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Key Event Title
Occurrence, renal proximal tubular necrosis
Key Event Components
|necrotic cell death||kidney tubule cell||occurrence|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|OAT1 inhibition||KeyEvent||Brendan Ferreri-Hanberry (send email)||Under Development: Contributions and Comments Welcome|
|Cox1 inhibition renal failure||KeyEvent||Agnes Aggy (send email)||Under Development: Contributions and Comments Welcome|
|unknown MIE renal failure||KeyEvent||Cataia Ives (send email)||Under Development: Contributions and Comments Welcome|
|Cyclooxygenase inhibition leading to acute kidney injury||KeyEvent||Arthur Author (send email)||Under development: Not open for comment. Do not cite|
|All life stages||High|
Key Event Description
Renal proximal tubular necrosis also known as acute tubular necrosis (ATN) is the result of inadequate renal perfusion leading to a reduction in glomerular filtration rate (GFR) while still maintaining tubular integrity (Gill et al., 2005).The cell injury that defines ATN is damage to renal tubular cells and subsequent cell death. There are still inconsistencies regarding the histopathological findings associated with ATN as most cases of ATN have very limited actual necrosis and damage may not be exclusive to the renal tubules. Decreased GFR can lead to three mechanisms capable of damaging tubular epithelial cells (1) arteriolar vasoconstriction (2) back leak of glomerular filtrate and (3) tubular obstruction (Hanif et al., 2021). Some morphological changes noted during ATN include swelling of the tubular epithelium, detachment of tubular cells, loss of the PAS-positive bush boarder, thinning of the epithelium, interstitial edema and casts collecting in the distal tubules (Silva, 2004). Clinically, ATN can be divided into four phases: initiating, extension, maintenance, and recovery phases. The Initiating phase may last hours, or days depending on the cause of ATN. Extension can occur if the injury is worsened by ongoing hypoxia or a secondary inflammatory response. The maintenance phase is characterized by a decrease in GFR causing the retention of substances typically cleared by the kidneys (urea, sulfate, potassium, and creatinine). Although ATN is associated with increased morbidity and mortality, the injury is often reversible. Recovery depends on whether necrotic cells and casts are removed allowing for adequate tissue regeneration. The repair of renal tissue takes place during the recovery period (Pathophysiology review: Acute tubular necrosis, 2010).
ATN can occur following ischemia, sepsis, or exposure to nephrotoxins. Any factors capable of causing prerenal azotemia, which is the rise in blood urea nitrogen and serum creatinine levels may lead to ischemic ATN. Conditions including vomiting, bleeding, dehydration, third fluid sequestration and renal losses via osmotic diuresis and diuretics may lead to a hypovolemic state limiting renal perfusion (Hanif et al., 2021). Nephrotoxic induced ATN may be brought on by drugs such as aminoglycoside, rapamycin, mTOR inhibitors, cisplatin, calcineurin inhibitors, acyclovir, and heavy metals such as lead and mercury (Hanif et al., 2021; Silva, 2004). Heme pigment-containing proteins are also able to exert toxic effects leading to ATN by causing proximal tubular injury, vasoconstriction, and tubular obstruction (Hanif et al., 2021).
How It Is Measured or Detected
Urine Microscopy (urinalysis)
The presence of renal tubular epithelial cells and cell casts and/or granular casts in urine sediment has shown to be a promising method of noninvasive ATN diagnosis. Urinalysis requires the examination of urine samples by an experienced nephrologist and can provide important histological insight into the health status of the kidneys (Kanbay et al., 2010). The employment of a urinary scoring system has also been used to differentiate ATN from pre-renal acute kidney injury (AKI), with a microscopy score >2 associated with a 74-fold increase in the odds of a final ATN diagnosis (Perazella et al., 2008). Additionally, measurement of proteinuria and enzymuria including elevated cystatin C and α1-microglobulin had high accuracy in predicting severe ATN (Herget-Rosenthal et al., 2004).
Urine sodium concentration:
This test can be used to differentiate ATN from prerenal disease as the kidneys will try to conserve plasma sodium levels during prerenal disease and will lose sodium during tubular injury. Therefore, a urine sodium concentration of more than 40-50 milliequivalents per litre (mEq/L) is indicative of ATN whereas a concentration less then 20 mEq/L suggests prerenal disease (Hanif et al., 2021). Urine sodium measurements may also be coupled with other measures of renal concentrating ability such as creatine levels to better differentiate between these two conditions (Winter & Gabow, 1981).
Blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI)
BOLD-MRI allows for a non-invasive measurement of tissue oxygenation, which is commonly used following surgery to assess renal dysfunction (Lal et al., 2018). BOLD MRI uses the transverse relaxation rate (R2*) as a measure of deoxygenated hemoglobin. Kidneys with ATN display lower R2* values then those with normal oxygenation. The drawback of this technique is that MRIs are expensive and require highly specialized equipment and staff to run (Bauer et al., 2017).
Domain of Applicability
ATN is not age or sex specific as it has been observed in adults and hospitalized children of both sexes (Perazella & Wilson, 2016 ; Perazella et al., 2008). Old age however is often associated with increased risk of ATN and delayed recovery (Abdel-Kader & Palevsky, 2009). ATN is most readily observed in humans however it can occur in a variety of species all of which rely on adequate renal perfusion (Gill et al., 2005; Perazella et al., 2008). Rats (BI et al., 2015) and mice (Perin et al., 2010) are typically used as models for ATN in humans. Adult and larval zebrafish have also been well defined as models to augment mammalian disease in kidney injury studies (Cirio et al., 2015; Kim et al., 2020; Wen et al., 2018). ATN has been diagnosed in many mammals including sheep (Ashrafihelan et al., 2014), cows (Collett et al., 2011) and dogs (Pozniak et al., 1992). ATN following nephrotoxin exposure has also been reported in birds including penguins, parrots, and waterfowl (Schmidt, 2006).
