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From December 1985 to October 1997, 500 simultaneous pancreas-kidney transplants (SPKs) were performed at the University of Wisconsin. Bladder drainage (BD) was used in 388 and enteric drainage (ED) in 112. All pancreas transplants were preserved in UW solution.Patient survival at 1, 5, and 10 years was 96.4%, 88.6%, and 76.3%; kidney function, 88.6%, 80.3%, and 66.6%; and pancreas function, 87.5%, 78.1%, and 67.2%. Thrombosis of the pancreas occurred in three to four (0.6% to 0.8%) and primary nonfunction in one (0.2%). There was a 4.2% acute tubular necrosis rate for the kidney. Conversion from BD to ED was required in 24% of cases. Primary indications for enteric conversion (EC) were leak (14%), urethritis and extravasation (7%), and chronic hematuria (3%). No graft was lost as a result of EC. There was no difference in 1-year graft survival between ED and BD. Leading causes of pancreas loss were rejection in 45 patients and death with a functioning graft in 27 patients. Since June 1995, mycophenolate mofetil was used for immunosuppression(n = 109). One-year survival rates with mycophenolate mofetil are patient, 98.1%; kidney, 94.2%; and pancreas, 93.1%. Steroid-resistant rejections decreased from 48% to 15%.This series represents the world's largest experience with SPK, including the longest follow-up for BD pancreatic transplants. Ten-year graft survival rates exceed those of all other transplants, with the exception of HLA-identical living-related grafts. This series confirms that SPK is a highly successful procedure for selected diabetic patients with renal failure.