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AOP: 472


A descriptive phrase 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

DNA adduct formation leading to kidney failure

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
DNA adduct formation leading to kidney failure
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.5

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
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The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Devon Barnes, Department of Pharmaceutical Sciences, Utrecht University

Manoe Janssen, Department of Pharmaceutical Sciences, Utrecht University

Rosalinde Masereeuw,  Department of Pharmaceutical Sciences, Utrecht University

Huan Yang, esqLABS GmbH

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Manoe Janssen   (email point of contact)


Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Manoe Janssen
  • Devon Barnes
  • Huan Yang


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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on April 29, 2023 16:03

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A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

This Adverse Outcome Pathway (AOP) depicts a possible sequence of key events that associate how DNA adduct formation caused by platinum anticancer drugs can induce tubular necrosis, resulting in the occurrence of kidney failure as the adverse outcome (AO). Currently, cisplatin, carboplatin and oxaliplatin are the three most utilised Pt-based drugs used globally for the treatment of cancer. The cytotoxicity of these agents are primarily determined by their DNA adducts. Increased intracellular concentrations following uptake of platinum anticancer agents into the nephron, mostly by proximal convoluted tubules, evoking a cascade of negative cellular responses that can cause tubular necrosis, potentially resulting in kidney failure. The aquation of platinum anticancer agents following cellular uptake produces electrophilic intermediates that covalently bind to nucleophilic sites on DNA to form adducts that represent the molecular initiating event (MIE). The nephrotoxic response following the formation of DNA adducts leads to DNA damage (KE1) and mitochondrial dysfunction (KE2). These events promote the release of reaction oxygen species (ROS) (KE3) to induce oxidative stress (KE4), causing cell death (KE5) and inflammation (KE6). As these cells detach from the basement membrane, they are deposited in the tubular lumen. Tubular obstruction and inflammatory responses to proximal tubule insult can cause secondary toxicity and tubular necrosis (KE7), further amplifying kidney injury and a progressive decline of function, finally resulting in kidney failure (AO). This information is primarily based on mechanisms of actions previously described in cited literature sources and intended as a resource template for AOP development and data organization. The primary species of this AOP is humans, most often observed following chemotherapeutic intervention when treating a range of tumours and multiple malignancies; supported by data with potential applicability for other species.

AOP Development Strategy


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. More help

DNA adduct formation leading to kidney failure

This Adverse Outcome Pathway (AOP) details the sequence of key events (KE) that connect DNA adduct formation to kidney failure. Platinum (Pt)-based antineoplastics that are routinely utilized as anticancer agents for the effective treatment of multiple cancer types, including breast, cervical, oesophageal, bladder, small cell lung and testicular cancer (1), can function as chemical stressors for the described pathway. Currently, cisplatin, carboplatin and oxaliplatin are the three most utilised Pt-based drugs used globally for the treatment of cancer, all possessing a similar chemical structure consisting of platinum, carrier and leaving groups, undergoing similar mechanisms of cytotoxicity. Renowned for being one of the most potent and effective chemotherapeutics available, preventing cancerous cells from multiplying by binding DNA strands, clinical application of Pt anticancer agents remains limited due to the moderate to life-threating severity of their adverse side effects, such as neurotoxicity, hepatoxicity, ototoxicity, cardiotoxicity and myelosuppression and dose-limiting nephrotoxicity (1, 2).

Nephrotoxicity associated with platinum antineoplastic chemotherapeutic intervention

