International Journal of Anatomy and Research



Welcome to International Journal of Anatomy and Research

b2



b3

 

 

Type of Article : Original Article

Year: 2014 | Volume 2 | Issue 4 | Page No. 768-776

Date of Publication: 31-12-2014

DOI: 10.16965/ijar.2014.545


EFFECT OF CYCLOSPORINE A ON THE KIDNEY OF RABBIT: A LIGHT AND ULTRASTRUCTURAL STUDY

Fathy Ahmed Fetouh, Abdelmonem Awad Hegazy *.

Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt.

Address: Dr. Abdelmonem Hegazy (M.D.), Associate Professor, Anatomy and Embryology Department,Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt.
E-Mail:
dr.abdelmonemhegazy@yahoo.com, ahegazy@zu.edu.eg

Abstract

Background: Nephrotoxicity is a relatively common problem in patients immunosuppressed with cyclosporine A (CsA) with an incidence reaching up to thirty percent. The present work aimed to study the histological and ultrastructural effects of CsA on the kidney of rabbit.
Materials and Methods: Two groups of Egyptian adult rabbits were used for this study (5 rabbits for each). One group was used as a control and the other group (experimental) was treated with CsA in a dose of 15 mg/kg of body weight for two weeks. The animals were anaesthetized; and kidney specimens were obtained, fixed and processed for light and electron microscopic examinations.
Results: CsA had adverse effects on the kidney especially renal corpuscles, proximal convoluted tubules, distal convoluted tubules and afferent glomerular arterioles. The renal corpuscles were observed with shrunken glomeruli, widening of Bowmanʼs space and thickening of the Bowmanʼs capsule. Also, there was obvious increase in mesangial cell number and overall glomerular obliteration due to large lining endothelial cells and encroachment of the mesangial cell matrix onto the capillary lumen. The renal tubules showed vacuolization and PAS positive inclusion bodies. The cells showed disordered brush border of microvilli. Many fibrocytes appeared inbetween the tubules. Peritubular capillary congestion was observed with an increase in the surrounding connective tissue. Ultrastructurally, the proximal convoluted tubules showed thick basement membrane with loss of the basal infolding. The mitochondria appeared degenerated with damaged transverse cristae. Electron dense lysosomes were seen in the cytoplasm. In distal convoluted tubules, the cells showed degenerated mitochondria and pyknotic nuclei. The afferent glomerular arterioles appeared with hyperplasia of juxtaglomerular cells that contained massive renin granules. The lining endothelial cells appeared protruding their nuclei into the lumen due to contraction of the smooth muscles.
Conclusions: It could be concluded that CsA had adverse structural changes on the kidney mainly on the nephron; renal corpuscles, proximal convoluted tubules, distal convoluted tubules and afferent glomerular arterioles. Defective renal function should always be a concern in the management of CsA treated patient.
KEYWORDS: Kidney, Cyclosporine A, Nephrotoxicity, Histology, Ultrastructure.

