of necrosis and severe renal damage including lesions and nephron hypoplasia. Other pathological findings included cellular and protein casts which align with AKI and overall renal failure (Morham et al., 1995). Elevated urea and creatinine levels are commonly used to diagnosis AKI and are elevated in COX-2 knockout mice. Nørregaard et al. (2011), found that plasma creatinine and urea levels were significantly elevated in COX-2 deficient versus wild-type mice (14.7 + 2.4 vs 7.3 +1.1 umol/l, p<0.05 and 24.6 + 6.5 vs 4.9 + 0.26 mmol/l, P<0.05, respectfully) when examining the effects of COX-2 disruption on vasopressin stores (Nørregaard et al., 2011).

Indirect evidence of essentially of the MIE for the AO

In fetal lambs administered Indomethacin, a nonspecific COX inhibitor, lambs developed decreased renal blood flow and increased sodium and chloride excretion as well as decreased plasma renin. These findings are consistent with the diagnosis of AKI and provide insight into the importance of COX in fetal renal function (Matson et al.,1981). Numerous observational studies have monitored the risk NSAID pose to AKI development. Chou et al. (2016), determined that individuals in Taiwan currently using (OR = 2.73) or recently using (OR = 1.17) NSAIDs were at higher risk of hospitalization with AKI then those who did not report use (Chou et al., 2016). Another meta-analysis, showed that individuals taking NSAIDs were 1.73 times more likely to develop AKI with that risk increasing to 2.51 times in older individuals (Zhang et al., 2017).

Direct and Indirect evidence of essentiality of the MIE for other KEs

In COX-2 gene deficient mice, PGE2 expression was significantly lower, nearing no expression at all in comparison to the wild-type control. This provides essentially for the role of COX-2 in PGE2 expression (Shen et a.,, 2006). Fibroblasts derived from COX-1 and COX-2 deficient mice exhibited a significant decrease in PGE2 production and increased interleukin 6 (IL-6) expression (Bukata et al., 2004). Elevated IL-6 has been proposed as a biomarker of AKI as increased expression can stimulate tubular atrophy and fibrosis (Su et al., 2017). IL-6 levels were rescued by adding exogenous PGE2, showing the importance of upstream COX in this relationship (Bukata et al., 2004). COX inhibition has also been directly studied in relation to renal plasma flow. Administration of parecoxib, a COX-2 selective NSAID, resulted in a significant decrease in renal blood flow to both the cortex and medulla in mice 20 minutes after administration (Kirkby et al., 2018).

WOE call for essentiality is MODERATE

COX knockout models have been used to demonstrate the direct essentiality of COX inhibition in AKI development. Knock out models were only available for rodents leaving uncertainty surrounding the essentially of COX inhibition in species with varying renal physiology such as fish and birds. Furthermore, there were only knock out models for the COX-2 isozyme and further studies are required to adequately assess the role COX-1 plays in this AOP(Dinchuk et al., 1995; Morham et al., 1995; Nørregaard et al., 2011). Studies have evaluated the indirect essentiality of COX inhibition on AKI development by using epidemiological data (Matson et al., 1981; Zhang et al., 2017). These studies however are at risk of confounding variables and recall bias when assessing the degree of exposure to COX inhibitors. Other rodent knockout models have assessed the essentially of COX inhibition in the development of downstream key events in this AOP including PGE2 expression and renal plasma flow (Bukata et al., 2004; Kirkby et al., 2018). Despite not providing direct evidence for COX inhibition in AKI development, these studies add to the essentially of COX inhibition in the overall AOP.

