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Event: 814

Key Event Title

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

Occurrence, Kidney toxicity

Short name

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Biological Context

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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
toxicity	kidney	occurrence

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	OECD Status
Kidney dysfunction	AdverseOutcome	Arthur Author (send email)	Under development: Not open for comment. Do not cite	Under Development
Inhibition of mitochondrial DNA polymerase gamma leading to kidney toxicity	AdverseOutcome	Agnes Aggy (send email)	Under development: Not open for comment. Do not cite	Under Development
Receptor mediated endocytosis and lysosomal overload leading to kidney toxicity	AdverseOutcome	Allie Always (send email)	Under development: Not open for comment. Do not cite	Under Development
Renal protein alkylation leading to kidney toxicity	AdverseOutcome	Evgeniia Kazymova (send email)	Not under active development	Under Development
TLR9 activation leading to Multi Organ Failure and ARDS	KeyEvent	Cataia Ives (send email)	Under development: Not open for comment. Do not cite
Inhibition of Mt-ETC complexes leading to kidney toxicity	AdverseOutcome	Agnes Aggy (send email)	Under development: Not open for comment. Do not cite	Under Development
Kidney failure induced by inhibition of mitochondrial ETC	KeyEvent	Brendan Ferreri-Hanberry (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
Sprague-Dawley	Sprague-Dawley		NCBI
human	Homo sapiens		NCBI

Life Stages

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Sex Applicability

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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

The kidneys are a crucial site of regulation of divalent cation levels in the plasma through filtration, reabsorption, and concentration (cite). On top of their excretion capabilities, the kidneys are also responsible for the production of hormones crucial for hematologic, cardiovascular, and skeletal muscle homeostasis (Bonventre et al., 2010). Nephrons are the functional units of the kidney and each kidney is made up of approximately 1 million nephrons (Bonventre et al., 2010). The nephrons are vital in reabsorption of these cations where 70% of transport has been shown to occur in the proximal tubule (Barbier et al., 2005). The kidneys are thought to be very susceptible to toxicity due to the increased concentration through their filtering structures with the tubular uptake mechanisms, specifically those of the proximal tubule, magnifying intracellular concentrations (Bonventre et al., 2010; Weber et al., 2017). Commonly, biomarkers like serum creatinine (sCr) and blood urea nitrogen (BUN) are utilized to identify kidney toxicity; however, these markers have been identified as nonspecific to the area of the kidney and slow in identification. Bonventre et al. (2010) has explored other biomarkers that may be used to identify segment specific injury. Proximal tubule injury can be identified using: albumin, RPB, NAG, clusterin, osteopontin, a1-microglobulin, and many others. Glomerulus damage can be identified through urinary Cystatin C, b2-microglobulin, a1-microglobulin, albumin, and more (Bonventre et al., 2010). These biomarkers do show some overlap between regions and can indicate damage to various areas of the nephron, though it is important to note the development of these specific techniques and therefore, the ability to develop more tailored and earlier identifying testing procedures.

