Sixty consecutive patients received 64 allografts (four double grafts). In all, 17 patients required dialysis and were considered to have DGF. Eight of these patients received marginal organs turned down by at least one other centre. Cold ischaemia time was significantly longer in patients with DGF (24 h vs. 19 h, P < 0.01) All patients were treated as planned and there were no major protocol violations. One patient had primary non-function and was excluded from analysis. CsA trough and Cav values were similar between groups. Mean serum creatinine levels (mg/mL) fell more slowly in patients with DGF but there was no significant difference by 3 months (1.7 vs. 1.5) and the creatinine clearance was not significantly different between the groups after 1 year (71 cm3/min in DGF vs. 61 cm3/min, P = 0.13). Our data demonstrate that alterations in routine immunosuppressive strategies may not be necessary to achieve equivalent outcomes in patients with DGF.
Acute rejection (AR) following transplantation may be due to episodic subtherapeutic cyclosporine (CsA) levels related to diurnal variation of hepatic drug metabolism. We postulated that asymmetrical dosing of CsA based on individualized pharmacokinetic profiles would optimize drug exposure and decrease the risk of AR. We prospectively treated all patients undergoing kidney transplantation with a diurnally split dose of CsA microemulsion given q 12 hours (3.5 mg/kg q a.m., 3.0 mg/kg qPM). Morning doses were adjusted to reach a day-time area under the concentration curve (AUC) of 7,800 ng hour/ml (utilizing 2 hour and 6 hour levels) and evening doses were adjusted to a morning trough of 300 ng/ml. Patients received high-dose steroids tapered to 20 mg prednisone by day 6. CsA was started within 36 hours and mycophenolate mofetil (1000 mg q 12 hour) was added on day 3 in most patients and continued for 3 months. Only one patient received antibody induction. Thirty kidneys (67% cadaveric) were transplanted into 28 adult patients (50% African American, 57% men). Therapeutic targets were reached in all patients prior to discharge and maintained during the study period. At 3 months follow-up, there was not a single episode of documented AR and mean creatinine was 1.5 +/- 0.1 mg/ml. Twelve patients required biopsy for allograft dysfunction; however no histological evidence of AR or CsA-toxicity was identified and the creatinine normalized in each case without altering immunosuppression. Patients continued to require increased CsA doses in the AM compared to the PM (P<0.05) throughout the study to maintain target levels. Diurnal dosing of CsA based on individual pharmacokinetic profiles optimizes CsA exposure and reduces the risk of AR during the first 3 months after transplantation.
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