International Journal of Anatomy and Research, Int J Anat ... · research on CsA nephrotoxicity in...

Int J Anat Res 2014, 2(4):768-76. ISSN 2321-4287 768

Original Article

EFFECT OF CYCLOSPORINE A ON THE KIDNEY OF RABBIT: A LIGHTAND ULTRASTRUCTURAL STUDYFathy Ahmed Fetouh, Abdelmonem Awad Hegazy*.

ABSTRACT

Address for Correspondence: Dr. Abdelmonem Hegazy (M.D.), Associate Professor, Anatomy andEmbryology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt.E-Mail: [email protected], [email protected]

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

Background: Nephrotoxicity is a relatively common problem in patients immunosuppressed with cyclosporineA (CsA) with an incidence reaching up to thirty percent. The present work aimed to study the histological andultrastructural 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). Onegroup was used as a control and the other group (experimental) was treated with CsA in a dose of 15 mg/kg ofbody weight for two weeks. The animals were anaesthetized; and kidney specimens were obtained, fixed andprocessed for light and electron microscopic examinations.Results: CsA had adverse effects on the kidney especially renal corpuscles, proximal convoluted tubules, distalconvoluted tubules and afferent glomerular arterioles. The renal corpuscles were observed with shrunkenglomeruli, widening of Bowman’s space and thickening of the Bowman’s capsule. Also, there was obviousincrease in mesangial cell number and overall glomerular obliteration due to large lining endothelial cells andencroachment of the mesangial cell matrix onto the capillary lumen. The renal tubules showed vacuolizationand PAS positive inclusion bodies. The cells showed disordered brush border of microvilli. Many fibrocytesappeared inbetween the tubules. Peritubular capillary congestion was observed with an increase in thesurrounding connective tissue. Ultrastructurally, the proximal convoluted tubules showed thick basementmembrane with loss of the basal infolding. The mitochondria appeared degenerated with damaged transversecristae. Electron dense lysosomes were seen in the cytoplasm. In distal convoluted tubules, the cells showeddegenerated mitochondria and pyknotic nuclei. The afferent glomerular arterioles appeared with hyperplasiaof juxtaglomerular cells that contained massive renin granules. The lining endothelial cells appeared protrudingtheir 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.

INTRODUCTION

International Journal of Anatomy and Research,Int J Anat Res 2014, Vol 2(4):768-76. ISSN 2321- 4287

DOI: 10.16965/ijar.2014.545

Received: 24 Nov 2014Peer Review: 24 Nov 2014 Published (O):31 Dec 2014Accepted: 09 Dec 2014 Published (P):31 Dec 2014

International Journal of Anatomy and ResearchISSN 2321-4287

www.ijmhr.org/ijar.htm

DOI: 10.16965/ijar.2014.545

Since its introduction in 1976, cyclosporine A(CsA) has markedly improved the survival of solidtransplants and has also been beneficial for thetreatment of autoimmune diseases [1]. Cyclos-

porine A, a neutral lipophilic cyclicundecapeptide isolated from the fungusTolypocladium inflatum gams. This moleculeexerted a rather wide spectrum of biologicactivities, including antiparasitic, fungicidal and

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Fetouh FA, Hegazy AA. EFFECT OF CYCLOSPORINE A ON THE KIDNEY OF RABBIT: A LIGHT AND ULTRASTRUCTURAL STUDY.

MATERIALS AND METHODS

Animals: Ten adult male Egyptian (Gabali)rabbits weighing 1.5-2 kg were used in this study.The animals were maintained in cages with foodand water ad libitum under controlled conditionsof light, humidity and temperature. They wereobtained from Animal House Colony of Facultyof Medicine, Zagazig University. Allexperimental procedures were conducted inaccordance with the guide for the care and useof laboratory animals and in accordance withthe local Animal Care and Use Committee.Chemicals: Cyclosporine A used in the presentstudy was in the form of oral solution(Sandimmum Neoral 100 mg/ml) and given tothe animals in a distilled water by gavage using

