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Background: Cyclosporine A (CsA) is an immunosuppressive drug which has been widely used to prevent rejection after organ transplantation. However, its therapeutic use is limited by nephrotoxicity, in part mediated by oxidative stress. The present study aims to investigate the protective effects of dimethyl fumarate (DMF) on CsA-induced nephrotoxicity by enhancing the antioxidant defense system., Methods: Male Sprague-Dawley rats were treated with CsA (n = 8, 20 mg/kg per day intraperitoneally) or CsA + DMF (n = 7, 50 mg/kg per day orally) for 28 days. Renal function, histopathology, malondialdehyde (MDA), myeloperoxidase levels, and antioxidant enzyme expression were determined., Results: The DMF cotreatment ameliorated CsA-induced renal dysfunction as evidenced by significant decrease in serum creatinine (CsA 0.79 ± 0.02 mg/dL vs CsA + DMF 0.62 ± 0.04 mg/dL, P = 0.001) and urea (CsA 66.9 ± 0.4 mg/dL vs CsA + DMF 53.3 ± 2.6 mg/dl, P < 0.0001) levels, as well as improvement of creatinine clearance. Dimethyl fumarate also significantly decreased serum MDA and renal tissue MDA and myeloperoxidase contents. The protein expression of NAD(P)H quinone oxidoreductase-1, a major cellular antioxidant and detoxifying enzyme, was significantly enhanced by DMF administration in kidney., Conclusions: Administration of DMF has a protective potential against CsA nephrotoxicity. The protection afforded by DMF is mediated in part through inhibiting oxidative stress and inflammation and enhancing the antioxidant capacity.

Background: Porcine islet xenotransplantation has been demonstrated in many animal studies to cure experimentally induced diabetes. However, several issues currently impede the translation of porcine islet xenotransplantation to sustained insulin independence clinically. Although adult pigs have mature islets that secrete insulin in response to a glucose challenge, and are physiologically similar to humans, there are logistical considerations with adult porcine tissue that are not present with juvenile porcine tissue. To circumvent these issues, we have identified 18- to 21-day-old preweaned juvenile pigs as islet donors as we have previously demonstrated superior islet yields and function from juvenile pigs using our islet isolation protocols., Methods: We evaluated the efficacy of islets isolated from 18- to 24-day-old Yorkshire swine in vitro using a standard glucose-stimulated insulin response assay, and in vivo after xenotransplantation under the kidney capsule of streptozotocin-induced 8- to 10-week-old male athymic nude mice. The mice were monitored for a period of 60 days after transplantation, after which the grafts were explanted and analyzed., Results: Diabetic athymic nude mice transplanted with 1500 to 3000 islet equivalents (IEq) of islets achieved sustained normoglycemia for up to 60 days after islet transplantation. When the grafts were explanted with the kidney, a rapid return to hyperglycemia was observed., Conclusions: Efficacy and dose-titration studies evaluating these islets in immunocompetent and nonobese diabetic mouse models are underway. The results of these studies will permit application for nonhuman primate and pivotal clinical trials in human diabetic patients in the near future.

Background: Transplantation of solitary pediatric renal allografts from donors 2 years of age or younger into adult recipients is controversial., Methods: Between 1998 and 2001, 15 solitary renal allografts from pediatric donors 2 years of age or younger were transplanted into adult recipients. Thirty-three en bloc renal allografts transplanted between 1994 and 2001 were used for comparison. En bloc kidneys were considered for separation if they measured greater than or equal to 6 cm in length. Renal function (creatinine clearance [CrCl]) was estimated using the Cockroft-Gault formula., Results: Two-year graft survival for the solitary and en bloc groups were 93% and 77%, respectively (P =0.405). Five grafts were lost because of arterial thrombosis (four en bloc and one solitary). Ureteral complications occurred in three grafts in the en bloc group. One-year postoperative CrCl of the surviving solitary (n=14) and en bloc (n=26) grafts were 51.4+/-26.2 mL/min and 55.1+/-27.5 mL/min (P >0.05), respectively. Donor weight and kidney length were greater in the solitary group (14.3+/-3.5 kg and 6.3+/-0.4 cm, respectively) compared with the en bloc group (10.8+/-2.6 kg and 5.9+/-0.3 cm, respectively) (P =0.001 and P <0.001)., Conclusions: Separation of en bloc pairs into solitary allografts can be considered when the graft measures greater than or equal to 6 cm in length and donor weight is greater than or equal to 14 kg. The transplantation of solitary pediatric kidneys into adult recipients is successful, and the majority of pediatric en bloc allografts can be separated before transplantation.