Evidence Assessment

The biological plausibility, empirical support, and quantitative understanding from each KER in an AOP are assessed together.  Biological plausibility of each of the KERs in the AOP is the most influential consideration in assessing WoE or degree of confidence in an overall hypothesised AOP for potential regulatory application (Meek et al., 2014; 2014a). Empirical support entails consideration of experimental data in terms of the associations between KEs – namely dose-response concordance and temporal relationships between and across multiple KEs. It is examined most often in studies of dose-response/incidence and temporal relationships for stressors that impact the pathway. While less influential than biological plausibility of the KERs and essentiality of the KEs, empirical support can increase confidence in the relationships included in an AOP. For clarification on how to rate the given empirical support for a KER, as well as examples, see pages 53- 55 of the User Handbook.  More help

KER

Summary of Bio. Plausibility Evidence

WOE call

KER1 (COX inhib. decreased PGE2)

The functional significance COX enzymes play in production of PGE2 has been well documented in textbooks (Golan & Tashjian, 2012; Middendorf & Williams, 2000) and review articles (Ferrer et al., 2019) and the biochemistry of COX inhibition has been eluded through various experiments (Rouzer & Marnett, 2003; Smith et al., 2000; Van der Donk et al., 2002). Furthermore, COX enzymes catalyze production of prostaglandins through a widely employed biochemical mechanism involving a two-step process of deoxygenation and reduction (Rouzer & Marnett, 2009).

High

KER2 (decreased PGE2 reduced renal plasma flow)

High

KER3 (reduced renal plasma flow renal tubular necrosis)

High

KER4 (renal tubular necrosis AKI)

High

KER5 (reduced renal plasma flow AKI)

Moderate   

KER

Summary of Empirical Evidence

WOE call

KER1 (COX inhib. decreased PGE2)

Empirical evidence supporting dose, temporal and incidence concordance was determined for this KER. The evidence spanned a wide variety of COX inhibitors from NSAIDs to novel compounds such as ciglitazone an antidiabetic agent and paeonol an anti-inflammatory derived from bark (Hazra & M Dubinett, 2007; Li, Tan, & Wang, 2014). Many studies however failed to measure both COX activity and PGE2 expression since they are so closely linked providing a lack of usable dose concordance and direct temporal concordance evidence.  

Moderate

KER2 (decreased PGE2 reduced renal plasma flow)

Moderate

KER3 (reduced renal plasma flow renal tubular necrosis)

High

KER4 (renal tubular necrosis AKI)

Moderate

KER5 (reduced renal plasma flow AKI)

Moderate

Quantitative Understanding

Some proof of concept examples to address the WoE considerations for AOPs quantitatively have recently been developed, based on the rank ordering of the relevant Bradford Hill considerations (i.e., biological plausibility, essentiality and empirical support) (Becker et al., 2017; Becker et al, 2015; Collier et al., 2016). Suggested quantitation of the various elements is expert derived, without collective consideration currently of appropriate reporting templates or formal expert engagement. Though not essential, developers may wish to assign comparative quantitative values to the extent of the supporting data based on the three critical Bradford Hill considerations for AOPs, as a basis to contribute to collective experience.Specific attention is also given to how precisely and accurately one can potentially predict an impact on KEdownstream based on some measurement of KEupstream. This is captured in the form of quantitative understanding calls for each KER. See pages 55-56 of the User Handbook for a review of quantitative understanding for KER's. More help

KER

Summary of Quantitative Understanding

WOE call

KER1 (COX inhib. decreased PGE2)

Despite many studies only measuring PGE2 levels following exposure to COX inhibiting agents, there is a strong correlation between increasing dose of COX inhibitors and decreasing PGE2 concentration (Jeffrey & Aspden, 2007; King et al., 2010). The COX modulation of PGE2 production has also been well eluded, allowing for precise quantification of modulating factors in this relationship (Limongelli et al., 2010). Furthermore, both COX inhibition and PGE2 expression can be easily quantified in lab through molecular biology techniques including ELISA and PCR enabling easy assessment an implementation into risk assessment protocols (Li, Tan, & Wang, 2014).  