Since there are many essential metals for cellular function, there are also many transporters responsible for facilitating ionic entry into the cell and the designated cellular compartment (cite). Some of these transporters are very specific to a given metal and some are more diverse in the metals they handle, therefore, these transporters can facilitate the transport of toxic metals into the cell, often through mimickery exhibited by those metals (Ballatori, 2002). DMT1 (divalent metal transporter 1) is a strong example of such transporters. The introduction of toxic divalent cations (Cd²⁺, Pb²⁺, Pt²⁺, etc.) is highly problematic in the kidneys due to increased toxicity and occupancy of DMT1 limiting the transport of essential trace elements. DMT1 is an essential transport molecule that is highly expressed in the kidneys, and is responsible for transport of essential trace divalent cations, as well as highly toxic ones; this competition increases strain on the kidneys exposed to toxic heavy metals (Barbier et al., 2005; Ballatori, 2002). DMT1 has been shown to transport Fe, Zn, Mn, Co, Cd, Cu, Ni, and Pb via a proton-coupled, membrane potential dependant mechanism (Ballatori, 2002). Some toxic metals can also enter a cell by forming complexes that mimic endogenous molecules in their structure. Arsenate and vanadate, for example, act as phosphate mimics both for transport and metabolism, assaulting cellular function by the same mechanism as their initial entry; cromate, selenite and molybdate mimic sulfate in a similar way (Ballatori, 2002). Many of the identified transporters fooled by this mimicry have been localized to the brush border membrane of the renal proximal tubule and epithelial cells. Some divalent metals such as Cd, Ba, and Sr have been shown to enter cells through voltage gated calcium channels. Another important example focused on by Ballatori (2002) is the action of inorganic mercury and methyl mercury (MeHg) that were shown to have high affinity for reduced sulfhydryl groups. These groups are seen on the amino acid cysteine, and importantly on glutathione (GSH), a vital enzymatic antioxidant. MeHg mimics methionine to enter the cell, after which it binds to GSH, and interferes with ATP production (Ballatori, 2002). Uranium has been shown to enter the blood rapidly and then either form stable complexes with plasma proteins, due to its high affinity for phosphate, carboxyl and hydroxyl groups, or binds to bicarbonate in the blood (Keith et al., 2013). In the kidneys, uranium can be released from bicarbonate to combine with other small proteins in the kidney tubular walls, disrupting cellular function (Keith et al., 2013). Uranium has been seen to enter the glomerulus, where it is filtered, via endocytosis as UO⁺² binding to anionic sites of proximal tubular epithelial brush borders (Shaki et al., 2012).

To further understand the mode of action of heavy metals within the kidneys, many studies have been conducted to determine the specific region primarily damaged. It is also important to note that variation of results may be found in some studies as experimental conditions as well as other factors may influence the mode of action of some metals. Zamora et al. (1998) found that kidney function decrease and cytotoxicity increase were correlated with uranium ingestion. However, no glomerular injury was detected, indicating that chronic uranium ingestion in rats (0.004 µg/kg to 9 µg/kg body weight) damages the proximal tubule and not the glomerulus (Zamora et al., 1998). Homma-Takeda et al. (2013) identifies the kidneys as the major site of depleted uranium toxicity. Studying the kidneys of rats of varying ages, exposed to 0.1-2mg/kg uranyl acetate, they found that the younger kidneys did not flush the uranium out as well. Accumulation of uranium and its damages was seen in the S3 segment of the proximal tubules (Homma-Takeda et al., 2013). Shaki et al. (2012), assessed the mechanism of depleted uranium-induced nephrotoxicity that revealed damage to the mitochondria isolated from uranyl acetate treated rat kidney cells. The damage included oxidative stress, mitochondrial swelling, mitochondrial membrane potential collapse, cytochrome C release, impaired ATP production, and damage to the electron transport chain complexes. Utilizing rat renal brush border vesicles, Goldman et al. (2006) found that exposure to uranyl acetate induced decreased rates of glucose transport, in part due to a decreased number of sodium-coupled glucose transporters; this decreased the ability of the kidneys to reabsorb glucose properly. Berradi et al. (2008) assessed the red blood cell (RBC) count of rats drinking water containing 40mg DU/L and found that chronic exposure to DU causes RBC reduction, pointing to nephrotoxicity as the kidneys play a major role in RBC synthesis. Heavy metals consistently aggregate in the kidneys, and more specifically in the S3 segment of the proximal tubules. Evidence also suggests that uranium and other heavy metals induce nephrotoxicity after endocytosis into cells by disrupting the electron transport chain, inducing oxidative stress. The oxidative stress leads to mitochondrial dysfunction followed by, apoptosis at low doses of uranium and necrosis at high doses of uranium. Finally, this induces renal injury and tissue damage to the proximal tubules, or nephrotoxicity.