Within the kidney, the proximal tubular cells are most sensitive to the toxic effects of Pt-based drugs. They are responsible for the reabsorption of most nutrients and low molecular weight proteins, and approximately 70% of filtered solutes and water. Furthermore, they use active transport to clear the blood of toxic side products and drug compounds. Uptake of these compounds takes place at the basolateral side of the cells which is exposed to the blood. After entering the cells compounds are again secreted at the apical side of the cells into the kidney filtrate and leave the body with the urine. The toxicity of xenobiotics is directly related to their exposure to proximal tubule cells, their uptake through transport proteins like the SLC22A2/organic cation transporter 2 (OCT2), there reactivity in the cytoplasm and secretion through efflux transporters like multi-antimicrobial extrusion protein transporter-1 (MATE1) and multidrug resistance-associated protein 2 (MRP2) (3). This also implies that (genetic) variations in drug transporter activity can have implications in an individual’s susceptibility to (Pt)-based antineoplastics (4). Over time, several generations of Pt-based antineoplastics have been developed to make this group of compounds less nephrotoxic. Cisplatin was the first generation of Pt-based antineoplastics approved by the U.S. Food and Drug administration (FDA) in 1978. Classified as an alkylating agent, cisplatin was shown to inhibit cell division of bacteria and was developed as a treatment for mesotheliomas (5). However, issues arose following reports of cisplatin-induced nephrotoxicity, most notably the prevalence of acute kidney injury (AKI) and acute tubular necrosis (ATN) following treatment (6, 7). This increased susceptibility to severe nephrotoxicity during these early clinical trials led to the revision of cisplatin as an applicable chemotherapeutic agent. Therefore, much of the initial attempts of Pt drug development was to determine less-toxic analogues of cisplatin that retained similar levels of anticancer activity. The second-generation Pt drug, carboplatin, was developed to decrease the dose-limiting toxicity of cisplatin. Carboplatin’s mechanism of action is similar to that of cisplatin, however it was shown to have fewer and less severe side effects (8), benefiting from a reduced aquation rate due to its bidentate cyclobutane dicarboxylate ligand (9), and later approved by the FDA for use in 1989. Due to its decreased nephrotoxicity, carboplatin was identified as a more suitable option for aggressive, high-dose chemotherapy. However, carboplatin was also dose-limited following reports of cumulative anaemia and myelosuppression (10). Carboplatin is also a nephrotoxic drug, albeit much lower compared to cisplatin due to its increased stability (11). Nephrotoxicity had been reported in patients treated with intraperitoneal carboplatin, high-dose carboplatin, or in combination with other drugs (12), with AKI also shown to occur within days and often only partially reversible (13). The third-generation Pt drug oxaliplatin was developed to overcome both cisplatin and carboplatin toxicity. Oxaliplatin possesses a Pt complex with (1R,2R)-1,2-diaminocyclohexane (DACH) ligand and oxalate functioning as a leaving group. The bidentate oxalate considerably decreases the reactivity of oxaliplatin, limiting toxicity (14). However, although less nephrotoxic than both cisplatin and carboplatin, oxaliplatin can still induce proximal tubular cell damage (15). Furthermore, oxaliplatin has also been reported to cause several forms of nephrotoxicity, such as kidney tubular vacuolization (16) and acidosis (17-19). Despite the reduced incidence of nephrotoxicity, carboplatin and oxaliplatin, along with cisplatin, have all been reported to induce AKI and thrombotic microangiopathy (20).


1.    Oun R, Moussa YE, Wheate NJ. The side effects of platinum-based chemotherapy drugs: a review for chemists. Dalton Trans. 2018;47(19):6645-53.

2.    Markman M. Toxicities of the platinum antineoplastic agents. Expert Opin Drug Saf. 2003;2(6):597-607.

3.    McSweeney KR, Gadanec LK, Qaradakhi T, Ali BA, Zulli A, Apostolopoulos V. Mechanisms of Cisplatin-Induced Acute Kidney Injury: Pathological Mechanisms, Pharmacological Interventions, and Genetic Mitigations. Cancers (Basel). 2021;13(7).

4.    Zazuli Z, Vijverberg S, Slob E, Liu G, Carleton B, Veltman J, et al. Genetic Variations and Cisplatin Nephrotoxicity: A Systematic Review. Front Pharmacol. 2018;9:1111.

5.    Brown A, Kumar S, Tchounwou PB. Cisplatin-Based Chemotherapy of Human Cancers. J Cancer Sci Ther. 2019;11(4).

6.    DeConti RC, Toftness BR, Lange RC, Creasey WA. Clinical and pharmacological studies with cis-diamminedichloroplatinum (II). Cancer Res. 1973;33(6):1310-5.