High

KER2 (decreased PGE2 reduced renal plasma flow)

Low

KER3 (reduced renal plasma flow renal tubular necrosis)

Moderate

KER4 (renal tubular necrosis AKI)

Moderate

KER5 (reduced renal plasma flow AKI)

Low

Considerations for Potential Applications of the AOP (optional)

At their discretion, the developer may include in this section discussion of the potential applications of an AOP to support regulatory decision-making. This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. While it is challenging to foresee all potential regulatory application of AOPs and any application will ultimately lie within the purview of regulatory agencies, potential applications may be apparent as the AOP is being developed, particularly if it was initiated with a particular application in mind. This optional section is intended to provide the developer with an opportunity to suggest potential regulatory applications and describe his or her rationale.To edit the “Considerations for Potential Applications of the AOP” section, on an AOP page, in the upper right hand menu, click ‘Edit.’ This brings you to a page entitled, “Editing AOP.” Scroll down to the “Considerations for Potential Applications of the AOP” section, where a text entry box allows you to submit text. In the upper right hand menu, click ‘Update AOP’ to save your changes and return to the AOP page or 'Update and continue' to continue editing AOP text sections.  The new text should appear under the “Considerations for Potential Applications of the AOP” section on the AOP page. More help

This AOP can be used in screening novel NSAIDs and other suspected COX inhibitors to determine the likelihood that their exposure will result in adverse effects on renal health. COX inhibitors with more potent effects on downstream KEs should be prioritized by regulators such as the FDA to reduce the global burden of disease attributed to AKI.

References

List the bibliographic references to original papers, books or other documents used to support the AOP. More help

United States Food and Drug Administration (FDA) (2006). Concomitant use of ibuprofen and aspirin: potential for attenuation of the anti-platelet effects of aspirin.

United States Food and Drug Administration (FDA) (2018). COX-2 Selective ( includes Bextra , Celebrex , and Vioxx ) and Non-Selective Non-Steroidal Anti- Inflammatory Drugs ( NSAIDs ). Retrieved from https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/cox-2-selective-includes-bextra-celebrex-and-vioxx-and-non-selective-non-steroidal-anti-inflammatory

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

Bukata, S. V., Gelinas, J., Wei, X., Rosier, R. N., Puzas, J. E., Zhang, X., … O’Keefe, R. J. (2004). PGE2 and IL-6 production by fibroblasts in response to titanium wear debris particles is mediated through a Cox-2 dependent pathway. Journal of Orthopaedic Research, 22(1), 6–12. https://doi.org/10.1016/S0736-0266(03)00153-0

Chandrasekharan, N. V, & Simmons, D. L. (2004). The cyclooxygenases. Genome Biology, 5(9), 241. https://doi.org/10.1186/gb-2004-5-9-241

Chou, C.-I., Shih, C.-J., Chen, Y.-T., Ou, S.-M., Yang, C.-Y., Kuo, S.-C., & Chu, D. (2016). Adverse Effects of Oral Nonselective and cyclooxygenase-2-Selective NSAIDs on Hospitalization for Acute Kidney Injury: A Nested Case-Control Cohort Study. Medicine, 95(9), e2645–e2645. https://doi.org/10.1097/MD.0000000000002645

Coca, S. G., Singanamala, S., & Parikh, C. R. (2012). Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney International, 81(5), 442–448. https://doi.org/https://doi.org/10.1038/ki.2011.379

Dinchuk, J. E., Car, B. D., Focht, R. J., Johnston, J. J., Jaffee, B. D., Covington, M. B., … Trzaskos, J. M. (1995). Renal abnormalities and an altered inflammatory response in mice lacking cyclooxygenase II. Nature, 378(6555), 406–409. https://doi.org/10.1038/378406a0

Dixit, M., Doan, T., Kirschner, R., & Dixit, N. (2010). Significant acute kidney injury due to non-steroidal antiinflammatory drugs: Inpatient setting. Pharmaceuticals, 3(4), 1279–1285. https://doi.org/10.3390/ph3041279

Ferrer, M. D., Busquets-Cortés, C., Capó, X., Tejada, S., Tur, J. A., & Sureda*, A. P. and A. (2019). Cyclooxygenase-2 Inhibitors as a Therapeutic Target in Inflammatory Diseases. Current Medicinal Chemistry. https://doi.org/http://dx.doi.org/10.2174/0929867325666180514112124

