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Event: 759

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increased, Kidney Failure

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. More help

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Organ

Organ term

The location/biological environment in which the event takes place.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. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Organ term
kidney

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). 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 signaling 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. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Process	Object	Action
kidney failure		increased

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
Kidney toxicity induced by activation of 5HT2C	AdverseOutcome	Arthur Author (send email)	Open for adoption
TLR9 activation leading to Multi Organ Failure and ARDS	KeyEvent	Cataia Ives (send email)	Under development: Not open for comment. Do not cite
Oxidation of Reduced Glutathione Leading to Mortality	KeyEvent	Agnes Aggy (send email)	Open for citation & comment
Kidney failure induced by inhibition of mitochondrial ETC	AdverseOutcome	Brendan Ferreri-Hanberry (send email)	Under development: Not open for comment. Do not cite
Activation of PKC leads to Kidney Failure	AdverseOutcome	Arthur Author (send email)	Under development: Not open for comment. Do not cite

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 KE.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

Life Stages

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

Life stage	Evidence
All life stages	High

Sex Applicability

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

Kidney failure is characterized by the irregular function of the kidneys such as inability to remove excess water from the blood to maintain chemical levels (National Cancer Institute, 2024). Once the kidneys are no longer excreting waste properly, nitrogenous waste is retained within the blood (Bindroo, 2023). When function drops 15% (typically based on glomerular flow rate (GFR)) below normal function it is considered kidney failure. Treatments for kidney failure include hemodialysis, peritoneal dialysis, and kidney transplant (NIH, 2024).

Kidney disease is ranked as the 9^th cause of death in the United States affecting 6 million citizens above the age of 18 (CDC, 2024). It is estimated that 850 million people globally have kidney disease which when chronic (CKD) leads to kidney failure (Francis, A., Harhay, M.N., Ong, A.C.M. et al, 2024). Kidney failure is also referred to as end stage renal disease (ESRD) (NIH, 2024). Kidney failure has a major effect on global health since it is a direct global cause of morbidity but also a very important and prominent risk factor for cardiovascular disease, the number one leading cause of death globally (GBD Chronic Kidney Disease Collaboration, 2020).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.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). Do not provide detailed protocols. More help

Kidney failure can be measured using a series of different blood tests to evaluate different levels of biological indicators. The levels of creatinine waste in the blood can be measured. Levels of blood urea nitrogen can be measured. The glomerular flow rate (GFR) can also be measured as an indication of kidney failure. Having a GFR of below 15 is considered kidney failure (NIH, 2024). GFR can be measured indirectly and directly, however the direct method is difficult by measuring the amounts of exogenous filtration markers through dried capillary blood spots. Instead, it is more frequently estimated through the measurement of endogenous filtration markers such as serum creatinine and cystatin C (Bjornstad, 2018).

In addition to these varying blood tests there is a urine test as well utilizing levels of albumin. High levels of albumin in the urine is an indication of kidney failure. This is evaluated either through a coulometric urine dipstick, or a urine albumin-to-creatinine ratio test (UACR) (NIH, 2024).

Renal biopsies of patients suffering from chronic kidney disease and kidney failure show abnormalities such as glomerular sclerosis and collapse, interstitial fibrosis and. Infiltration, and tubular fibrosis and atrophy (Selvarajah, 2016).

Biomonitoring: Useful tool for measuring levels of a chemical in the body. However, considering how kidney disease progression, chronic kidney disease, and kidney failure go undiagnosed or diagnosed too late, it would be useful to incorporate biomonitoring for urinary markers of kidney failure for high-risk populations to help quicken diagnosis and treatment regiments. Biomonitoring is a non-invasive technique.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

Taxonomic Applicability: All vertebrates have kidneys; however, kidneys differ in structure and function based on the environment and the class of animal. The kidneys all differ between the number of nephrons present between animal species, and therefore differences in kidney function exist. However it is biologically plausible that all vertebrates undergo some form of kidney failure by definition.