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

Assay Type & Measured Content	Description	Dose Range Studied	Assay Characteristics (Length/Ease of use/Accuracy)
Kidney Function Assay Measuring total urinary protein, albumin, transferrin, b2-microglobulin, retinolbinding protein, brush border tubular antigens, N-acetyl-b-Dglucosaminidase activity, serum and urinary creatine (de Burbure et al., 2003)	“All analyses of a given parameter were performed under similar experimental conditions in the same laboratories within 6mo of collection. Total urinary protein (Prot-T-U) was determined by the Coomassie blue G250 binding method. Albumin (Alb-U), transferrin (Transf-U), β2-microglobulin (β2m-U), and retinolbinding protein (RBP-U) in urine were quantified by latex immunoassay (Bernard & Lauwerys, 1983). Acceptable limits for precision and accuracy of measurements and external quality controls were the same as those described in the Cadmibel study (Lauwerys et al., 1990). The brush border tubular antigens (BBA-U) were analyzed by a sandwich enzyme-linked immunoassay using monoclonal antibodies (Mutti et al., 1985). The total activity of N-acetyl-β-Dglucosaminidase (NAG-T-U) in urine was determined colorimetrically using a kit (PPR Diagnostics Ltd.) as described elsewhere (Price et al., 1996). Only total NAG (NAG-T) was used for the purpose of this study. Serum and urinary creatinine (Creat-U) were measured by the methods of Heinegard and Tiderström (1973), and Jaffé, respectively (Henry, 1965).” (de Burbure et al., 2003)	“The soil contamination in the area varied from 100 to 1700ppm lead (with values higher than 1000ppm in the immediate vicinity of the factories), 0.7 to 233ppm cadmium, and 101 to 22,257ppm zinc, with the highest concentrations being recorded within 500 m of the 2 factories”
NAG Assay Measuring N-acetyl-b-D-Glucosaminidase urinary content (Lim et al., 2016)	“Urinary NAG activity was measured by using NAG Quantitative Kit (Shionogi, Osaka, Japan). After storing a synthetic substrate solution (1 mL) at 37°C for five minutes, the solution was mixed with the supernatant of the urine samples (50 mL) received after centrifugation. After storing it at 37°C for 15 min, stopping solution (2 mL) was added to and mixed with it. By using a spectrophotometer, its fluorescence intensities were measured with a wavelength of 580 nm (13,14). Urinary β2-MG was measured by using Enzygnost β2-MG Micro Kit (Behring Institute, Mannheim, Germany). Its method used the principle of solid phase enzyme-linked immunosorbent assay (ELISA). Monoclonal anti-β2-MG antibody and anti-2-MG-horseradish peroxidase conjugate solution were used. After that, color intensities were measured with a wavelength of 450 nm by using a spectrophotometer (13,14).” (Lim et al., 2016)	Pb: 0.0221ppm (converted from blood Pb µg/dL) Cd: 1.08ppm (converted from Urinary Cd μg/g creatinine)	Fast, easy, accurate
Kidney Dysfunction Assay Measuring BUN and creatinine serum blood levels (Shaki et al., 2012)	“For studies in vivo rats were fasted overnight, then animals were divided into two groups, with six rats in each group. The control group (vehicle) received a single intraperitoneal (i.p.) injection of saline solution (1 ml per 100 g body weight). Uranyl acetate was dissolved in normal saline. Rats were treated with single intraperitoneal (i.p.) injections of UA in doses 0.5, 1 and 2 mg/kg body weight. These dosages was selected based on previous studies [28], which is sufficient to induce oxidative stress in kidney without causing death and none died within the duration of experiments. Blood urea nitrogen (BUN) and creatinine, marker of kidney dysfunction, were determined by commercial reagents (obtained from Parsazmoon Co., Iran). The rats were killed by decapitation 24 h after injection. The kidney were immediately removed and placed in ice-cold mitochondria isolation medium (0.225 M D-mannitol, 75 mM sucrose, and 0.2 mM EDTA, pH=7.4)” (Shaki et al., 2012)	Control, 0.5, 1, 2 mg/kg Uranyl Acetate (UA)	Fast, easy, medium accuracy