anti-inflammatory effects. It was subsequentlydiscovered to be a powerful immunosuppressiveagent [2]. The immunosuppressive properties ofCsA allowed its utilization in several diseasessuch as uveitis, rheumatoid arthritis, nephroticsyndromes and others [3, 4]. However, thebenefits of cyclosporine A therapy have beenpotentially offset by the occurrence of nephro-toxicity. CsA nephrotoxicity which has beenreported since the early 1980s occurs even whenlow doses of the drug are used in the treatmentof autoimmune diseases [1]. Also, in the sittingof cardiac transplantation, CsA nephrotoxicityhas been related to the development of end-stage renal failure in about 10 % of patients [5].CsA nephrotoxicity is classified into two majorcategories: functional and structural. The func-tional is the consequence of vasoconstriction ofthe afferent arteriole, the structural lesion,affecting the afferent arteriole, glomerulus andtubule-interstitium [6]. Acute CsA nephrotoxic-ity occurs early after initiation of therapy andpresents clinically with a transient elevation ofthe serum creatinine and arterial hypertensionin the majority of cases [7]. Experimentalresearch on CsA nephrotoxicity in rabbit is farless frequent than in the rat [8]. One study inNew Zealand rabbits revealed morphologicalchanges similar to those seen in man [9]. Thepresent work aimed to study toxic effects ofcyclosporine A on the structures of the kidneyunder light and electron microscopic investiga-tion in rabbit.

sterile equipments. CsA was administered in adose of 15 mg/kg of body weight for 2 weeksaccording to Rezzani [10] who stated that dailyadministration of CsA ranging from 15 to 25mg/kg was well tolerated and showed immuno-suppressive effects like those observed intransplant patients; and also found that chronicCsA nephrotoxicity occurs as early as 2 weeksafter treatment.Experimental design: The rabbits were dividedinto two groups (five rabbits for each) and treatedas follows: the first group served as controlgroup and received distilled water; the secondgroup animal (CsA-treated rabbits) were dailyadministered 15 mg/kg of body weight for 2weeks. 24 hours after the last dose, the animalswere anaesthetized by intra-abdominal injectionof thiopental. A midline abdominal incision wasperformed and the kidneys were dissected outand processed for light and electron microscopicexamination.For light microscopic examination, the kidneyswere fixed in 10% neutral formol-saline for 24hours and were processed to prepare 5 micronthick paraffin sections. Paraffin sections werestained with periodic-acid Schiff (PAS) whichstains basal lamina and the brush border of theproximal convoluted tubules and also positivefor the granules of the juxtaglomerular cells[11,12] and the cytoplasmic lysosome-proteinbodies in the proximal convoluted tubules [13].Also, the sections were stained with Massontrichrome which stains the brush border (green)[14].For electron microscopic examination, the cortexwas cut into small pieces and immediately fixedin 2.5% glutaraldehyde buffered with 0.1Mphosphate buffer at PH 7.4 for 2 hours at 4Co

and then washed with the phosphate buffer,post-fixed in 1% osmium tetraoxide in the samebuffer for one hour at 4 Co. After washing inphosphate buffer, specimens were dehydratedwith ascending grades of ethanol and then wereput in propylene oxide for 30 minutes at roomtemperature, impregnated in a mixture ofpropylene oxide and resin (1:1) for 24 hours andin a pure resin for another 24 hours. Then, thespecimens were embedded in Embed-812 resinin BEEM capsules at 60Co for 24 hours. Semi-thin sections of about one micron thick were


obtained by glass knives and stained with 1%toluidine blue and examined by light microscopy.Ultrathin sections of about 50-70nm thick werecut using diamond knives and mounted on acopper grids, stained with uranyle acetate andlead citrate [15,16].The sections were examined using a JEOL JEM1010 transmission electron microscope inHistology Department, Faculty of Medicine,Zagazig University and also, SEO model PEMtransmission electron microscope in MilitaryMedical Academy.

RESULTS

In control animals, the renal cortex examinedby the light microscopy showed renalcorpuscles, proximal convoluted tubules, distalconvoluted tubules and afferent arterioles. Theproximal tubules had large cuboidal cells withlarge round nuclei and prominent nucleoli. Thelumen was filled with brush border formed bymicrovilli. The distal tubules had a wide lumendue to absence of the brush border (Figs. 1-5).The afferent arterioles appeared near the renalcorpuscles with juxtaglomerular cells in theirwalls (Figs. 4,5).By electron microscopic examination, the cellsof proximal convoluted tubules showednumerous basal infoldings which were seenextending into the cytoplasm with interveningmitochondria. The mitochondria were foundnumerous, elongated and distributed all over thecytoplasm, mostly at the base. Some vesicleswere seen near the apex. The nucleus was ovaland regular in shape. The apical border showedan extensive amount of microvilli (Fig. 6). Thedistal convoluted tubules showed numerousmitochondria and the lumen showed scantymicrovilli (Fig. 7). The renal corpuscles showedglomerular capillaries, podocytes and mesangialcells. The capillaries appeared with wide lumenscontaining red blood cells. The podocytesappeared near the capillaries with their pedicles(processes) grasping the capillaries. Themesangial cells were seen in-between thecapillary lumens (Figs. 8-10). The afferentarteriole appeared with its lumen containing redblood cells and lined by endothelial cells.

