CardioVascular and Interventional Radiology

, Volume 42, Issue 12, pp 1777–1785 | Cite as

Investigating the Possible Protective Role of Direct Intra-arterial Administration of Mannitol and N-Acetylcysteine and Per Os Administration of Simvastatin Against Contrast-Induced Nephropathy: An Experimental Study in a Rabbit Model

  • Thomas E. KalogirouEmail author
  • Soultana Meditskou
  • Sotiria Davidopoulou
  • Ioannis Savvas
  • Apostolos G. Pitoulias
  • Georgios A. Pitoulias
Laboratory Investigation Other
Part of the following topical collections:
  1. Other



Contrast-induced nephropathy (CIN) is one of the leading causes of hospital-acquired acute kidney injury due to the use of iodinated contrast media in various interventional procedures like endovascular aneurysm repair. Its pathophysiology remains mostly unclear. The purpose of the present study was to comparatively study the possible protective role of direct intra-arterial administration of mannitol and acetylcysteine and per os administration of simvastatin in a histopathological level.

Materials and Methods

In the present study, we administered iopromide directly in the infrarenal aorta of 24 New Zealand white rabbits after laparotomy. Animals were divided in four groups of six: G1 received iopromide with no protection, G2 iopromide with mannitol, G3 iopromide with acetylcysteine, and G4 iopromide with simvastatin. Renal function blood parameters were assessed prior to the administration, and in 48 h; histopathological evaluation of the kidneys was performed.


CIN was evident only in the no protection group G1. Moreover, G1 demonstrated significantly more severe lesions than groups G2, G3, and G4 regarding histopathological findings in glomeruli, vacuolization of tubular epithelial cells, tubular proteinaceous casts, and tubular necrosis. According to our results, intra-arterial administration of mannitol seems to be effective in protection against tubular necrosis.


In general, all three agents demonstrated a protective role in preventing the development of CIN, although it seems that there are various pathways that remain to be investigated further.


Contrast-induced nephropathy Acetylcysteine Mannitol Simvastatin Intra-arterial Rabbit model CIN protection 



This study was not supported by any funding.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This experimental study strictly met all the criteria and the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institute of Health. The protocol was approved by the National Committee of Agricultural Economy and Veterinary Medicine of Central Macedonia (Thessaloniki, 29 September 2015, Αριθμ. Πρωτ. 326491/2358) according to the 2010/63/EU directive of the European Parliament and of the Council (2 September 2010, on the protection of animals used for scientific purposes) and the relevant adaptation of the Greek law (L 276/33/20.10.2010, ΦΕΚ 106/τ.Ά/30.04.2013). All operations were performed in the veterinary clinic of Aristotle University of Thessaloniki under general anesthesia, with the use of ketamine and/or sodium pentobarbital, induced by a veterinary anesthesiologist and all efforts were made to minimize suffering.

Human and Animal Rights

This article does not contain any studies with human participants performed by any of the authors.

Informed Consent

For this type of study, informed consent is not required.

Consent for Publication

For this type of study, consent for publication is not required.


