Rat models of colistin nephrotoxicity: previous experimental researches and future perspectives

  • Cihan HeybeliEmail author
  • Mehmet Ası Oktan
  • Zahide Çavdar


Colistin is an old antibiotic, which is abandoned decades ago because of high nephrotoxicity rates. However, it is reintroduced to clinical medicine due to lack of newly discovered antibiotics and is still widely used for the treatment of resistant gram-negative infections. Discovering mechanisms to reduce nephrotoxicity risk is of significant importance since exposed patients may have many other factors that alter kidney functions. Several agents were evaluated in animal models of colistin nephrotoxicity as a means to prevent kidney injury. Considerable heterogeneity exists in terms of reporting colistin dosing and experimental designs. This issue leads clinicians to face difficulties in designing studies and sometimes may lead to report dosing strategies inadequately. Here, we present a review according to animal models of colistin nephrotoxicity using data gathered from previous experiments to draw attention on possible complexities that researchers may encounter.


Animal model Colistin Nephrotoxicity 


Author contributions

Conception and Design: CH.

Analysis and interpretation of data: CH, MAO.

Drafting the work or revising it critically for important intellectual content: CH, MAO.

Final approval of the version to be published: CH, MAO, ZÇ.

Supervision: ZÇ.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Tran TB, Velkov T, Nation RL et al (2016) Pharmacokinetics/pharmacodynamics of colistin and polymyxin B: are we there yet? Int J Antimicrob Agents 48:592Google Scholar
  2. 2.
    Ordooei Javan A, Shokouhi S, Sahraei Z (2015) A review on colistin nephrotoxicity. Eur J Clin Pharmacol 71(7):801–810. Google Scholar
  3. 3.
    Zavascki AP, Nation RL (2017) Nephrotoxicity of polymyxins: is there any difference between colistimethate and polymyxin B? Antimicrob Agents Chemother 61(3):e02319–e02316. Published 2017 Feb 23. Google Scholar
  4. 4.
    He H, Li JC, Nation RL et al (2013) Pharmacokinetics of four different brands of colistimethate and formed colistin in rats. J Antimicrob Chemother 68(10):2311–2317Google Scholar
  5. 5.
    Gauthier TP, Lantz E, Frederick C, Masmouei H, Ruiz-Serrano L, Smith L, Wolowich WR, Abbo LM (2014) Variability within investigations of intravenous colistin: the scope of the problem. Clin Infect Dis 58(9):1340–1342. Google Scholar
  6. 6.
    Falagas ME, Kasiakou SK (2006) Use of international units when dosing colistin will help decrease confusion related to various formulations of the drug around the world. Antimicrob Agents Chemother 50(6):2274–2275Google Scholar
  7. 7.
    Li J, Nation RL, Turnidge JD (2006) Defining the dosage units for colistin methanesulfonate: urgent need for international harmonization. Antimicrob Agents Chemother 50(12):4231 author reply 4231-2Google Scholar
  8. 8.
    Nation RL, Li J, Cars O, Couet W, Dudley MN, Kaye KS, Mouton JW, Paterson DL, Tam VH, Theuretzbacher U, Tsuji BT, Turnidge JD (2014) Consistent global approach on reporting of colistin doses to promote safe and effective use. Clin Infect Dis 58(1):139–141. Google Scholar
  9. 9.
    American Society of Health System Pharmacists. Warning! Dosing confusion with colistimethate for injection. Available at: Accessed 30 December 2018.
  10. 10.
    Yun B, Azad MA, Wang J et al (2014) Imaging the distribution of polymyxins in the kidney. J Antimicrob Chemother 70(3):827–829Google Scholar
  11. 11.
    Gupta S, Govil D, Kakar PN et al (2009) Colistin and polymyxin B: a re-emergence. Indian J Crit Care Med 13(2):49–53Google Scholar
  12. 12.
    Eadon MT, Hack BK, Alexander JJ, Xu C, Dolan ME, Cunningham PN (2013) Cell cycle arrest in a model of colistin nephrotoxicity. Physiol Genomics 45(19):877–888Google Scholar
  13. 13.
    Azad MA, Finnin BA, Poudyal A et al (2013) Polymyxin B induces apoptosis in kidney proximal tubular cells. Antimicrob Agents Chemother 57(9):4329–4335Google Scholar
  14. 14.
    Ozkan G, Ulusoy S, Orem A et al (2013) How does colistin-induced nephropathy develop and can it be treated? Antimicrob Agents Chemother 57(8):3463–3469Google Scholar
  15. 15.