An internal elastic lamina appeared above theendothelial cells followed by smooth musclecells (Fig. 11).In treated animals with CsA, light microscopyexamination showed the proximal convolutedtubules, distal convoluted tubules, renalcorpuscles, and afferent arterioles. The renaltubules showed vacuolization and PAS positiveinclusion bodies. The nuclei of the liningepithelial cells of the proximal convolutedtubules were generally reduced in size and someappeared pyknotic. The cells showed disorderedbrush border of microvilli. Many fibrocytesappeared in-between the tubules. Peritubularcapillary congestion was observed with increaseof the surrounding connective tissue formation(Fig.12-15). The renal corpuscles were observedwith shrunken glomeruli, widening of Bowman’sspace and thickening of the Bowman’s capsule(Fig. 14). The afferent glomerular arteriolesappeared with hyperplasia of juxtaglomerularcells that contained massive renin granules (Figs.15,16).By electron microscopic examination, the cellsof the proximal convoluted tubules showed thickbasement membrane with loss of basal infoldingand decrease in number of mitochondria. Themitochondria appeared degenerated withdamaged transverse cristae. Electron denselysosomes were seen in the cytoplasm.Numerous and large vacuoles appeared near theapex (Fig. 17). In distal convoluted tubules, thecells showed degenerated mitochondria andpyknotic nuclei. In some cells, the damagedmitochondria appeared in addition to normalmitochondria. The damaged mitochondriaappeared swollen and even some appearedvacuolated (Figs. 18,19). The renal corpuscleswere observed with evident increase inmesangial cell number that were seeninterposited between the capillaries andpodocytes. There was an overall glomerularobliteration due to large lining endothelial cellsand encroachment of the mesangial cell matrixonto the capillary lumen. Thick basementmembrane of the capillary was observed (Figs.20,21). The afferent arteriole was observed withlining endothelial cells that appeared protrudingtheir nuclei into the lumen due to contraction ofthe smooth muscles (Fig. 22).




Fig. 1: A photomicrograph of a sectionin the renal cortex of control rabbitshowing normal kidney structures;proximal convoluted tubules (p),distal convoluted tubules (d), renalcorpuscles (rc) and afferent arteriole(aa). (PAS X 200).

Fig. 2: A photomicrograph of asection in the renal cortex of controlrabbit showing normal kidney struc-tures; the proximal convolutedtubules (p) appear in longitudinaland cross sections with luminalbrush border (green color), renal cor-puscles (rc) and afferent arteriole(aa). (Masson trichrome X200).

Fig. 3: A photomicrograph of a sec-tion with higher magnification in therenal cortex of control rabbit show-ing the proximal convoluted tubuleswith their epithelial cells are cov-ered with a brush border (bb) ofdense microvilli (stained green).(Masson trichrome X400).

Fig. 4: A photomicrograph of a semi-thin section in the renal cortex ofcontrol rabbit. It shows renalcorpuscles (rc), proximal (P) anddistal (d) convoluted tubules. Theproximal tubules have largecuboidal cells with large roundnuclei and prominent nucleoli. Thelumen is filled with the brush border(bb) formed by the microvilli. Afferentarterioles (aa) appear near thecorpuscles with juxtaglomerular cells(jgc) in their walls. (Toluidine blueX400).

Fig. 5: A photomicrograph of a highermagnification of the previous figure.It shows part of renal corpuscles (rc),proximal (p) and distal (d) convo-luted tubules. The proximal tubuleshave large cuboidal cells with largeround nuclei and prominentnucleoli. The lumen is filled withthe brush border (bb) formed by themicrovilli. Afferent arteriole (aa)appears near by the corpuscle withjuxtaglomerular cells (jgc) in theirwalls. (Toluidine blue X1000).