Domain of Applicability

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

Higher order animals (mammals) with functional and complete kidneys

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

References

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

Al Dera, H. S. (2016). Protective effect of resveratrol against aluminum chloride induced nephrotoxicity in rats. Saudi Med J, 37(4), 369-378. doi:10.15537/smj.2016.4.13611

Andjelkovic, M., Djordjevic, A. B., Antonijevic, E., Antonijevic, B., Stanic, M., Kotur-Stevuljevic, J., . . . Bulat, Z. (2019). Toxic effect of acute cadmium and lead exposure in rat blood, liver, and kidney. International Journal of Environmental Research and Public Health, 16, 247. doi:10.3390/ijerph16020274

Arzuaga , X., Rieth, S. H., Bathija, A. & Cooper, G. S. (2010) Renal Effects of Exposure to Natural and Depleted Uranium: A Review of the Epidemiologic and Experimental Data, Journal of Toxicology and Environmental Health, Part B, 13:7-8, 527-545, DOI:10.1080/10937404.2010.509015

Ballatori, N. (2002). Transport of toxic metals by molecular mimicry. Environmental Health Perspectives, 110, 689-694. doi:10.1289/ehp.02110s5689

Barnes, P., Yeboah, J. K., Gbedema, W., Saahene, R. O., & Amoani, B. (2020). Ameliorative effect of vernonia amygdalina plant extract on heavy metal-induced LIver and kidney dysfunction in rats. Advances in Pharmacological and Pharmaceutical Sciences, 2020, 1-7. doi:10.1155/2020/2976905

Barbier, O., Jcquillet, G., Tauc, M., Cougnon, M., & Poujeol, P. (2005). Effect of heavy metals on, and handling by, the kidney. Nephron Physiology, 99, 105-110. doi:10.1159/000083981

Bonventre, J. V., Vaidya, V. S., Schmouder, R., Feig, P., & Dieterle, F. (2010). Next-generation biomarkers for detecting kidney toxicity. Nature biotechnology, 28(5), 436–440. https://doi.org/10.1038/nbt0510-436

Brzoska, M. M., Kaminski, M., Supernak-Bobko, D., Zwierz, K., & Moniuszko-Jakoniuk, J. (2003). Changes in the strucutre and function of the kidney of rats chronically exposed to cadmium. I. biochemical and histopathological studies. Arch.Toxicol., 77, 344-352. doi:10.1007/s00204-003-0451-1

Buelna-Chontal, M., Franco, M., Hernandez-Esquivel, L., Pavon, N., Rodriguez-Zalvala, J. S., Correa, F., . . . Chavez, E. (2017). CDP-choline circumvents mercury-induced mitochondrial damage and renal dysfunction. Cell Biology International, 41, 1356-1366. doi:10.1002/cbin.10871

Chtourou, Y., Garoui, E. m., Boudawara, T., & Zeghal, N. (2014). Protective role of silymarin against manganese-induced nephrotoxicity and oxidative stress in rat. Environ Toxicol, 29, 1147-1154. doi:10.1002/tox.21845

Durante, P., Romero, F., Perez, M., Chavez, M., & Parra, G. (2010). Effect of uric acid on nephrotoxicity induced by mercuric chloride in rats. Toxicology and Industrial Health, 26(3), 163-174. doi:10.1177/0748233710362377

García-Niño, W. R., Tapia, E., Zazueta, C., Zatarain-Barrón, Z. L., Hernández-Pando, R., Vega-García, C. C., & Pedraza-Chaverrí, J. (2013). Curcumin pretreatment prevents potassium dichromate-induced hepatotoxicity, oxidative stress, decreased respiratory complex I activity, and membrane permeability transition pore opening. Evidence-Based Complementary and Alternative Medicine, (424692), 1-19. doi:10.1155/2013/424692

Goldman, M., Yaari, A., Doshnitzki, Z., Cohen-Luria, R., & Moran, A. (2006). Nephrotoxicity of uranyl acetate: Effect on rat kidney brush border membrane vesicles. Archives of Toxicology, 80(7), 387-393. doi:10.1007/s00204-006-0064-6

Homma-Takeda S, Kokubo T, Terada Y, Suzuki K, Ueno S, Hayao T, Inoue T, Kitahara K, Blyth BJ, Nishimura M, Shimada Y. Uranium dynamics and developmental sensitivity in rat kidney. J Appl Toxicol. 2013 Jul;33(7):685-94. doi: 10.1002/jat.2870. Epub 2013 Apr 26. PMID: 23619997.

