Emine DÜNDAR, Mahmut ÖZDEMİR, Yasemin AKTAN, M. İpek CİNGİ, Nilüfer TEL, Ömer ÇOLAK

Siklosporin A nefrotoksisitesine karşı vitamin E' nin etkisi

Siklosporin A (CsA) organ transplantasyonlarında ve otoimmün hastalıkların tedavisinde sıklıkla kullanılan immünosüpresif bir ilaçtır. Nefrotoksik etkisi en ciddi yan tesiridir ve doz kısıtlayıcı özellik gösterir. CsA 'nın preglomerüler arteriyollerde vazokonstriksiyon yaparak nefrotoksisiteye neden olabileceği ileri sürülmüsse de bu yan tesirinin mekanizması halen tam olarak açıklanamamıştır. Vitamin E (Vit E) antioksidan özelliği ile peroksidleri ve serbest oksijen radikallerini nötralize eder. Bu etkisi ile hücre membranını oksidatif zedelenmeye karsı korur. Bu çalışmada CsA nefrotoksisitesine karsı Vit E'nin protektif etkisi araştırıldı. Bu amaçla 3 gruba ayrılan sıçanların (n=7) l. Grubuna serum fizyolojik (i.p.), II.Grubuna 30 mg/kg/gün dozunda CsA (oral), III.Grubuna ise aynı doz CsA ile birlikte 10 mg/kg/gün dozunda Vit E (i.p.) olarak 10 gün süreyle uygulandı. 10.gün sonunda hayvanların 24 saatlik idrarları toplandı, kan örnekleri alındı ve histopatolojik inceleme için böbrekleri çıkarıldı. İdrarda Naf, kreatinin ve ürik asid, plazmada ise bunlara ilave olarak kan üre azotu düzeyleri ölçüldü. Kreatinin klerensi (CICr), fraksiyonel sodyum ekskresyonu (FENa) standart formüller kullanılarak hesaplandı. Sonuçlar ANOVA ve Fisher Tam Olasılık Testi kullanılarak karşılaştırıldı. Biyokimyasal ve histopatolojik incelemeler sonucunda Vit E'nin CsA nefrotoksisitesine karsı protektif etkinlik gösterdiği bulundu.

Effects of vitamin E on cyclosporine A nephrotoxicity

Cyclosporine A (CsA) is the major agent used to immunosuppression. Nephrotoxicity is the most serious side effect of CsA. The pathogenesis of CsA nephrotoxicity is still unclear, however, many experimental studies suggested that nephrotoxicity dependents on preglomerular vasoconstriction. Vitamin E (Vit E) is an antioxidant and free radical scavenger. It may prevent cell membrane from oxidative damage.In this study the [protective ëffectlof Vit E on CsA nephrotoxicity was investigated. Animals were randomly divided into three experimental groups (n=7).' Group I (Control group) received isotonic saline i.p. Group II received CsA (30 mg/kg/day, orally). Vit E (10 mg/kg/day i.p.) and CsA ( 30 mg/kg/day, orally) were administered to the animals in Group III. Kidneys were removed for the histopathological assessment after blood and urine samples of animals were collected at the end of 10 th day. Concentrations of sodium, creatinine, uric acid and urea nitrogen (only plasma) were measured in plasma and urine. Creatinine clerence (CICr) and fractional sodium excretion (FENa) were calculated using standard formulas. ANOVA and Fischer's test were used for statistical analysis. Our results suggest that Vit E has protective effect to CsA nephrotoxicity.

PDF

___

1. Chancerelle Y, De Lorgeil M, Viret R, et al: Increased lipid proxidation in cyclosporin-treated heart transplant recipients . Am J Cardiol 1991, 68:813.
2. Dawidson I, Rooth P, Fry WR, et al: Preventation of acute cyclosporine induced renal blood inhibition and improved immunosuppresion with verapamil. Transplantation 1989, 48:4:575-80.
3. De Lorgeil M, Boissonnat P, Salen P, et al: The beneficial effect of dietary antioxidant supplementation on platelet aggregation and cyclosporine treatment in heart transplant recipients. Transplantation 1994, 58:2:193-95.
4. Dieperink H, Leyssac PP, Starklint H, et al: Nephrotoxicity of cyclosporine A: a lithium clearence and micropuncture study in rats. Eur J Clin Invest 1986, 16:69.
5. Ferrari R, Ceconi C, Curello S, et al: Role of oxygen in myocardial ischaemic and reperfusion damage:effect of alfa-tocopherol. Acta Vitaminol Enzymol 1985, 7Suppl:61-70.
6. Kunisaki M, Umeda F, Inoguchi T, et al: Vitamin E binds to spsific binding sites and enhances prostacyclin production by cultured aortic endotelial cells. Thromb Haemost 1992, 68:774.
7. MaCay PB, King MM: Vitamin E: Its role as a biological free radical scavenger and its relationship to the microsomal mixed-function oxidase system. Vitamin E, New York, 1980, Marcel Dekker Inc, pp:289-317.
8. Marubayashi S, Dohi K, Ochi K, et al: Role of the free radicals in ischemic rat liver cell injury: preventation of damage by α-tocopherol administration. Surgery 1986, 99:2:184-191.
9. Mason J, Welsch J, Torhorst J: The contribution of vascular obstruction to the functional defect that follows renal ischemia. Kidney Int 1987, 31:65-71.
10. Murray BM, Paller MS, Ferris TF: Effects of CsA administration on renal hemodynamic in conscious rats. Kidney Int 1985, 28:767-74.
11. Nussenblatt RB, Palestine AG: Cyclosporine immunology, pharmacology and therapeutic uses. Surv Ophthalmol 1986, 31:159.
12. Orugun EO, Smart LM, Whiting PH: The effect of calcium blockade with verapamil on experimental cyclosporine nephrotoxicity. Transplant Proc 1991, 23:1:354-5.
13. Pascoe GA, Reed DJ: Cell calcium, vitamin E and the thiol redox system in cytotoxicity. Free Radical Biology and Medicine 1989, 6:209-24.
14. Salducci MD, Chauvet-Monges AM, Berland Y, et al: The restoration of ATP synthesis may explain in protective effect of calcium antagonists against Cyclosporine A nephrotoxicity. Life Sciences 1992, 50:2053-58.
15. Slakey D, Roza G, Johnson C, et al: Ascorcic acid and α-tocopherol prolong rat cardiac allograft survival. Transplant Proc 1993, 25:1:610-11.
16. Strzelecki T, Kumar S, Khaulý R, et al: Impairment by cyclosporine of membrane-mediated functions in kidney mitochondria. Kidney Int 1988, 34:234-240.
17. Takenaka M, Tatsukawa Y, Dohi K, et al: Protective effect of α-tocopherol and coenzyme 010 on warm ishchemic damages of the rat kidney.