Fig. 6: An electron photomicrographof ultrathin section in the renal cor-tex of control rabbit showing part ofthe proximal convoluted tubule in atransverse section. Numerous basalinfoldings (arrows) are seen extend-ing into the cytoplasm with interven-ing mitochondria (M). The mitochon-dria appear numerous, elongatedand distributed mostly at the base.Some vesicles (V) are seen near theapex. The nucleus (N) is oval andregular in shape. The apical bordershows extensive amount of microvilli(MV). (X 3000).

Fig. 7: An electron photomicrographof ultrathin section in the renal cor-tex of control rabbit showing distalconvoluted tubule in a transversesection. The lining cells show numer-ous mitochondria (M). The lumen (L)shows scanty microvilli (arrow). (X3000).

Fig. 8: An electron photomicrographof ultrathin section in the renal cor-tex of control rabbit showing part ofrenal corpuscle where the glomeru-lar capillaries (GC) appear lined byendothelial cell (EC) and contain redblood cells (RBC). 2 podocytes (P) withtheir nuclei (N) appear extendingtheir processes into the neighboringcapillaries in one side and relatedto the Bowman’s space (BC) at theother side. (× 4000)

Fig. 9: An electron photomicrographof a higher magnification of the pre-vious figure showing one podocyte(P) extending pedicles (PD) to theouter surface of the glomerularcapillary. Filtration slits (FS) appearin-between the pedicles. The glom-erular capillary shows the basementmembrane (BM) lined by fenestratedendothelium (arrows). (× 10000)


Fig. 10: An electron photomicrographof another higher magnificationshowing one mesangial cell (MC) in-between 2 capillary lumens (CL). Thecapillary lumen appears wide andcontains red blood cells (RBC) withpedicles (PD) of podocyte (P) reach-ing to the capillary. (× 8000)

Fig. 11: An electron photomicrographof ultrathin section in the renal cor-tex of control rabbit showing part ofthe wall in afferent arteriole. Thelumen (L) contains red blood cells(RBC) and lined by endothelial cell(EC). An internal elastic lamina (IEL)appears above the endothelial cellfo llowed by smooth muscle cells(SM). (× 6000)

Fig. 12: A photomicrograph of a sec-tion in the renal cortex of CsA treatedrabbit. The renal tubules show vacu-olization (v) and PAS positive inclu-sion bodies (arrows). (PAS X 400)

Fig. 13: A photomicrograph of a sec-tion in the renal cortex of CsA treatedrabbit showing peritubular capillarycongestion (cc) and increase in thesurrounding connective tissue for-mation (arrows). (Masson trichromeX200).

Fig. 14: A photomicrograph of a sec-tion in the renal cortex of CsA treatedrabbit showing the proximal convo-luted tubules (P) with disorderedbrush border (bb) of microvilli(stained green). The renal cor-puscles contain shrunken glomeruli(g) with widening of the Bowman’sspace (Bs) and thickening ofBowman’s capsule (arrow). (Massontrichrome X400).

Fig. 15: A photomicrograph of a semi-thin section in the renal cortex of CsAtreated rabbit showing renalcorpuscles (rc) with reduced capillarylumens of the glomerulus. Thenuclei of the lining epithelial cellsof the proximal tubules are generallyreduced in size and some appearpyknotic (arrow). Many fibrocytes(double headed arrows) appear in-between the tubules. Afferentglomerular arterioles (aa) appearwith narrow lumens and hyperplasiaof juxtaglomerular cells (jgc) withrenin granules (r) in their walls areseen. (Toluidine blue X400).

Fig. 16: A photomicrograph of a highermagnification of a semi-thin sectionin the renal cortex of CsA treatedrabbit. Afferent glomerular arteri-oles (aa) appear with hyperplasia ofjuxtaglomerular cells (jgc) containingmassive renin granules (r) in theirwalls. (Toluidine blue X1000).

Fig. 17: An electron photomicrograph of ultrathinsection in the renal cortex of CsA treated rabbitshowing one of the epithelial cells of the proximalconvoluted tubule. The cell shows thick basementmembrane (bm) with loss of the basal infoldings withdecrease in the number of mitochondria. Themitochondria (M) appear degenerated with damagedtransverse cristae. Electron-dense lysosomes (ly) areseen in the cytoplasm. Numerous and large vacuoles(v) appear near the apex. (X 9000)

Fig. 18: An electron photomicrographof ultrathin section in the renal cor-tex of CsA treated rabbit showing oneof the epithelial cells of the distalconvoluted tubule. The cell showsdegenerated mitochondria (M) andpyknotic nucleus (N). (X 12000).