Forni, L. G., Darmon, M., Ostermann, M., Oudemans-van Straaten, H. M., Pettilä, V., Prowle, J. R., … Joannidis, M. (2017). Renal recovery after acute kidney injury. Intensive Care Medicine, 43(6), 855–866. https://doi.org/10.1007/s00134-017-4809-x

Fujimoto, Y., Sakuma, S., Inoue, T., Uno, E., & Fujita, T. (2002). The endocrine disruptor nonylphenol preferentially blocks cyclooxygenase-1. Life Sciences, 70(19), 2209–2214. https://doi.org/https://doi.org/10.1016/S0024-3205(01)01538-7

Golan, D. E., & Tashjian, A. H. (2012). Principles of pharmacology : the pathophysiologic basis of drug therapy. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins.

Hazra, S., & M Dubinett, S. (2007). Ciglitazone mediates COX-2 dependent suppression of PGE2 in human non-small cell lung cancer cells. Prostaglandins, Leukotrienes and Essential Fatty Acids, 77(1), 51–58. https://doi.org/https://doi.org/10.1016/j.plefa.2007.05.006

Jawerbaum, A., Gonzalez, E., Sinner, D., Pustovrh, C., White, V., & Gimeno, M. (2000). PGE2 production and 3H-PGE2 transport in diabetic rat embryos and in rat embryos cultured in the presence of diabetic serum. Diabetes Research and Clinical Practice, 50, 214. https://doi.org/https://doi.org/10.1016/S0168-8227(00)82187-7

Jeffrey, J. E., & Aspden, R. M. (2007). Cyclooxygenase inhibition lowers prostaglandin E2 release from articular cartilage and reduces apoptosis but not proteoglycan degradation following an impact load in vitro. Arthritis Research & Therapy, 9(6), R129–R129. https://doi.org/10.1186/ar2346

Kermia, A. E. B., Fouial-Djebbar, D., & Trari, M. (2016). Occurrence, fate and removal efficiencies of pharmaceuticals in wastewater treatment plants (WWTPs) discharging in the coastal environment of Algiers. Comptes Rendus Chimie, 19(8), 963–970. https://doi.org/https://doi.org/10.1016/j.crci.2016.05.005

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

King, J. N., Rudaz, C., Borer, L., Jung, M., Seewald, W., & Lees, P. (2010). In vitro and ex vivo inhibition of canine cyclooxygenase isoforms by robenacoxib: A comparative study. Research in Veterinary Science, 88(3), 497–506. https://doi.org/10.1016/j.rvsc.2009.11.002

Kirkby, N. S., Sampaio, W., Etelvino, G., Alves, D. T., Anders, K. L., Temponi, R., … Mitchell, J. A. (2018). Cyclooxygenase-2 Selectively Controls Renal Blood Flow Through a Novel PPARβ/δ-Dependent Vasodilator Pathway. Hypertension, 71(2), 297–305. https://doi.org/10.1161/HYPERTENSIONAHA.117.09906

Kristensen, D. M., Skalkam, M. L., Audouze, K., Lesné, L., Desdoits-Lethimonier, C., Frederiksen, H., … Leffers, H. (2011). Many putative endocrine disruptors inhibit prostaglandin synthesis. Environmental Health Perspectives, 119(4), 534–541. https://doi.org/10.1289/ehp.1002635

Kugathas, S., Audouze, K., Ermler, S., Orton, F., Rosivatz, E., Scholze, M., & Kortenkamp, A. (2016). Effects of common pesticides on prostaglandin D2 (PGD2) inhibition in SC5 mouse sertoli cells, evidence of binding at the cox-2 active site, and implications for endocrine disruption. Environmental Health Perspectives, 124(4), 452–459. https://doi.org/10.1289/ehp.1409544

