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Decreased proximal tubular vectorial transport leads to Chemical induced Fanconi syndrome
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Inhibition of complex I of the electron transport chain leading to chemical induced Fanconi syndrome||adjacent||Not Specified||Not Specified||Marvin Martens (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
A direct consequence of decreased vectorial transport at the proximal tubule is a lack of reabsorption of water and solutes from the primary urine. This can lead to a sustained deficiency in electrolytes (bicarbonate, phosphate, potassium) and water characteristic of Fanconi syndrome.
Evidence Collection Strategy
Evidence Supporting this KER
Chemical-induced forms of Fanconi syndrome have been described. As in congenital forms, these are characterised by a loss of water and solutes in the urine due to insufficient reabsorption at the proximal tubule. Chemicals that show such an effect on the apical to basolateral transport in proximal tubule cells in vitro are thus likely to have this effect in vivo. Other aspects of the etiology that are not modeled by in vitro proximal tubule models are bone-related illnesses and weight faltering.
Uncertainties and Inconsistencies
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Di Cataldo, A., Palumbo, M., Pittalà, D., Renis, M., Schilirò, G., Russo, A., ... Li Volti, S. (1999). Deletions in the mitochondrial DNA and decrease in the oxidative phosphorylation activity of children with Fanconi syndrome secondary to antiblastic therapy. American Journal of Kidney Diseases : The Official Journal of the National Kidney Foundation, 34(1), 98–106. https://doi.org/10.1053/AJKD03400098
Hall, A. M., Bass, P., & Unwin, R. J. (2014). Drug-induced renal fanconi syndrome. Qjm, 107(4), 261–269. https://doi.org/10.1093/qjmed/hct258
Karras, A., Lafaurie, M., Furco, A., Bourgarit, A., Droz, D., Sereni, D., ... Molina, J. (2003). Tenofovir‐Related Nephrotoxicity in Human Immunodeficiency Virus–Infected Patients: Three Cases of Renal Failure, Fanconi Syndrome, and Nephrogenic Diabetes Insipidus. Clinical Infectious Diseases, 36(8), 1070–1073. https://doi.org/10.1086/368314
Knights, M., Thekkekkara, T., Morris, A., & Finlay, E. (2016). Sodium valproate-induced Fanconi type proximal renal tubular acidosis: Table 1. BMJ Case Reports, 2016, bcr2015213418. https://doi.org/10.1136/bcr-2015-213418
Lande, M. B., Kim, M. S., Bartlett, C., & Guay-Woodford, L. M. (1993). Reversible Fanconi syndrome associated with valproate therapy. The Journal of Pediatrics, 123(2), 320–2. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7688423
Tourret, J., Deray, G., & Isnard-Bagnis, C. (2013). Tenofovir effect on the kidneys of HIV-infected patients: a double-edged sword? Journal of the American Society of Nephrology : JASN, 24(10), 1519–27. https://doi.org/10.1681/ASN.2012080857
Yoshikawa, H., Watanabe, T., & Abe, T. (2002). Fanconi syndrome caused by sodium valproate: report of three severely disabled children. https://doi.org/10.1053/ejpn.2002.0585