  1. 1.
    Briguori C, Marenzi G. Contrast-induced nephropathy: pharmacological prophylaxis. Kidney Int Suppl. 2006;100:S30–S3838.CrossRefGoogle Scholar
  2. 2.
    Rear R, Bell RM, Hausenloy DJ. Contrast-induced nephropathy following angiography and cardiac interventions. Heart. 2016;102(8):638–48.CrossRefGoogle Scholar
  3. 3.
    Ali-Hassan-Sayegh S, Mirhosseini SJ, Ghodratipour Z, Sarrafan-Chaharsoughi Z, Rahimizadeh E, Karimi-Bondarabadi AA, et al. Strategies preventing contrast-induced nephropathy after coronary angiography : a comprehensive meta-analysis and systematic review of 125 randomized controlled trials. Angiology. 2017;68(5):389–413.CrossRefGoogle Scholar
  4. 4.
    Navarese EP, Gurbel PA, Andreotti F, Koøodziejczak MM, Palmer SC, Dias S, et al. Prevention of contrast-induced acute kidney injury in patients undergoing cardiovascular procedures—a systematic review and network meta-analysis. PLoS ONE. 2017;12(2):e0168726.CrossRefGoogle Scholar
  5. 5.
    Aspelin P, Aubry P, Fransson S-G, Strasser R, Willenbrock R, Berg KJ. Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med. 2003;348(6):491–9.CrossRefGoogle Scholar
  6. 6.
    De Almeida LS, Barboza JR, Freitas FPS, Porto ML, Vasquez EC, Meyrelles SS, et al. Sildenafil prevents renal dysfunction in contrast media-induced nephropathy in Wistar rats. Hum Exp Toxicol. 2016;35(11):1194–202.CrossRefGoogle Scholar
  7. 7.
    Ozkan G, Ulusoy S, Orem A, Ersoz S, Alkanat M, Yucesan FB, et al. Protective effect of the grape seed proanthocyanidin extract in a rat model of contrast-induced nephropathy. Kidney Blood Press Res. 2012;35(6):445–53.CrossRefGoogle Scholar
  8. 8.
    Zhao Y, Tao Z, Xu Z, Tao Z, Chen B, Wang L, et al. Toxic effects of a high dose of non-ionic iodinated contrast media on renal glomerular and aortic endothelial cells in aged rats in vivo. Toxicol Lett. 2011;202(3):253–60.CrossRefGoogle Scholar
  9. 9.
    Kiss N, Hamar P. Histopathological evaluation of contrast-induced acute kidney injury rodent models. Biomed Res Int. 2016;2016:3763250.CrossRefGoogle Scholar
  10. 10.
    Navaneethan SD, Singh S, Appasamy S, Wing RE, Sehgal AR. Sodium bicarbonate therapy for prevention of contrast-induced nephropathy: a systematic review and meta-analysis. Am J Kidney Dis. 2009;53(4):617–27.CrossRefGoogle Scholar
  11. 11.
    Pettersson G, Towart R, Grant D, Thyberg K, Golman K. The rabbit renal toxicity test: a sensitive in vivo test for the nephrotoxicity of contrast agents. Acad Radiol. 2002;9(Suppl 1):S62–S6464.CrossRefGoogle Scholar
  12. 12.
    Tsamouri M-M, Rapti M, Kouka P, Nepka C, Tsarouhas K, Soumelidis A, et al. Histopathological evaluation and redox assessment in blood and kidney tissues in a rabbit contrast-induced nephrotoxicity model. Food Chem Toxicol. 2017;108(Pt A):186–93.CrossRefGoogle Scholar
  13. 13.
    Faul F, Erdfelder E, Buchner A, Lang A-G. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods. 2009;41(4):1149–60.CrossRefGoogle Scholar
  14. 14.
    Lauver DA, Carey EG, Bergin IL, Lucchesi BR, Gurm HS. Sildenafil citrate for prophylaxis of nephropathy in an animal model of contrast-induced acute kidney injury. PLoS ONE. 2014;9(11):e113598.CrossRefGoogle Scholar
  15. 15.
    Mehta CR, Patel NR, Senchaudhuri P. Efficient Monte Carlo methods for conditional logistic regression. J Am Stat Assoc. 2000;95(449):99–108.CrossRefGoogle Scholar
  16. 16.
    Linkermann A, Heller J-O, Prokai A, Weinberg JM, De Zen F, Himmerkus N, et al. The RIP1-Kinase inhibitor Necrostatin-1 prevents osmotic nephrosis and contrast-induced AKI in mice. J Am Soc Nephrol. 2013;24(10):1545–57.CrossRefGoogle Scholar
  17. 17.
    Mapara M, Thomas BS, Bhat KM. Rabbit as an animal model for experimental research. Dent Res J (Isfahan). 2012;9(1):111–8.CrossRefGoogle Scholar
  18. 18.
    Bhargava AS, Hofmeister R, Siegmund F, Schöbel C, Günzel P. Effect of three non-ionic contrast media on rats and rabbits with regard to renal changes. Interspecies comparison. Arzneimittelforschung. 1990;40(7):822–9.PubMedGoogle Scholar
  19. 19.
    Golshahi J, Nasri H, Gharipour M. Contrast-induced nephropathy; A literature review. J Nephropathol. 2014;3(2):51–6.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Dickenmann M, Oettl T, Mihatsch MJ. Osmotic nephrosis: acute kidney injury with accumulation of proximal tubular lysosomes due to administration of exogenous solutes. Am J Kidney Dis. 2008;51(3):491–503.CrossRefGoogle Scholar
  21. 21.
    Andreucci M, Faga T, Pisani A, Sabbatini M, Russo D, Michael A. Prevention of contrast-induced nephropathy through a knowledge of its pathogenesis and risk factors. Sci World J. 2014;2014:823169.CrossRefGoogle Scholar
  22. 22.
    Li JX, Jin EZ, Yu LH, Li NN, Dong YM, et al. Oral N-acetylcysteine for prophylaxis of contrast induced nephropathy in patients following coronary angioplasty: a meta analysis. Exp Ther Med. 2017;14(2):1568–76.CrossRefGoogle Scholar
  23. 23.
    Ari E, Kedrah AE, Alahdab Y, Bulut G, Eren Z, Baytekin O, et al. Antioxidant and renoprotective effects of paricalcitol on experimental contrast-induced nephropathy model. Br J Radiol. 2012;85(1016):1038–43.CrossRefGoogle Scholar
  24. 24.
    Altunoren O, Balli M, Eren N, Tasolar H, Caglayan CE, Yavuz YC, et al. Is Nebivolol really effective in preventing contrast induced nephropathy? Kidney Blood Press Res. 2015;40(5):533–41.CrossRefGoogle Scholar
  25. 25.
    Ari E, Elden A, Alahdab Y, et al. Protective effect of the vasopressin agonist terlipressin in a rat model of contrast-induced nephropathy. Am J Nephrol. 2011;33(3):269–76.CrossRefGoogle Scholar
  26. 26.
    Briguori C, Colombo A, Airoldi F, Morici N, Sangiorgi GM, Violante A, et al. Nephrotoxicity of low-osmolality versus iso-osmolality contrast agents: impact of N-acetylcysteine. Kidney Int. 2005;68(5):2250–5.CrossRefGoogle Scholar
  27. 27.
    Jorgensen AL. Contrast-induced nephropathy: pathophysiology and preventive strategies. Crit Care Nurse. 2013;33(1):37–46.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2019

Authors and Affiliations

  1. 1.Department of Vascular Surgery, 2nd Surgical Department, General Hospital of Thessaloniki “G.Gennimatas”Aristotle University of ThessalonikiThessalonikiGreece
  2. 2.Laboratory of Histology- EmbryologyAristotle University of ThessalonikiThessalonikiGreece
  3. 3.Veterinary Anaesthesia, Analgesia, and Intensive Care Unit of Anaesthesiology, and Intensive Care Companion Animal Clinic, Faculty of Veterinary Medicine, School of Health SciencesAristotle University of ThessalonikiThessalonikiGreece

Personalised recommendations