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Relationship: 1676


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increase, Cytotoxicity (renal tubular cell) leads to Occurrence, Kidney toxicity

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Inhibition of mitochondrial DNA polymerase gamma leading to kidney toxicity adjacent High Moderate Angela Mally (send email) Under development: Not open for comment. Do not cite Under Development
Receptor mediated endocytosis and lysosomal overload leading to kidney toxicity adjacent High Moderate Angela Mally (send email) Under development: Not open for comment. Do not cite Under Development
Renal protein alkylation leading to kidney toxicity adjacent High Moderate Angela Mally (send email) Not under active development Under Development
Inhibition of mitochondrial electron transport chain (ETC) complexes leading to kidney toxicity adjacent Not Specified Not Specified Baki Sadi (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Excessive renal tubular cytotoxicity, both apoptotic and necrotic, leads to the eventual failure of the kidneys (Priante et al., 2019). This is because the mass cytotoxicity of renal tubular cells leads to the inability of the nephrons to properly filter nutrients and waste from the blood (Pirante et al., 2019). The kidneys can make compensational adjustments to the nephrons to continue adequate filtration up to the loss of 75% of the nephrons, beyond this amount of nephron loss, the kidneys lose function (Orr and Bridges, 2017).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

Renal tubular cells are very important functional units of the nephrons (Priante et al., 2019). The tubular cells are essential for the proper removal of waste material from the blood, as well as retaining essential nutrients, water, and salt levels for homeostatic blood content (Priante et al., 2019). The S3 segment of the proximal tubule in particular is highly susceptible to damage by environmental toxicants (Lentini et al., 2017). Apoptosis is the preferred method of cell death for renal tubule cells, as injured cells need to be removed without inducing an inflammatory response (Priante et al., 2019). By forming apoptotic bodies that can be recycled via phagocytes or epithelial cells, the kidney avoids the induction of an inflammatory response which causes the injury of surrounding, healthy cells. However, when apoptotic bodies are not phagocytosed quickly enough, their membranes can become damaged. This causes the apoptotic bodies to enter secondary necrosis, lysing and releasing their contents to the extracellular space. The immune cells will instigate an inflammatory response as a result, causing the injury to nearby tubular cells through the release of granule contents of by the immune cells (Priante et al., 2019). Remarkably, thanks to compensatory functional, molecular, and structural changes in the kidney, the remaining healthy nephrons are able to function adequately until more than 75% of them die (Orr and Bridges, 2017). After the loss of more than 75% of the nephrons however the remaining nephrons are no longer able to effectively remove environmental toxicants or waste from the filtrate, resulting in failed renal function (Orr and Bridges, 2017).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

There are no currently known inconsistencies or uncertainties for this relationship.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help

There are several known modulating factors of the relationship between renal tubular cytotoxicity and kidney failure. One modulator of this relationship is age. 

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help

There is a defined response-response relationship for renal tubule cytotoxicity leading to kidney failure. The loss of 75% of the nephrons to damage is the threshold for kidney failure (Orr and Bridges, 2017). This is due to the ability of the kidneys to make changes in the structure and function of the remaining nephrons at a molecular level to compensate for the lost nephrons (Orr and Bridges, 2017). The kidneys are able to retain adequate functioning until only 25% of the original nephrons remain, at which point the compensatory changes cannot maintain kidney functioning and kidney failure is final (Orr and Bridges, 2017).

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

There are no known feedforward/feedback loops that influence this relationship.

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

The domain of applicability only includes vertebrates, as invertebrates and non-animals do not have kidneys (Mahasen, 2016).


List of the literature that was cited for this KER description. More help

Lentini, P., Zanoli, L., Granata, A., Signorelli, S. S., Castellino, P., & Dell'aquila, R. (2017).

Kidney and heavy metals - the role of environmental exposure (review). Molecular Medicine Reports, 15(3413), 3419. doi:10.3892/mmr.2017.6389

Mahasen, L. M. A. (2016). Evolution of the kidney. Anatomy Physiol. Biochem. Int. J., 1(1),

555554. doi:10.19080/APBIJ.2016.01.555554

Orr, S. E., & Bridges, C. C. (2017). Chronic kidney disease and exposure to nephrotoxic

metals. International Journal of Molecular Sciences, 18 doi:10.3390/ijms18051039

Priante, G., Gianesello, L., Ceol, M., Del Prete, D., & Anglani, F. (2019). Cell death in the

kidney. International Journal of Molecular Sciences, 20(14), 3598. doi: 10.3390/ijms20143598. doi:10.3390/ijms20143598

Sano, K., Fujigaki, Y., Miyaji, T., Ikegaya, N., Ohishi, K., Yonemura, K., & Hishida, A. (2000).

Role of apoptosis in uranyl acetate-induced acute renal failure and acquired resistance to uranyl acetate. Kidney International, 57(4), 1560-1570. doi:10.1046/j.1523-1755.2000.00777.x