Li, M., Tan, S. Y., & Wang, X. F. (2014). Paeonol exerts an anticancer effect on human colorectal cancer cells through inhibition of PGE2 synthesis and COX-2 expression. Oncology Reports, 32(6), 2845–2853. https://doi.org/10.3892/or.2014.3543

Limongelli, V., Bonomi, M., Marinelli, L., Gervasio, F. L., Cavalli, A., Novellino, E., & Parrinello, M. (2010). Molecular basis of cyclooxygenase enzymes (COXs) selective inhibition. Proceedings of the National Academy of Sciences, 107(12), 5411 LP – 5416. https://doi.org/10.1073/pnas.0913377107

Makris, K., & Spanou, L. (2016). Acute Kideny Injury: Definition, Pathophysiology and Clinical Phenotypes. Clinical Biochemist Reviews, 37(2), 85–98.

Matson, J. R., Stokes, J. B., & Robillard, J. E. (1981). Effects of inhibition of prostaglandin synthesis on fetal renal function. Kidney International, 20(5), 621–627. https://doi.org/10.1038/ki.1981.185

Middendorf, P. J., & Williams, P. L. (2000, March 17). Nephrotoxicity: Toxic Responses of the Kidney. Principles of Toxicology. https://doi.org/https://doi.org/10.1002/0471231800.ch6

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Morthorst, J. E., Lister, A., Bjerregaard, P., & Der Kraak, G. Van. (2013). Ibuprofen reduces zebrafish PGE2 levels but steroid hormone levels and reproductive parameters are not affected. Comparative Biochemistry and Physiology - C Toxicology and Pharmacology, 157(2), 251–257. https://doi.org/10.1016/j.cbpc.2012.12.001

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Rouzer, C. A., & Marnett, L. J. (2003). Mechanism of Free Radical Oxygenation of Polyunsaturated Fatty Acids by Cyclooxygenases. Chemical Reviews, 103(6), 2239–2304. https://doi.org/10.1021/cr000068x

Rouzer, C. A., & Marnett, L. J. (2009). Cyclooxygenases: structural and functional insights. Journal of Lipid Research, 50 Suppl(Suppl), S29–S34. https://doi.org/10.1194/jlr.R800042-JLR200

See, E. J., Jayasinghe, K., Glassford, N., Bailey, M., Johnson, D. W., Polkinghorne, K. R., … Bellomo, R. (2019). Long-term risk of adverse outcomes after acute kidney injury: a systematic review and meta-analysis of cohort studies using consensus definitions of exposure. Kidney International, 95(1), 160–172. https://doi.org/https://doi.org/10.1016/j.kint.2018.08.036

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Shiao, C. C., Chang, Y. H., Yang, Y. F., Lin, E. T., Pan, H. C., Chang, C. H., … Huang, C. C. (2020). Association between regional economic status and renal recovery of dialysis-requiring acute kidney injury among critically ill patients. Scientific Reports, 10(1), 1–10. https://doi.org/10.1038/s41598-020-71540-7

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van der Donk, W. A., Tsai, A.-L., & Kulmacz, R. J. (2002). The Cyclooxygenase Reaction Mechanism. Biochemistry, 41(52), 15451–15458. https://doi.org/10.1021/bi026938h

Wang, K. H., Kao, A. P., Chang, C. C., Lin, T. C., & Kuo, T. C. (2013). Bisphenol A at environmentally relevant doses induces cyclooxygenase-2 expression and promotes invasion of human mesenchymal stem cells derived from uterine myoma tissue. Taiwanese Journal of Obstetrics and Gynecology, 52(2), 246–252. https://doi.org/10.1016/j.tjog.2013.04.016

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Zhang, X., Donnan, P. T., Bell, S., & Guthrie, B. (2017). Non-steroidal anti-inflammatory drug induced acute kidney injury in the community dwelling general population and people with chronic kidney disease: Systematic review and meta-analysis. BMC Nephrology, 18(1), 1–12. https://doi.org/10.1186/s12882-017-0673-8