Skip to main content
Intended for healthcare professionals
Restricted access
Research article
First published online January 19, 2021

Method used to establish a large animal model of drug-induced acute kidney injury

Abstract

Acute kidney injury is a serious health hazard disease due to its complex etiology and lack of effective treatments, resulting in high medical costs and high mortality. At present, a large number of basic research studies on acute kidney injury have been carried out. However, acute kidney injury models established in rodents sometimes do not simulate the course of human disease well. Research in large animal models of acute kidney injury is relatively rare, and methods to build a mature model of acute kidney injury have failed. Because its kidney anatomy and morphology are very similar to those in humans, the mini pig is an ideal animal in which to model kidney disease. Nephrotoxic drug-induced acute kidney injury has a high incidence. In this study, we established models of acute kidney injury induced by two drugs (gentamicin and cisplatin). Finally, the model of cisplatin-induced acute kidney injury was developed successfully, but we found the model of gentamycin-induced acute kidney injury was not reproducible. Compared to other models, these models better represent acute kidney injury caused by antibiotics and chemotherapeutic drugs and provide a basis for the study of new treatments for acute kidney injury in a large animal model.

Get full access to this article

View all access and purchase options for this article.

References

1. Lewington AJ, Cerdá J, Mehta RL. Raising awareness of acute kidney injury: a global perspective of a silent killer. Kidney Int 2013; 84:457–67
2. Susantitaphong P, Cruz DN, Cerda J, Abulfaraj M, Alqahtani F, Koulouridis I, Jaber BL. World incidence of AKI: a meta-analysis. Clin J Am Soc Nephrol 2013; 8:1482–93
3. Li S, Krawczeski CD, Zappitelli M, Devarajan P, Thiessen-Philbrook H, Coca SG, Kim RW, Parikh CR. Incidence, risk factors, and outcomes of acute kidney injury after pediatric cardiac surgery: a prospective multicenter study. Crit Care Med 2011; 39:1493–9
4. Hayward RS, Harding J, Molloy R, Land L, Longcroft-Neal K, Moore D, Ross JDC. Adverse effects of a single dose of gentamicin in adults: a systematic review. Br J Clin Pharmacol 2018; 84:223–38
5. Vicente-Vicente L, Casanova AG, Hernández-Sánchez MT, Pescador M, López-Hernández FJ, Morales AI. A systematic Meta-analysis on the efficacy of pre-clinically tested nephroprotectants at preventing aminoglycoside nephrotoxicity. Toxicology 2017; 377:14–24
6. Percie Du Sert N, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, Browne WJ, Clark A, Cuthill IC, Dirnagl U, Emerson M, Garner P, Holgate ST, Howells DW, Karp NA, Lazic SE, Lidster K, MacCallum CJ, Macleod M, Pearl EJ, Petersen OH, Rawle F, Reynolds P, Rooney K, Sena ES, Silberberg SD, Steckler T, Würbel H. The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. Br J Pharmacol 2020; 177:3617–24
7. Cui J, Bai XY, Sun X, Cai G, Hong Q, Ding R, Chen X. Rapamycin protects against gentamicin-induced acute kidney injury via autophagy in mini-pig models. Sci Rep 2015; 5:11256
8. Zhu S, Pabla N, Tang C, He L, Dong Z. DNA damage response in cisplatin-induced nephrotoxicity. Arch Toxicol 2015; 89:2197–205
9. Zhang D, Liu Y, Wei Q, Huo Y, Liu K, Liu F, Dong Z. Tubular p53 regulates multiple genes to mediate AKI. J Am Soc Nephrol 2014; 25:2278–89
10. Madias NE, Harrington JT. Platinum nephrotoxicity. Am J Med 1978; 65:307–14
11. Madsen LB, Thomsen B, Sølvsten CAE, Bendixen C, Fredholm M, Jørgensen AL, Nielsen AL. Identification of the porcine homologous of human disease causing trinucleotide repeat sequences. Neurogenetics 2007; 8:207–18
12. Cooper DKC, Hara H, Iwase H, Yamamoto T, Jagdale A, Kumar V, Mannon RB, Hanaway MJ, Anderson DJ, Eckhoff DE. Clinical pig kidney xenotransplantation: how close are we? J Am Soc Nephrol 2020; 31:12–21