References

  1. Sund S, Forre O, Berg KJ, Kvien TK, Hovig T. Morphological and functional renal effects of long-term low-dose cyclosporin A treatment in patients with rheumatoid arthritis. Clin Nephrol. 1994;41:33-40.
  2. Borel JF, Feurer C, Gubler HU, Stahelin H. Biological effects of CsA: a new antilymphocytic agent. Agents Action 1976; 6: 468- 475.
  3. Bougneres PF, Carel JC, Castano L, Boitard C, Gardin JP, Landais P, Hors J, Mihatsch MJ, Paillard M, Chaussain JL, Bach JF. Factors associated with early remission of type I diabetes in children treated with cyclosporine. New Engl J Med 1988; 318: 663- 670.
  4. Durkan AM, Hodson EM, Willis NS, Craig JC. Immunosuppressive agents in childhood nephrotic syndrome: a meta-analysis of randomized controlled trails. Kidney Int 2001; 59: 1919- 1927.
  5. Goldstein DJ, Zuech N, Sehgal V. Cyclosporine-associated end-stage nephropathy after cardiac transplantation. Transplantation 1997;63: 664
  6. Bennett WM, Demattos A, Meyer MM, Andoh T, Barry JM. Chronic CsA nephropathy: The Achillesʼ heel of immunosuppressive therapy. Kidney Int 1996; 50:1089-1100.
  7. Morales JM, Andres A, Rengel M, Rodicio JL. Influence of cyclosporin, tacrolimus and rapamycin on renal function and arterial hypertension after renal transplantation. Nephrol Dial Transplant 2001;16 (1): 121-124.
  8. Thliveris JA, Yatscoff RW, Lukowski MP, Copeland KR. Cyclosporine nephrotoxicity-experimental models. Clin Biochem 1991a;24: 93-95.
  9. Thliveris JA, Yatscoff RW, Lukowski MP, Copeland KR, Jeffery JR, Murphy GF. Chronic cyclosporine nephrotoxicity: A rabbit model. Nephron 1991b;57: 470-476
  10. Rezzani R. Cyclosporine A and adverse effects on organs: histochemical studies. Prog Histochem Cytochem 2004; 39: 85-128.
  11. Thijssen S, Lambrichts I, Maringwa J, kerkhove EV. Changes in expression of fibrotic markers and histopathological alternations in kidneys of mice chronically exposed to low and high Cd doses. Toxicol., 2007; 238: 200-210.
  12. Gartner PL, Hiatt J. Color Atlas of Histology, 3rd ed., Lippincott Williams and Wilkins, London, Sydney and Tokyo, 2000; pp: 327.
  13. Bancroft JD, Gamble M.: Theory and Practice of Histological Techniques 5th ed., Churchill Livingstone, New York, London, Philadelphia, 2002.
  14. Kuehnel W. Color Atlas of Cytology, Histology and Microscopic Anatomy, 4th ed., Thieme Flexibook, Stuttgard, New York, 2002, pp: 364 & 368.
  15. Bozzola JJ, Russell LD. Electron microscopy principles and techniques for biologists. Jones and Bartlett publisher, Boston, 1995.
  16. Glauert AM, Lewis PR. Biological specimen preparation for transmission electron microscopy. Vol 17, Portland press, London, 1998.
  17. Pour ZM, Vessal M, Zal F, Khoshdel Z, Torabinejad S. Protective effects of vitamin E and/or quercetin co-supplementation on the morphology of kidney in cyclosporine A- treated rats. Iran J Med Sci 2009; 34(4):271-276.
  18. Alden CL, Frith CH. Urinary system. In: Haschek WM, Rousseaux CG (eds). Handbook of toxicologic pathology. Academic Press, San Diego 1991, pp 315-387.
  19. Abdel Fattah EA, Hashem HE, Ahmed FA, Ghallab MA, Varga I, Polak S. Prophylactic role of curcumin against cyclosporine-induced nephrotoxicity: histological immunohistological study. Gen Physiol Biophys 2010; 29(1): 85-94.
  20. Clarke H, Ryan MP. Cyclosporine A-induced alterations in magnesium homiostasis in the rat. Life Sciences 1999; 64(15):1295-1306.
  21. Owen RA. Acute tubular lesions, kidney rat. In: Jones TC, Mohr U, Hunt RD (eds). Monographs on pathology of laboratory animals. Urinary system. Springer-Verlag, Berlin 1986, pp 229-238.
  22. DellʼAntonio G, Randhawa PS. Striped pattern of medullary ray fibrosis in allograft biopsies from kidney transplant recipients maintained on tacrolimus. Transplantation 1999; 67:484-486.
  23. Agnieszka K, Mariusz M, Grazyna C, Monika O. Ultrastructural examination of renal tubular epithelial cells and hepatocytes in the course of chronic cyclosporine A treatment-A possible link to oxidative stress. Ultrastructural pathology 2013;37(5):332-339.