Abdel-Kader, K., & Palevsky, P. M. (2009). Acute kidney injury in the elderly. Clinics in Geriatric Medicine, 25(3), 331–358. https://doi.org/10.1016/j.cger.2009.04.001
Ashrafihelan, J., Eisapour, H., Erfani, A. M., Kalantary, A. A., Amoli, J. S., & Mozafari, M. (2014). High mortality due to accidental salinomycin intoxication in sheep. Interdisciplinary Toxicology, 7(3), 173–176. https://doi.org/10.2478/intox-2014-0024
Bauer, F., Wald, J., Bauer, F. J., Dahlkamp, L. M., Seibert, F. S., Pagonas, N., … Westhoff, T. H. (2017). Detection of Acute Tubular Necrosis Using Blood Oxygenation Level-Dependent (BOLD) MRI. Kidney and Blood Pressure Research, 42(6), 1078–1089. https://doi.org/10.1159/000485600
Bi, L., Wang, G., Yang, D., Li, S., Liang, B. I. N., & Han, Z. (2015). Effects of autologous bone marrow-derived stem cell mobilization on acute tubular necrosis and cell apoptosis in rats. Experimental and Therapeutic Medicine, 10(3), 851–856. https://doi.org/10.3892/etm.2015.2592
Cirio, M. C., de Caestecker, M. P., & Hukriede, N. A. (2015). Zebrafish Models of Kidney Damage and Repair. Current Pathobiology Reports, 3(2), 163–170. https://doi.org/10.1007/s40139-015-0080-4
Collett, M. G., Thompson, K. G., & Christie, R. J. (2011). Photosensitisation, crystal-associated cholangiohepatopathy, and acute renal tubular necrosis in calves following ingestion of Phytolacca octandra (inkweed). New Zealand Veterinary Journal, 59(3), 147–152. https://doi.org/10.1080/00480169.2011.567966
Gill, N., Nally, J. V, & Fatica, R. A. (2005). Renal Failure Secondary to Acute Tubular Necrosis: Epidemiology, Diagnosis, and Management. Chest, 128(4), 2847–2863. https://doi.org/https://doi.org/10.1378/chest.128.4.2847
Hanif, Muhammad., Bali, Atul., Ramphul, K. (2021). Acute Renal Tubular Necrosis. https://doi.org/10.1001/jama.1967.03120150130036
Herget-Rosenthal, S., Poppen, D., Hüsing, J., Marggraf, G., Pietruck, F., Jakob, H. G., … Kribben, A. (2004). Prognostic Value of Tubular Proteinuria and Enzymuria in Nonoliguric Acute Tubular Necrosis. Clinical Chemistry, 50(3), 552–558. https://doi.org/10.1373/clinchem.2003.027763
Kanbay, M., Kasapoglu, B., & Perazella, M. A. (2010). Acute tubular necrosis and pre-renal acute kidney injury: Utility of urine microscopy in their evaluation - A systematic review. International Urology and Nephrology, 42(2), 425–433. https://doi.org/10.1007/s11255-009-9673-3
Kim, M.-J., Moon, D., Jung, S., Lee, J., & Kim, J. (2020). Cisplatin nephrotoxicity is induced via poly(ADP-ribose) polymerase activation in adult zebrafish and mice. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 318(5), R843–R854. https://doi.org/10.1152/ajpregu.00130.2019
Lal, H., Mohamed, E., Soni, N., Yadav, P., Jain, M., Bhadauria, D., … Sharma, R. K. (2018). Role of Blood Oxygen Level-dependent MRI in Differentiation of Acute Renal Allograft Dysfunction. Indian Journal of Nephrology, 28(6), 441–447. https://doi.org/10.4103/ijn.IJN_43_18
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Perazella, M. A., Coca, S. G., Kanbay, M., Brewster, U. C., & Parikh, C. R. (2008). Diagnostic Value of Urine Microscopy for Differential Diagnosis of Acute Kidney Injury in Hospitalized Patients. Clinical Journal of the American Society of Nephrology, 3(6), 1615–1619. https://doi.org/10.2215/CJN.02860608
Perazella, M. A., & Wilson, F. P. (2016). Acute kidney injury: Preventing acute kidney injury through nephrotoxin management. Nature Reviews Nephrology, 12(9), 511–512. https://doi.org/10.1038/nrneph.2016.95
Perin, L., Sedrakyan, S., Giuliani, S., Da Sacco, S., Carraro, G., Shiri, L., … De Filippo, R. E. (2010). Protective effect of human amniotic fluid stem cells in an immunodeficient mouse model of acute tubular necrosis. PloS One, 5(2), e9357–e9357. https://doi.org/10.1371/journal.pone.0009357
Pozniak, M. A., Kelcz, F., D’Alessandro, A., Oberley, T., & Stratta, R. (1992). Sonography of renal transplants in dogs: the effect of acute tubular necrosis, cyclosporine nephrotoxicity, and acute rejection on resistive index and renal length. American Journal of Roentgenology (1976), 158(4), 791–797. https://doi.org/10.2214/ajr.158.4.1546594
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Silva, F. G. (2004). Chemical-induced nephropathy: A review of the renal tubulointerstitial lesions in humans. Toxicologic Pathology, 32(SUPPL. 2), 71–84. https://doi.org/10.1080/01926230490457530
Wen, X., Cui, L., Morrisroe, S., Maberry Donald, J., Emlet, D., Watkins, S., … Kellum, J. A. (2018). A zebrafish model of infection-associated acute kidney injury. American Journal of Physiology. Renal Physiology, 315(2), F291–F299. https://doi.org/10.1152/ajprenal.00328.2017
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