First Experiences With Kidney Transplantation in a Model of Sensitized Rhesus Macaques

[Background] Sensitized patients comprise up to a third of the kidney waiting list. Preformed and de-novo alloantibody post transplantation (TX) significantly deteriorate graft survival. Currently used desensitization strategies are time-consuming, expensive and moderately effective. To better understand the mechanisms involved in allograft rejection in sensitized patients we aim to establish a rigorous model of solid organ TX in sensitized non-human primates (NHP). [Methods] Fully mismatched rhesus macaques were sensitized with kidney or skin TX. Immunologic responses were monitored by T-cell crossmatch by flow cytometry. After stabilization the animals underwent native nephrectomy and kidney TX from their prior kidney/skin donor. Immunosuppression (IS) included Basiliximab (0.3mg/kg IV day 0,4), Tacrolimus (0.05mg/kg IM BID, trough level 10-15ng/ml) and Mycophenolate mofetil (MMF; 30mg/kg PO BID) combined with tapered methylprednisolone. Assessment comprised laboratory testing, urine output and clinical monitoring. After sacrifice kidney grafts were submitted to pathology for H&E, PAS and C4d staining. Survival results were compared to a group of non-sensitized monkeys with comparable mismatch and IS for 140 days post kidney TX. [Results] 5 monkeys were transplanted. T-cell flow crossmatch showed mean fluorescence intensities between 1.7 and 6.5 fold over baseline on the day of the TX. Survival calculated by Kaplan-Meier method was median 6 days compared to 183 days in the non-sensitized group (p<0.001). All sensitized animals had to be sacrificed due to worsening clinical state and concomitant kidney failure. Histology revealed mixed cellular and humoral rejection in 2/5 grafts, BANFF ACRIIa, C4d1 and ACRIII, C4d2; these had the longest survival, 4 and 8 days respectively. Other grafts showed acute tubular injury/necrosis without signs of rejection. [Conclusion] These results show that kidney TX into sensitized recipients using conventional IS leads to aggressive and rapid mixed rejection. These results support the use of more potent induction therapies, such as T cell depletion, in order to overcome the immune barrier established in sensitized patients. Currently we are optimizing such therapies for the use in NHP. We believe that this preclinical model will be an invaluable tool in the development of novel desensitization therapies.