13. Swindle MM, Makin A, Herron AJ, Clubb FJ Jr., Frazier KS. Swine as models in biomedical research and toxicology testing. Vet Pathol 2012; 49:344–56
14. Swindle MM, Smith AC, Hepburn BJ. Swine as models in experimental surgery. J Invest Surg 1988; 1:65–79
15. Picard W, Bazin F, Clouzeau B, Bui HN, Soulat M, Guilhon E, Vargas F, Hilbert G, Bouchet S, Gruson D, Moore N, Boyer A. Propensity-based study of aminoglycoside nephrotoxicity in patients with severe sepsis or septic shock. Antimicrob Agents Chemother 2014; 58:7468–74
16. Lopez-Novoa JM, Quiros Y, Vicente L, Morales AI, Lopez-Hernandez FJ. New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view. Kidney Int 2011; 79:33–45
17. Choi JJ, Moffett BS, McDade EJ, Palazzi DL. Altered gentamicin serum concentrations in obese pediatric patients. Pediatr Infect Dis J 2011; 30:347–9
18. Balakumar P, Rohilla A, Thangathirupathi A. Gentamicin-induced nephrotoxicity: do we have a promising therapeutic approach to blunt it? Pharmacol Res 2010; 62:179–86
19. Carlsen S, Boel J, Jarløv JO, Gjørup I, Søborg C, Arpi M. The effect of short-course gentamicin therapy on kidney function in patients with bacteraemia – a retrospective cohort study. Eur J Clin Microbiol Infect Dis 2018; 37:2307–12
20. Muraki K, Koyama R, Honma Y, Yagishita S, Shukuya T, Ohashi R, Takahashi F, Kido K, Iwakami S-I, Sasaki S, Iwase A, Takahashi K. Hydration with magnesium and mannitol without furosemide prevents the nephrotoxicity induced by cisplatin and pemetrexed in patients with advanced non-small cell lung cancer. J Thorac Dis 2012; 4:562–8
21. Sato K, Watanabe S, Ohtsubo A, Shoji S, Ishikawa D, Tanaka T, Nozaki K, Kondo R, Okajima M, Miura S, Tanaka J, Sakagami T, Koya T, Kagamu H, Yoshizawa H, Narita I. Nephrotoxicity of cisplatin combination chemotherapy in thoracic malignancy patients with CKD risk factors. BMC Cancer 2016; 16:222
22. Prasaja Y, Sutandyo N, Andrajati R. Incidence of cisplatin-induced nephrotoxicity and associated factors among cancer patients in Indonesia. Asian Pac J Cancer Prev 2015; 16:1117–22
23. Mousavi SSB, Zadeh MH, Shahbazian H, Khanzadeh A, Hayati F, Ghorbani A, Golzari K, Valavi E, Motemednia F, Mousavi MB. The protective effect of theophyline in cisplatin nephrotoxicity. Saudi J Kidney Dis Transpl 2014; 25:333–37
24. Shi M, McMillan KL, Wu J, Gillings N, Flores B, Moe OW, Hu MC. Cisplatin nephrotoxicity as a model of chronic kidney disease. Lab Invest 2018; 98:1105–21
25. Santiago MJ, Fernández SN, Lázaro A, González R, Urbano J, López J, Solana MJ, Toledo B, Del Castillo J, Tejedor A, López-Herce J. Cisplatin-induced non-oliguric acute kidney injury in a pediatric experimental animal model in piglets. PLoS One 2016; 11:e0149013–e13
26. Lee Y-J, Li K-Y, Wang P-J, Huang H-W, Chen M-J. Alleviating chronic kidney disease progression through modulating the critical genus of gut microbiota in a cisplatin-induced lanyu pig model. J Food Drug Anal 2020; 28:103–14
27. Skinner R, Parry A, Price L, Cole M, Craft AW, Pearson AD. Persistent nephrotoxicity during 10-year follow-up after cisplatin or carboplatin treatment in childhood: relevance of age and dose as risk factors. Eur J Cancer 2009; 45:3213–9
28. Latcha S, Jaimes EA, Patil S, Glezerman IG, Mehta S, Flombaum CD. Long-term renal outcomes after cisplatin treatment. Clin J Am Soc Nephrol 2016; 11:1173–9
29. Tixier F, Ranchon F, Iltis A, Vantard N, Schwiertz V, Bachy E, Bouafia-Sauvy F, Sarkozy C, Tournamille JF, Gyan E, Salles G, Rioufol C. Comparative toxicities of 3 platinum-containing chemotherapy regimens in relapsed/refractory lymphoma patients. Hematol Oncol 2017; 35:584–90
30. Kurt E, Manavoglu O, Dilek K, Orhan B, Evrensel T. Effect of cisplatin on plasma renin activity and serum aldosterone levels. Clin Nephrol 1999; 52:397–8
31. Tang C, Ma Z, Zhu J, Liu Z, Liu Y, Liu Y, Cai J, Dong Z. P53 in kidney injury and repair: mechanism and therapeutic potentials. Pharmacol Ther 2019; 195:5–12