7.    Eustace P. History and development of cisplatin in the management of malignant disease. Cancer Nurs. 1980;3(5):373-8.

8.    Hydes PC, Russell MJ. Advances in platinum cancer chemotherapy. Advances in the design of cisplatin analogues. Cancer Metastasis Rev. 1988;7(1):67-89.

9.    Calvert AH, Harland SJ, Newell DR, Siddik ZH, Jones AC, McElwain TJ, et al. Early clinical studies with cis-diammine-1,1-cyclobutane dicarboxylate platinum II. Cancer Chemother Pharmacol. 1982;9(3):140-7.

10.  Suzuki K, Matsumoto K, Hashimoto K, Kurokawa K, Jinbo S, Suzuki T, et al. Carboplatin-based combination chemotherapy for testicular cancer: relationship among administration dose of carboplatin, renal function and myelosuppression. Hinyokika Kiyo. 1995;41(10):775-80.

11.  Stewart DJ. Mechanisms of resistance to cisplatin and carboplatin. Crit Rev Oncol Hematol. 2007;63(1):12-31.

12.  English MW, Skinner R, Pearson AD, Price L, Wyllie R, Craft AW. Dose-related nephrotoxicity of carboplatin in children. Br J Cancer. 1999;81(2):336-41.

13.  Deray G, Ben-Othman T, Brillet G, Baumelou B, Gabarre J, Baumelou A, et al. Carboplatin-induced acute renal failure. Am J Nephrol. 1990;10(5):431-2.

14.  Kidani Y, Inagaki K, Iigo M, Hoshi A, Kuretani K. Antitumor activity of 1,2-diaminocyclohexane--platinum complexes against sarcoma-180 ascites form. J Med Chem. 1978;21(12):1315-8.

15.  Haschke M, Vitins T, Lude S, Todesco L, Novakova K, Herrmann R, et al. Urinary excretion of carnitine as a marker of proximal tubular damage associated with platin-based antineoplastic drugs. Nephrol Dial Transplant. 2010;25(2):426-33.

16.  Joybari AY, Sarbaz S, Azadeh P, Mirafsharieh SA, Rahbari A, Farasatinasab M, et al. Oxaliplatin-induced renal tubular vacuolization. Ann Pharmacother. 2014;48(6):796-800.

17.  Sonnenblick A, Meirovitz A. Renal tubular acidosis secondary to capecitabine, oxaliplatin, and cetuximab treatment in a patient with metastatic colon carcinoma: a case report and review of the literature. Int J Clin Oncol. 2010;15(4):420-2.

18.  Negro A, Grasselli C, Galli P. Oxaliplatin-induced proximal renal tubular acidosis. Intern Emerg Med. 2010;5(3):267-8.

19.  Linch M, Cunningham D, Mingo O, Stiles A, Farquhar-Smith WP. Renal tubular acidosis due to oxaliplatin. Ann Oncol. 2007;18(4):805-6.

20.  Gupta S, Portales-Castillo I, Daher A, Kitchlu A. Conventional Chemotherapy Nephrotoxicity. Adv Chronic Kidney Dis. 2021;28(5):402-14 e1.



Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

This AOP is being developed as part of the ONTOX consortium. The aim of this consortium is to provide a generic strategy to create innovative new approach methodologies (NAMs) in order to predict systemic repeated dose toxicity effects that, upon combination with tailored exposure assessment, will enable human risk assessment. Part of this approach is the development of physiological maps, quantitative adverse outcome pathway networks and ontology frameworks. This project is funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 963845.

Within the ONTOX consortium in vitro test batteries are being developed to evaluate toxicity in the liver, (steatosis and cholestasis), kidneys (tubular necrosis and crystallopathy) and developing brain (neural tube closure and cognitive function defects). This AOP focusses on kidney tubular necrosis as a result of exposure to a DNA-adduct forming compound (Pt-based drugs).

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


Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes 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. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (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

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

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. More help

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Essentiality of the Key Events

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. More help

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help
Modulating Factor (MF) Influence or Outcome KER(s) involved

Quantitative Understanding

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Considerations for Potential Applications of the AOP (optional)

Addressess 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. More help


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