    Ceylan B, Ozansoy M, Kılıç Ü et al (2018) N-acetylcysteine suppresses colistimethate sodium-induced nephrotoxicity via activation of SOD2, eNOS, and MMP3 protein expressions. Ren Fail 40(1):423–434Google Scholar
  16. 16.
    Dai C, Li J, Tang S, Li J, Xiao X (2014) Colistin-induced nephrotoxicity in mice involves the mitochondrial, death receptor, and endoplasmic reticulum pathways. Antimicrob Agents Chemother 58(7):4075–4085Google Scholar
  17. 17.
    Dai C, Tang S, Deng S et al (2014) Lycopene attenuates colistin-induced nephrotoxicity in mice via activation of the Nrf2/HO-1 pathway. Antimicrob Agents Chemother 59(1):579–585Google Scholar
  18. 18.
    Dai C, Tang S, Wang Y, Velkov T, Xiao X (2017) Baicalein acts as a nephroprotectant that ameliorates colistin-induced nephrotoxicity by activating the antioxidant defence mechanism of the kidneys and down-regulating the inflammatory response. J Antimicrob Chemother 72(9):2562–2569Google Scholar
  19. 19.
    Lee SH, Kim JS, Ravichandran K, Gil HW, Song HY, Hong SY (2015) P-glycoprotein induction ameliorates colistin induced nephrotoxicity in cultured human proximal tubular cells. PLoS One 10(8):e0136075. Published 2015 Aug 19. Google Scholar
  20. 20.
    Hori Y, Aoki N, Kuwahara S et al (2017) Megalin blockade with cilastatin suppresses drug-induced nephrotoxicity. J Am Soc Nephrol 28(6):1783–1791Google Scholar
  21. 21.
    Suzuki T, Yamaguchi H, Ogura J, Kobayashi M, Yamada T, Iseki K (2013) Megalin contributes to kidney accumulation and nephrotoxicity of colistin. Antimicrob Agents Chemother 57(12):6319–6324Google Scholar
  22. 22.
    Heidari R, Behnamrad S, Khodami Z, Ommati MM, Azarpira N, Vazin A (2019) The nephroprotective properties of taurine in colistin-treated mice is mediated through the regulation of mitochondrial function and mitigation of oxidative stress. Biomed Pharmacother 109:103–111. Google Scholar
  23. 23.
    Hanedan B, Ozkaraca M, Kirbas A, Kandemir FM, Aktas MS, Kilic K, Comakli S, Kucukler S, Bilgili A (2018) Investigation of the effects of hesperidin and chrysin on renal injury induced by colistin in rats. Biomed Pharmacother 108:1607–1616. Google Scholar
  24. 24.
    Ghlissi Z, Hakim A, Mnif H, Zeghal K, Rebai T, Boudawara T, Sahnoun Z (2018) Combined use of vitamins E and C improve nephrotoxicity induced by colistin in rats. Saudi J Kidney Dis Transpl 29(3):545–553. Google Scholar
  25. 25.
    Talih G, Esmaoğlu A, Bayram A, Yazici C, Deniz K, Talih T (2018) Does dexmedetomidine prevent colistin nephrotoxicity? Rev Bras Anestesiol 68(4):383–387. Google Scholar
  26. 26.
    Azad MAK, Sivanesan S, Wang J et al (2017) Methionine ameliorates polymyxin-induced nephrotoxicity by attenuating cellular oxidative stress. Antimicrob Agents Chemother 62(1):e01254–e01217. Google Scholar
  27. 27.
    Arslan BY, Arslan F, Erkalp K, Alagöl A, Sevdi MS, Yıldız G, Küçük SH, Altınay S (2016) Luteolin ameliorates colistin-induced nephrotoxicity in the rat models. Ren Fail 38(10):1735–1740. Google Scholar
  28. 28.
    Ghlissi Z, Hakim A, Sila A, Mnif H, Zeghal K, Rebai T, Bougatef A, Sahnoun Z (2014) Evaluation of efficacy of natural astaxanthin and vitamin E in prevention of colistin-induced nephrotoxicity in the rat model. Environ Toxicol Pharmacol 37(3):960–966. Google Scholar
  29. 29.
    Ozyilmaz E, Ebinc FA, Derici U, Gulbahar O, Goktas G, Elmas C, Oguzulgen IK, Sindel S (2011) Could nephrotoxicity due to colistin be ameliorated with the use of N-acetylcysteine? Intensive Care Med 37(1):141–146. Google Scholar
  30. 30.
    Edrees NE, Galal AAA, Abdel Monaem AR, Beheiry RR, Metwally MMM (2018) Curcumin alleviates colistin-induced nephrotoxicity and neurotoxicity in rats via attenuation of oxidative stress, inflammation and apoptosis. Chem Biol Interact 294:56–64. Google Scholar
  31. 31.
    Sivanesan SS, Azad MAK, Schneider EK et al (2017) Gelofusine ameliorates colistin-induced nephrotoxicity. Antimicrob Agents Chemother 61(12):e00985–e00917. Published 2017 Nov 22. Google Scholar
  32. 32.
    Yousef JM, Chen G, Hill PA, Nation RL, Li J (2011) Melatonin attenuates colistin-induced nephrotoxicity in rats. Antimicrob Agents Chemother 55(9):4044–4049Google Scholar
  33. 33.
