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Event: 1603

Key Event Title

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

Chronic kidney disease

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

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
Oxidative stress in chronic kidney disease	AdverseOutcome	Brendan Ferreri-Hanberry (send email)	Under development: Not open for comment. Do not cite
ACE/Ang-II/AT1R axis, chronic kidney disease (CKD)	AdverseOutcome	Cataia Ives (send email)	Under development: Not open for comment. Do not cite
CYP450 upregulation leads to Chronic kidney disease	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
humans	Homo sapiens	High	NCBI
cats	Felis catus	High	NCBI

Life Stages

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

Life stage	Evidence
Adult	High

Sex Applicability

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

Term	Evidence
Mixed	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

Chronic kidney disease is the presence of kidney damage or an overall lowered estimated glomerular filtration rate of less than 60 ml/min that has persisted for 3 months or more, regardless of the cause. This disease is progressive and can be characterized as the loss of kidney function through kidney damage, ultimately resulting in dialysis treatment or a kidney transplantation. Kidney damage can be seen when abnormalities either suggested by imaging studies through a renal biopsy, abnormalities in urinary sediment, or increased urinary albumin excretion rates are observed. The most common risk for kidney disease are genetic predisposition or chronic kidney injury through inflammation, xenobiotic exposure, or persistent infection. For example, sickle cell trait and the presence of 2 APOL1 risk alleles may double the chance of chronic kidney disease. Without treatment, this condition is almost always lethal (Vaidya & Aeddula et al., 2022, Chen et al., 2019).

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

Chronic kidney disease can be directly measured by calculating the glomerular filtration rate. This can be achieved by urine sample analysis through the clearance of administered chemicals such as iohexol or iothalamate (Brown & O’Reilly, 1991). More recently, filtration markers current in the blood have been used such as creatinine ratio, a metabolite of creatine. To gauge the level of kidney damage and therefore the stage of kidney disease, in addition to filtration rate, urine albumin-to-creatine ratio can be calculated again from urine sample analysis. In addition, Cystatin C, which is a kidney injury molecule, and neutrophil gelatinase-associated lipocalin sera levels are more sensitive than serum creatinine in the detection of acute kidney injury (Al-Naimi et al., 2019). Kidney imagining by ultrasound can also be done to assess kidney disease stages through morphology and obstruction assessment (Chen et al., 2019).
In human’s chronic kidney disease can be detected through routine screening with serum chemistry profile and urine studies. Many early stages of kidney diseases are asymptomatic however some later stage symptoms such as foamy urine ( also called gross hematuria which is a sign of albuminuria), the need to urinate in the middle of the night (nocturia), side pain, or decreased urine output are strong indications of chronic kidney disease. If the disease is advanced, symptoms may also include fatigue, loss of appetite, vomiting, unintentional weight loss, pruritus, dyspnea, changes in mental state. or peripheral edema (Chen et al., 2019).

Domain of Applicability

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

D: Taxonomic applicability: Chronic kidney disease can occur in many vertebrate species including cats, dogs, and humans (Bartges et al., 2012, Chen et al., 2019, Brown & O’Reilly, 1991).
E: Life stages: The domain of applicability for life stages is all life stages.
F: Sex applicability: The domain of applicability for sex is both males and females.

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 and its related endpoints are a large public health threat and as such exposure to known nephrotoxic drugs are regulated and newer nephrotoxins are surveilled by the government of Canada (https://dhpp.hpfb-dgpsa.ca). Interestingly, the number of clinical trials in nephrology lags behind many other fields. This can be due to the fact that clinical endpoints require progression and can take years to decades to be prevalent in patients. Standard and traditional biomarkers, such as serum creatinine may lack sensitivity and predictive value as it takes a lot of time to build up and be detected. One way to help to accelerate nephrology clinical trials can be by finding new biomarkers that can be detected quicker to serve as a new/ surrogate endpoint in clinical trials (Hartung, 2016).

References

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

Al-Naimi, M. S., Rasheed, H. A., Hussien, N. R., Al-Kuraishy, H. M., & Al-Gareeb, A. I. (2019). Nephrotoxicity: Role and significance of renal biomarkers in the early detection of acute renal injury. Journal of advanced pharmaceutical technology & research, 10(3), 95–99.

Bartges JW. Chronic kidney disease in dogs and cats. (2012) Vet Clin North Am Small Anim Pract. Jul;42(4):669-92,

Brown SC, O’Reilly PH. (1991) Iohexol clearance for the determination of glomerular filtration rate in clinical practice: evidence for a new gold standard. J Urol. ;146(3):675–679.

Chen, T. K., Knicely, D. H., & Grams, M. E. (2019). Chronic Kidney Disease Diagnosis and Management: A Review. JAMA, 322(13), 1294–1304

Gouvernement du Canada. (2024, June 15). Government of Canada. Drug and Health Products Portal. https://dhpp.hpfb-dgpsa.ca

Hartung E. A. (2016). Biomarkers and surrogate endpoints in kidney disease. Pediatric nephrology (Berlin, Germany), 31(3), 381–391.

Vaidya SR, Aeddula NR. (2022) Chronic Kidney Disease. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 202