  24. Ghiggeri GM, Altieri P, Oleggini R, Valenti F. Cyclosporine enhances the synthesis of selected extracellular matrix proteins by renal cells ( in culture).  Different cell responses and phenotype characterization. Transplantation 1994;57:1382-1388.
  25. Johnson DW, Saunders HJ, Johnson FJ. Cyclosporine exerts a direct fibrogenic effect on human tubulointerstitial cells: Roles of insulin-like growth factor 1, transforming growth factor beta 1, and platelet-derived growth factor. J Pharmacol Exp Ther 1999;289:535-542.
  26. Paul LC, de Fijter JH. Cyclosporine-induced renal dysfunction. Transplant Proc 2004;36 (2suppl): 224s-228s.
  27. Kahn GC, Shaw LM, Kane MD. Routine monitoring of cyclosporine in whole blood and in kidney tissue using high performance liquid chromatography. J Anal Toxicol 1986;10:28-34.
  28. Wang C, Salahudeen AK. Cyclosporine nephrotoxicity: attenuation by an antioxidant-inhibitor of lipid peroxidation in vitro and vivo. Transplantation 1994;58(8):940-946.
  29. Nitta K, Friedman AL, Nicastri AD. Granular juxtaglomerular cell hyperplasia caused by cyclosporine. Transplantation 1987; 44:417- 421.
  30. English J, Evan A, Houghton DC. Cyclosporine-induced acute renal dysfunction in the rat. Evidence of arteriolar vasoconstriction with preservation of tubular function. Transplantation 1987;44 :135-141
  31. Laskow DA, Curtis JJ, Luke RG, Julian BA, Jones P. Cyclosporine- induced changes in glomerular filtration rate and urea excretion. Am J Med. 1990; 5(88): 497-502.
  32. Issa N, Kukla A, Ibrahim HN. Calcineurin inhibitor nephrotoxicity: a review and perspective of the evidence. Am J Nephrol. 2013; 37(6): 602-612.
  33. Bergamasco L, Sainaghi PP, Castello L, Letizia C, Bartoli E. In vitro effect of cyclosporine A on angiotensins secretion by glomerular cells. Nephrology 2008; 13:302-308.
  34. Ishikawa, Suzuki K, Fujita K. Mechanisms of cyclosporune-induced nephrotoxicity. Transplant Proc 1999;31:1127-1128.
  35. Bertani T, Ferrazzi P, Schieppati A. Nature and extend of glomerular injury induced by cyclosporine in heart transplant patient. Kidney Int 1991;40:243-250.
  36. Naesens M, Kuypers DR, Sarwal M. Calcineurin Inhibitor Nephrotoxicity. Clin J Am Soc Nephrol. 2009; 4:481-508.
  37. Bobadilla NA, Gamba G. New insights into the pathophysiology of cyclosporine nephrotoxicity: a role of aldosterone. Am J Physiol Renal Physiol. 2007; 293 (1):F2-9.
  38. Hoorn EJ, Walsh SB, Mc Cormick JA, Furstenberg A, Yang CL. The calcineurin inhibitor tacrolimus activates the renal sodium chloride transport to cause hypertension. Nat Med. 2011; 17(10): 1304-1309.
  39. Krauskopf A, Buetler TM, Nguyen NS, Mace K, Ruegg UT. Cyclosporin A-induced free radical generation is not mediated by cytochrome P-450. Br J Pharmacol 2002;135(4): 977-986.      
  40. Galletti P, Di Gennaro CI, Migliardi V, Indaco S, Della RF, Manna C. Diverse effects of natural antioxidants on cyclosporine cytotoxicity in rat renal tubular cells. Nephrol Dial Transplant 2005;20(8):1551-1558.
  41. Hussein SA, Ragab OA, El-Eshmawy MA. Renoprotective effect of dietary fish oil on cyclosporine A: Induced nephrotoxicity in rats. Asian Journal of  Biochemistry 2014;9:71-85.
  42. Ghaznavi R, Zahmatkesh M, Kadkhodaee M, Mahdavi-Mazdeh M. Cyclosporine effects on the antioxidant capacity of rat renal tissues. Transplant Proc 2007;39:866-867.
  43. Antje Albring, Laura Wendt, Nino Harz, Engler H, Wilde B, Witzke O, Schedlowsk M. Short-term treatment with the calcineurin inhibitor cyclosporine A decreases HPA axis activity and plasma noradrenaline levels in healthy male volunteers. Pharmacology Biochemistry and Behavior, 2014; 126: 73–76.


Fetouh FA, Hegazy AA. EFFECT OF CYCLOSPORINE A ON THE KIDNEY OF RABBIT: A LIGHT AND ULTRASTRUCTURAL STUDY. Int J Anat Res 2014;2(4):768-776. DOI: 10.16965/ijar.2014.545

b2



b3




Search

Volume 1 (2013)

Volume 2 (2014)

Submit Manuscript