    Yousef JM, Chen G, Hill PA, Nation RL, Li J (2011) Ascorbic acid protects against the nephrotoxicity and apoptosis caused by colistin and affects its pharmacokinetics. J Antimicrob Chemother 67(2):452–459Google Scholar
  34. 34.
    Fluri F, Schuhmann MK, Kleinschnitz C (2015) Animal models of ischemic stroke and their application in clinical research. Drug Des Devel Ther 9:3445–3454. Published 2015 Jul 2. Google Scholar
  35. 35.
    Hackbarth H, Büttner D, Jarck D, Pothmann M, Messow C, Gärtner K (1983) Distribution of glomeruli in the renal cortex of Munich Wistar Frömter (MWF) rats. Ren Physiol 6(2):63–71Google Scholar
  36. 36.
    Wei Q, Wang MH, Dong Z (2005) Differential gender differences in ischemic and nephrotoxic acute renal failure. Am J Nephrol 25:491–499Google Scholar
  37. 37.
    Turner PV, Brabb T, Pekow C, Vasbinder MA (2011) Administration of substances to laboratory animals: routes of administration and factors to consider. J Am Assoc Lab Anim Sci 50(5):600–613Google Scholar
  38. 38.
    Gurjar M (2015) Colistin for lung infection: an update. J Intensive Care 3(1):3. Google Scholar
  39. 39.
    Lewis RE, Kunz AL, Bell RE (1966) Error of intraperitoneal injections in rats. Lab Anim Care 16:505–509Google Scholar
  40. 40.
    Keirstead ND, Wagoner MP, Bentley P, Blais M, Brown C, Cheatham L, Ciaccio P, Dragan Y, Ferguson D, Fikes J, Galvin M, Gupta A, Hale M, Johnson N, Luo W, McGrath F, Pietras M, Price S, Sathe AG, Sasaki JC, Snow D, Walsky RL, Kern G (2014) Early prediction of polymyxin-induced nephrotoxicity with next-generation urinary kidney injury biomarkers. Toxicol Sci 137(2):278–291. Google Scholar
  41. 41.
    Morton DB, Jennings M, Buckwell A, Ewbank R, Godfrey C, Holgate B, Inglis I, James R, Page C, Sharman I, Verschoyle R, Westall L, Wilson AB, Joint Working Group on Refinement (2001) Refining procedures for the administration of substances. Report of the BVAAWF/FRAME/RSPCA/UFAW Joint Working Group on Refinement. British Veterinary Association Animal Welfare Foundation/Fund for the Replacement of Animals in Medical Experiments/Royal Society for the Prevention of Cruelty to Animals/Universities Federation for Animal Welfare. Lab Anim 35:1–41Google Scholar
  42. 42.
    Azushima K, Gurley SB, Coffman TM (2018) Modelling diabetic nephropathy in mice. Nat Rev Nephrol 14(1):48–56. Google Scholar
  43. 43.
    Falagas ME, Fragoulis KN, Kasiakou SK, Sermaidis GJ, Michalopoulos A (2005) Nephrotoxicity of intravenous colistin: a prospective evaluation. Int J Antimicrob Agents 26(6):504–507Google Scholar
  44. 44.
    Miano TA, Lautenbach E, Wilson FP, Guo W, Borovskiy Y, Hennessy S (2018) Attributable risk and time course of colistin-associated acute kidney injury. Clin J Am Soc Nephrol 13(4):542–550. Google Scholar
  45. 45.
    Fiaccadori E, Antonucci E, Morabito S, d’Avolio A, Maggiore U, Regolisti G (2016) Colistin use in patients with reduced kidney function. Am J Kidney Dis 68(2):296–306. Google Scholar
  46. 46.
    Hakim A, Kallel H, Sahnoun Z, Badraoui R, Jammoussi K, Bouaziz M, Zeghal KM, Rebaii T (2008) Lack of nephrotoxicity following 15-day therapy with high doses of colistin in rats. Med Sci Monit 14(4):BR74–BR77Google Scholar
  47. 47.
    Ghlissi Z, Hakim A, Mnif H, Ayadi FM, Zeghal K, Rebai T, Sahnoun Z (2013) Evaluation of colistin nephrotoxicity administered at different doses in the rat model. Ren Fail 35(8):1130–1135. Google Scholar
  48. 48.
    Zager RA, Vijayan A, Johnson AC (2012) Proximal tubule haptoglobin gene activation is an integral component of the acute kidney injury “stress response”. Am J Physiol Renal Physiol 303:F139–F148Google Scholar
  49. 49.
    Wei Q, Dong Z (2012) Mouse model of ischemic acute kidney injury: technical notes and tricks. Am J Physiol Renal Physiol 303(11):F1487–F1494. Google Scholar
  50. 50.
    de Caestecker M, Humphreys BD, Liu KD et al (2015) Bridging translation by improving preclinical study design in AKI. J Am Soc Nephrol 26(12):2905–2916Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Internal Medicine, Division of NephrologyDokuz Eylül University School of MedicineIzmirTurkey
  2. 2.Department of Molecular MedicineDokuz Eylül University Health Sciences InstituteIzmirTurkey

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