JOURNAL OF SURGICAL RESEARCH 51, 341-343 (19%) Effect of Timing of Cyclosporine Administration on Recovery from Renal lschemia in Rats’ ZHONGKUN DING, NABIL SUMRANI,~ AND JOON H. HONG State University of New York Health Science Center at Brooklyn, Brooklyn, New York 11203 Submitted for publication August 27, 1990 The effect of timing of cyclosporine administration on functional recovery from renal ischemia was studied in Sprague-Dawley rats. Animals were given cyclo- sporine and subjected to renal ischemia by temporarily occluding both the renal artery and vein. Our data dem- onstrate no significant difference in serum creatinine among rats subjected to renal ischemia, cyclosporine, or cyclosporine-vehicle cremophor EL administration, or the control group. On the other hand, renal ischemia in combination with cyclosporine resulted in rapid and marked deterioration in renal function with serum cre- atinine peaking on Day 2. The most significant rise was in rats that received cyclosporine 4 hr prior to induc- tion of renal ischemia (4.7 ? 0.5 mg/dl), followed by those that received cyclosporine 4 and 24 hr postisch- emia (2.8 +_0.5 and 3.2 +_0.7 mg/dl, respectively). Cy- closporine administration 24 hr prior to renal ischemia resulted in the least elevation of the serum creatinine (2.1 f 0.5 mg/dl) and the earliest return to the baseline value. Our data suggest that the timing of cyclosporine administration in rats subjected to renal ischemia influ- ences the extent of renal injury and the subsequent re- covery of renal function. 0 1991 Academic PESS, k. Cyclosporine (CyA) is a very potent and effective im- munosuppressive agent in the prevention of rejection in solid organ transplantation [ 1,2]. Its nephrotoxicity is a serious and well-documented side effect and can be a major factor in determining the outcome of renal trans- plants 131. It is generally understood that allografts im- paired by both ischemia and rejection are more suscepti- ble to CyA toxicity. Several investigators [4,5] reported higher rates of prolonged allograft dysfunction among cadaver donor renal allograft recipients treated with i This work was supported by a grant from The Foundation For Surgical Education and Investigation, State University of New York, Brooklyn, NY. * To whom reprint requests should be addressed at Transplantation Division, Department of Surgery, State University of New York Health Science Center at Brooklyn, 450 Clarkson Ave., Box 40, Brooklyn, NY 11203. CyA compared to those treated with azathioprine or anti-lymphocyte globulin preparations, with delayed graft function adversely influencing ultimate graft func- tion. Less information is available regarding renal func- tion relative to the timing of CyA administration. We thus studied the effect of timing of CyA administration on renal function of ischemically injured kidneys in rats and the patterns of subsequent recovery. MATERIALS AND METHODS Adult male Sprague-Dawley rats (Harlan, Madison, WI) weighing between 200 and 250 g were maintained on rat chow and tap water ad lib. Rats were anesthetized initially with ether inhalation followed by pentobarbital (30 mg/kg) intraperitoneally (ip). A midline abdominal incision was made. All rats underwent right nephrec- tomy. Studies were performed during two experimental pe- riods as follows: Group I (control rats, N = 5), the left kidney was mobilized and the abdomen closed; Group II (N = 5), the left renal artery and vein were identified and clamped with tight vascular clips for 60 min, thus stop- ping all renal blood flow; Group III (N = 5), left kidney was mobilized and cyclosporine-vehicle cremophor EL (Sandoz Pharmaceuticals, East Hanover, NJ) (325 mg/ kg) was administered ip immediately after closure of the abdomen; and Group IV (N = 6), left kidney was mobi- lized and CyA (25 mg/kg) was given ip immediately after closure of the abdomen. In the second period, all rats were subjected to renal ischemia by temporarily occlud- ing both left renal artery and vein for 60 min and re- ceived one dose of CyA (25 mg/kg ip) as follows: Group A (N = lo), CyA was given 24 hr before renal ischemia; Group B (N = lo), CyA was given 4 hr prior to renal ischemia; Group C (N = 13), CyA was given 4 hr after renal ischemia; and Group D (N = ll), CyA was given 24 hr after renal ischemia. Rats were kept in metabolic cages with fluid intake ad Zibitum and fed with Purina rat chow. Serum creatinine concentration was measured from blood samples obtained from tail veins on postoper- ative Days 0,2,5, and 10 in order to assess the extent of renal injury and subsequent recovery of renal function. 341 0022-4So4/91 $1.50 Copyright 0 1991 by Academic Press, Inc. All rights of reproduction in any form reserved.