Fig. 19: An electron photomicrographof ultrathin section in the renal cor-tex of CsA treated rabbit showing dis-tal convoluted tubule with its lumen(L) in a transverse section. The lin-ing cells show damaged mitochon-dria (M1) in addition to normal mi-tochondria (M2). The damaged mito-chondria are swollen with loss oftransverse cristae and even someappear vacuolated. Two of the nu-clei (N) appear irregular and py-knotic. (×3000)

Fig. 20: An electron photomicrographof ultrathin section in the renal cor-tex of CsA treated rabbit showing partof renal corpuscle where there is anevident increase in mesangial cellnumber (MC) interposited betweenthe capillaries and the podocytes(P). There is an overall glomerularobliteration due to narrowing of thecapillary lumen (CL), large lining en-dothelial cells (EC) and encroach-ment of the mesangial cells. Thenuclei (N) are heterochromatic anddarkly stained. (× 4000)

Fig. 21: An electron photomicrographof a higher magnification of the pre-vious figure showing one mesangialcell (MC) and surrounding matrix en-croaching onto the nearby capillarylumen (CL). The capillary lumen ap-pears narrow with large lining en-dothelial cell (EC) and thick base-ment membrane (arrow). (× 10000)

Fig. 22: An electron photomicrograph of ultrathin sec-tion in the renal cortex of CsA treated rabbit showingpart of the wall of afferent arteriole surrounding a lu-men (L). The lining endothelial cells (EC) appear pro-tracting their nuclei (N) into the lumen due to contrac-tion of the smooth muscles (SM). (× 6000)

DISCUSSION

In the present study, treatment with CsAadversely affected the structure of the kidneymainly the tubular epithelium, renal corpuscles,and afferent arterioles. The proximal convolutedtubules revealed vacuolization and PAS positiveinclusion bodies and some nuclei appearedpyknotic with disordered brush border ofmicrovilli. Ultrastructurally, thick basementmembrane with loss of basal infolding wasobserved and the mitochondria appeared degen-erated with damaged transverse cristae. Inaddition, electron dense lysosomes were seen

in the cytoplasm. This is in accordance withRezzani [10], and Pour et al. [17] who observedacute tubular changes in the form of loss of brushborders, presence of inclusion bodies andisometric vacuolization, which are usuallyobserved in proximal tubules as early as 4 daysafter treatment with CsA. Alden and Frith [18]found that vacuolization may represent aninitial stage preceding cell degeneration. Also,Abdel Fattah et al. [19] found that, CsA treatedgroup showed renal tubules with vacuolatedcytoplasm and others with darkly stainedpyknotic nuclei. Apical brush borders of proxi-mal tubules were undefined and PAS positivegranules were noticed in their cytoplasm. Clarkeand Ryan [20] found that the proximal tubularepithelia of CsA-treated animals were seen tohave considerable damage to the mitochondria,including swelling and rounding of theseorganelles with dissolution of their cristae.There were increased levels of vacuolizationwith vacuoles of various sizes being present inCsA treated cells. Damage to the brush borderof the cells was widely observed. Structurally,Owen [21] investigated the intracytoplasmicinclusions and suggested that they may repre-sent myeloid bodies, giant mitochondria, orproliferation of smooth endoplasmic reticulum,usually involving the epithelium of proximaltubules. Also, Dell’Antonio and Randhawa [22]