Cite article

Cite article

Cite article

OR

Download to reference manager

If you have citation software installed, you can download article citation data to the citation manager of your choice

Share options

Share

Share this article

Share with email
EMAIL ARTICLE LINK
Share on social media

Share access to this article

Sharing links are not relevant where the article is open access and not available if you do not have a subscription.

For more information view the Sage Journals article sharing page.

Information, rights and permissions

Information

Published In

Article first published online: January 19, 2021
Issue published: April 2021

Keywords

  1. Acute kidney injury
  2. drug-induced model
  3. mini pig

Rights and permissions

© 2021 by the Society for Experimental Biology and Medicine.
PubMed: 33467911

Authors

Affiliations

Si-Yang Wang
Department of Nephrology, the First Medical Centre, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing 100853, China
953th Hospital, Shigatse Branch, Xinqiao Hospital, Army Medical University (Third Military Medical University), Shigatse 857000, China
Chao-Yang Zhang
Department of Nephrology, the First Medical Centre, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing 100853, China
Guang-Yan Cai
Department of Nephrology, the First Medical Centre, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing 100853, China
Xiang-Mei Chen
Department of Nephrology, the First Medical Centre, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing 100853, China

Notes

Guang-Yan Cai. Email: [email protected]

Authors’ contributions

W SY, ZH CY, C GY and C XM contributed to the conception of the study. W SY and ZH CY performed the analysis and experiments. W SY contributed significantly to analysis and manuscript preparation. All authors approve the final version

Metrics and citations

Metrics

Journals metrics

This article was published in Experimental Biology and Medicine.

VIEW ALL JOURNAL METRICS

Article usage*

Total views and downloads: 119

*Article usage tracking started in December 2016


Altmetric

See the impact this article is making through the number of times it’s been read, and the Altmetric Score.
Learn more about the Altmetric Scores



Articles citing this one

Receive email alerts when this article is cited

Web of Science: 3 view articles Opens in new tab

Crossref: 3

  1. Animal Models of Kidney Disease: Challenges and Perspectives
    Go to citation Crossref Google Scholar
  2. Modeling Cisplatin-Induced Kidney Injury to Increase Translational Pot...
    Go to citation Crossref Google Scholar
  3. Experimental models of acute kidney injury for translational research
    Go to citation Crossref Google Scholar

Figures and tables

Figures & Media

Tables

View Options

Get access

Access options

If you have access to journal content via a personal subscription, university, library, employer or society, select from the options below:

SEBM members can access this journal content using society membership credentials.

SEBM members can access this journal content using society membership credentials.


Alternatively, view purchase options below:

Purchase 24 hour online access to view and download content.

Access journal content via a DeepDyve subscription or find out more about this option.

View options

PDF/ePub

View PDF/ePub

Full Text

View Full Text