Keith, S., Faroon, O., N., R., Scinicariello, F., Wilbur, S., Ingerman, L., . . . Diamond, G. (2013). Toxicological profile for uranium. U.S. Department of Health and Human Services. Agency for Toxic Substances and Disease Registry.

Kharroubi, W., Dhibi, M., Mekni, M., Haouas, Z., Chreif, I., Neffati, F., . . . Sakly, R. (2014). Sodium arsenate induce changes in fatty acids profiles and oxidative damage in kidney of rats. Environ Sci Pollut Res, 21, 12040-12049. doi:10.1007/s11356-014-3142-y

Lunyera, J., & Smith, S. R. (2017). Heavy metal nephropathy: Considerations for exposure analysis. Kidney International, 92, 548-550. doi:http://dx.doi.org/10.1016/j.kint.2017.04.043

Sabath, E., & Robles-Osorio, M. L. (2012). Renal health and the environment: Heavy metal nephrotoxicity. Revista Nefrologia, doi:10.3265/Nefrologia.pre2012.Jan.10928

Santos, N. A. G., Catão, C. S., Martins, N. M., Curti, C., Bianchi, M. L. P., & Santos, A. C. (2007). Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria. Archives of Toxicology, 81(7), 495-504. doi:10.1007/s00204-006-0173-2

Shaki, F., Hosseini, M. J., Ghazi-Khansari, M., & Pourahmad, J. (2012). Toxicity of depleted uranium on isolated rat kidney mitochondria. Biochimica Et Biophysica Acta - General Subjects, 1820(12), 1940-1950. doi:10.1016/j.bbagen.2012.08.015

Soussi, A., Gargouri, M., & El Feki, A. (2018). Effects of co-exposure to lead and zinc on redox status, kidney variables and histopathology in adult albino rats. Toxicology and Industrial Health, 34(7), 469-480. doi:10.1177/0748233718770293

Spreckelmeyer, S., Estrada-Ortiz, N., Prins, G. G. H., van der Zee, M., Gammelgaard, B., Sturup, S., . . . Casini, A. (2017). On the toxicity and transportation mechanisms of cisplatin in kidney tissues in comparison to a gold-based cytotoxic agent. Metallomics, 9, 1786. doi:10.1039/c7mt00271h

Turk, E., Kandemir, F. M., Yildirim, S., Caglayan, C., Kucukler, S., & Kuzu, M. (2019). Protective effect of hesperidin on sodium arsenite-induced nephrotoxicity and hepatotoxicity in rats. Biological Trace Element Research, 189, 95-108. doi:10.1007/s12011-018-1443-6

Weber, E. J., Himmelfarb, J., & Kelly, E. J. (2017). Concise review: Current emerging biomarkers of nephrotoxicity. Curr Opin Toxicol., 4, 16-21. doi:10.1016/j.cotox.2017.03.002

Yeh, Y., Lee, Y., Hsieh, Y., & Hwang, D. (2011). Dietary taurine reduces zinc-induced toxicity in male wistar rats. Journal of Food Science, 76(4), 90-98. doi:10.1111/j.1750-3841.2011.02110.x

Zamora, L. M., Tracy, B. L., Zielinski, J. M., Meyerhof, D. P., & Moss, M. A. (1998). Chronic ingestion of uranium in drinking water: A study of kidney bioeffects in humans. Toxicological Sciences, 43(1), 68-77. doi:10.1006/toxs.1998.242