Introduction: Simultaneous pancreas-kidney transplantation (SPK) has become the treatment of choice for patients with end-stage renal disease due to Type 1 Diabetes Mellitus. SPK is associated with a relative high rate of acute rejections (AR) compared to kidney transplantation alone. Previously, we showed that a steroid-free regime with Alemtuzumab induction significantly reduced AR rates compared to ATG. Here we investigated time to and risk factors for rejection including inadequate overall immune suppression. In addition, we evaluated whether repopulation with specific alloreactive immune cells is associated with rejection. Methods: 158 SPK recipients were included, and current induction therapy Alemtuzumab (n=73) was compared to historical controls treated with ATG (n=85). Maintenance therapy consisted of Tacrolimus, MMF and, in case of ATG, Prednisone. Data regarding trough levels, immunosuppressive therapy and side effects were collected retrospectively. Peripheral blood was obtained from 30 patients (13 at time of AR,17 controls) for mixed lymphocyte cultures (MLC) and flow cytometric analysis of immune cells. Results: A significant decline in AR rate was seen in the Alemtuzumab group (20.5%) compared to ATG (43.5%). There was no difference in the amount of infections, immunizations or Tacrolimus trough levels between both groups. Within the ATG group 94.6% of the AR occurred within 30 days. In contrast, with Alemtuzumab a biphasic distribution was seen, 20% of the AR occurring within 30 days and 80% after 90 days. In the ATG group, 3 out of 37 patients had inadequate trough levels prior to AR, however in most patients no identifiable cause was found. With Alemtuzumab, most AR (10 out of 15) were related to adjustments of immunosuppressives due to viral infections, leukopenia and gastrointestinal symptoms. Preliminary MLC results in the latter group showed repopulation without a difference in alloimmune reactivity between stable and rejecting patients. Conclusion: In SPK recipients, Alemtuzumab induction significantly reduced AR rates and showed a biphasic distribution. Rejection was attributable to adjustments of immunosuppressives in the majority of the patients. Therefore a reduction in immunosuppressives at the time of repopulation of immune cells must be carefully considered.

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