Sex Applicability: All though potentially some physiological differences between the kidneys for male and female animals and humans, it is still biologically plausible that kidney failure occurs for both sexes therefore the key event is not sex specific (Bairey, 2019).

Life stage Applicability: The key event is not life stage specific as all stages of life can undergo kidney failure. However, incidence of kidney failure increases with age (O’Hare, 2007).

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Chronic kidney disease (CKD)/kidney failure is ranked as the 9th cause of death in the United States. This is a significant adverse outcome that lacks in diagnosis and monitoring techniques. Once the disease has progressed to a certain severity, the kidneys can not recover and therefore management of disease progession is also needed. Kidney failure/CKD also plays a significant role in other diseases such as cardiovascular disease. As mentioned in the OECD Guidance Document on Developing and Assessing Adverse Outcome Pathways, there are several reasons why this AO is of regulatory significance including its use of catergorizing chemicals as potentially harmful to the kidney, being used as part of an intergrated approach for testing and assessment (IATA), and it is relevant to an organ that is a part of ADME (excretion).

References

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

Bairey Merz, C. N., Dember, L. M., Ingelfinger, J. R., Vinson, A., Neugarten, J., Sandberg, K. L., Sullivan, J. C., Maric-Bilkan, C., Rankin, T. L., Kimmel, P. L., Star, R. A., & participants of the National Institute of Diabetes and Digestive and Kidney Diseases Workshop on “Sex and the Kidneys” (2019). Sex and the kidneys: current understanding and research opportunities. Nature reviews. Nephrology, 15(12), 776–783. https://doi.org/10.1038/s41581-019-0208-6

Bindroo, S., Quintanilla Rodriguez, B. S., & Challa, H. J. (2023). Renal Failure (Archived). In StatPearls. StatPearls Publishing.

Bjornstad, P., Karger, A. B., & Maahs, D. M. (2018). Measured GFR in Routine Clinical Practice-The Promise of Dried Blood Spots. Advances in chronic kidney disease, 25(1), 76–83. https://doi.org/10.1053/j.ackd.2017.09.003

CDC (2024, April 28). FASTSTATS - kidney disease. Centers for Disease Control and Prevention. https://www.cdc.gov/nchs/fastats/kidney-disease.htm

Francis, A., Harhay, M.N., Ong, A.C.M. et al. Chronic kidney disease and the global public health agenda: an international consensus. Nat Rev Nephrol (2024). https://doi.org/10.1038/s41581-024-00820-6

GBD Chronic Kidney Disease Collaboration (2020). Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet (London, England), 395(10225), 709–733. https://doi.org/10.1016/S0140-6736(20)30045-3

National Cancer Institute (2024). NCI Dictionary of Cancer terms. Comprehensive Cancer Information - NCI. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/kidney-failure

NIH (2024). Chronic kidney disease tests & diagnosis - NIDDK. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/kidney-disease/chronic-kidney-disease-ckd/tests-diagnosis

NIH (2024). What is kidney failure? - niddk. National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/kidney-disease/kidney-failure/what-is-kidney-failure

O'Hare, A. M., Choi, A. I., Bertenthal, D., Bacchetti, P., Garg, A. X., Kaufman, J. S., Walter, L. C., Mehta, K. M., Steinman, M. A., Allon, M., McClellan, W. M., & Landefeld, C. S. (2007). Age affects outcomes in chronic kidney disease. Journal of the American Society of Nephrology : JASN, 18(10), 2758–2765. https://doi.org/10.1681/ASN.2007040422

Selvarajah, M., Weeratunga, P., Sivayoganthan, S., Rathnatunga, N., & Rajapakse, S. (2016). Clinicopathological correlates of chronic kidney disease of unknown etiology in Sri Lanka. Indian journal of nephrology, 26(5), 357–363. https://doi.org/10.4103/0971-4065.167280