found that, the inclusion bodies in the tubularcells were corresponding to giant mitochondriaand microcalcification. In chronic CsA treatment,Agnieszka et al. [23] found that tubular epithe-lium cells revealed dilatation of endoplasmicreticulum, injury to mitochondria, formation ofautolysosomes and presence of single apoptoticcells.In the present study, many fibrocytes appearedin-between the tubules. Peritubular capillarycongestion was observed with increase ofsurrounding connective tissue formation. Thisis in agreement with Rezzani [10] whomentioned that chronic CsA nephrotoxicity leadsto interstitial fibrosis, tubular atrophy, andarteriolar hyalinosis. Ghiggeri et al. [24] foundthat very low concentration of CsA inducedcollagen synthesis in a variety of cultured humanand rat renal fibroblasts. Also, Abdel Fattah etal. [19] found that inflammatory cellular infiltratewith increase in the collagen fibers wereobserved between the renal tubules. Manyauthors explained the increased fibrosis in CsAtreatment. Johnson et al. [25] found that in vitroexperiments with renal resident cells derivedfrom rodents, primates and humans have shownthat, CsA stimulates the production of collagen.Paul and de Fijter [26] found that CsA exerts renaltubular toxicity by local induction of vasoactiveand chemotactic mediators that are secretedtowards the baso-lateral compartment wherethey may induce interstitial inflammation andfibrosis. On the other hand, CsA may directlydamage renal cells and induces cell death andsubsequent fibrosis [27,28]In the present study, the renal corpuscles wereobserved with shrunken glomeruli, widening ofBowman’s space and thickening of Bowman’scapsule. Ultrastructurally, there was an overallglomerular obliteration which was mostly dueto large lining endothelial cells and encroach-ment of the mesangial cell matrix onto thecapillary lumen. Thick basement membrane ofthe capillaries was observed. This is inagreement with Abdel Fattah et al. [19] whofound that in CsA treated group, the renalcorpuscles contained shrunken glomeruli withwidening of their Bowman’s space. Also,Ghiggeri et al. [24] found that CsA increasescollagen synthesis in a variety of cultured human

and rat renal mesangial cells, Rezzani [10]observed focal glomerular scaring in chronic CsAnephrotoxicity.In the present study, the afferent glomerulararterioles appeared with hyperplasia ofjuxtaglomerular cells that contained a massiveamount of renin granules. Ultrastructurally, theafferent arteriole was observed with liningendothelial cells that appeared protruding theirnuclei into the lumen due to contraction of thesmooth muscles. This is in accordance with otherauthors who observed that CsA treatmentresults in extreme hyperplasia of thejuxtaglomerular cells along the afferentarterioles [26,29]. Also, many researchers haveshown a change in vascular flow with a decreasediameter of the afferent arteriole andprogressive narrowing with CsA treatment [30-32]. CsA is capable of inducing a strongvasoconstriction in the afferent arteriole [30],which is mainly mediated by a rise inangiotensins secretion [33] and this would bethe main mechanism of CsA inducednephrotoxicity [34,35].The true aetiology of acute arterial effects hasyet to be clearly established. It is thought to bemultifactorial, resulting from a combination ofan increase in vasoconstrictive factors(endothelin and thromboxane), activation of therenin-angiotensin-aldosterone system (RAAS),reduction of vasodilator factors (nitric oxide andprostacycline), and formation of free radicals[32,36,37]. Activation of RAAS system withcalcineurin inhibitors involves both direct andindirect mechanisms. Directly, calcineurininhibitors can activate juxtaglomerular cells torelease renin. Indirectly, they can cause reninrelease from decreased perfusion as a result ofarteriolar vasoconstriction [36-38].Radical oxygen species (ROS) and lipidperoxidation have been involved in CsA inducednephrotoxicity by many researchers. CsAtherapy causes dose and time relateddeterioration of kidney functions. The mechanismof effect is associated with increase in ROS,thromboxane secretion and also decrease ofglomereular filtration rate with ROS,throm-boxane and lipid peroxidates overproduction [39,40]. CsA administration inducedsignificant elevation in lipid peroxidation along



with elevation in lipid peroxidation along withsignificant decrease in antioxidant enzymeactivities, non enzymatic antioxidant, totalantioxidant capacity and nitric oxide level in therat kidney [41,42]. Also, treatment with CsA wasfound to significantly reduce plasmaconcentrations of adrenocorticotropic hormone(ACTH), cortisol, and noradrenaline [43].CONCLUSIONIt could be concluded that CsA had adversestructural effects on the kidney mainly on thenephron; renal corpuscles, proximal convolutedtubules, distal convoluted tubules and afferentglomerular arterioles. Defective renal functionshould always be a concern in the managementof CsA treated patient. Further studies areneeded to clarify more about the exact mecha-nisms of CsA nephrotoxicity.AcknowledgmentsNo funding was provided. We acknowledgeScientific and medical research center ‘ZSMRC’of Zagazig Faculty of Medicine for its support.

Conflicts of Interests: None

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How to cite this article:Fetouh FA, Hegazy AA. EFFECT OF CYCLOSPORINE A ON THEKIDNEY OF RABBIT: A LIGHT AND ULTRASTRUCTURAL STUDY. IntJ Anat Res 2014;2(4):768-776. DOI: 10.16965/ijar.2014.545

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