Effect of Cyclosporine Withdrawal on Apoptotic Cell Death in a Model of Chronic Cyclosporine Nephrotoxicity

Choi, Bum Soon; Kim, Hyung Wook; Yoon, Hye Eun; Kim, Ji Hyun; Sun, Bo Kyung; Im, Sun Woo; Lee, Chan; Yang, Chul Woo; Kim, Yong Soo; Choi, Euy Jin; Chang, Yoon Sik; Bang, Byung Kee

Abstract

BACKGROUND
Cyclosporine (CsA) used in a dual or triple regimen is the current primary immunosuppressant for prevention of renal allograft rejection. Although the introduction of CsA into clinical practice has resulted in a 10 to 15% increase of the 1-year graft survival rate, little has been gained to improve long-term graft survival. Long-term administration of CsA causes a progressive renal failure, a renal striped interstitial fibrosis, a tubular atrophy, and a hyalinosis of the afferent arteriole. Previous studies have shown that apoptotic cell death is increased in CsA-treated kidneys and plays a role in interstitial fibrosis. This study evaluates the effect of CsA withdrawal on CsA nephrotoxicity. METHODS: Sprague-Dawley rats on low-salt diet had been treated with CsA (7.5 mg/kg/day) for five weeks and then CsA had been withdrawn for the next five weeks. The weights, systolic blood pressure, plasma CsA concentration, renal function (serum creatinine, creatinine clearance) and histologic parameter (arteriolopathy, interstitial fibrosis) of the rats were compared. Apoptotic cell death was detected by TUNEL assay. RESULTS: CsA-treated rats showed decreased renal function compared with vehicle (VH) group. With CsA withdrawal, renal function was significantly improved compared with the CsA-treated rats. CsA-treated rats showed increased arteriolopathy and interstitial fibrosis compared with VH group. With CsA withdrawal, renal histology was significantly improved. CsA-treated rats showed increased TUNEL-positive cell compared with VH group. With CsA withdrawal, apoptotic cell death was decreased. Using bivariate correlation analysis, CsA induced apoptotic cell death correlated with arteriolopathy and interstitial fibrosis. CONCIUSION: CsA withdrawal in CsA nephrotoxicity decreased apoptotic cell death and improved renal function and renal histiology. This finding provides a rationale for CsA withdrawal in CsA nephrotoxicity. Further investigation should be directed to explore the effects of the accumulated CsA dose and the timing of CsA withdrawal for regression CsA nephrotoxicity.