Introduction. Xenotransplantation has the potential to alleviate the organ supply shortage, yet pig-to-primate renal xenotransplant has met limited success due to natural preformed anti-pig antibody. Genetically altered pigs lacking expression of xenoantigens, most notably galactose-α1,3-galactose (Gal), have improved outcomes but median survival times remain low. We report long-term survival in pig-to-primate renal transplant using Gal knockout/CD55 transgenic pigs. Methods. Serum samples from Rhesus macaque transplant candidates were incubated with pig GGTA1KO PBMC and stained with anti-human IgM and IgG to measure preformed anti-pig antibody titers. Four primates with the lowest preformed IgG titers and one macaque with the highest were selected for transplantation. Animals underwent bilateral nephrectomy then life-sustaining renal transplant from donor transgenic GGTA1KO/hDAF pigs. Animals were treated with T cell depletion (anti-CD4 and anti-CD8) plus costimulation blockade with either anti-CD154 (n=3) or belatacept (n=2) plus daily MMF/steroids. Post-transplant renal biopsies were submitted for H&E, trichrome, PAS, and Von Kossa staining. Serum creatinine>5mg/dL or BUN>100mg/dL on two consecutive measurements defined clinical rejection. Results. Animals with low anti-pig antibody titers survived longer than the high-titer monkey (MST=90.5 days [n=4]; vs MST=6 days [n=1]; p<0.05). Within the low-titer group, anti-CD154 costimulation blockade prolonged survival more than belatacept (MST=235 days [160 and 310 days, n=2] vs MST=17.5 days [14 and 21 days, n=2]). At rejection, xenografts of long-term survivors showed evidence of AMR with IgG deposition and positive C4d staining. Electron microscopy revealed glomerulopathy in both xenografts, and one long-term survivor developed significant proteinuria. Conclusions. Pre-transplant antibody screening and costimulation blockade promote renal xenograft survival in a pig-to-macaque kidney transplant model. This description of the longest-reported survival, 160 & 310 days, offers important insight into late renal xenograft rejection. Late failure is antibody-mediated and associated with proteinuria. Deletion of additional non-Gal antigens is likely important for avoidance of late AMR.

CITATION INFORMATION: Higginbotham L, Kim S, Mathews D, Stephenson A, Breeden C, Larsen C, Ford M, Newell K, Tector A, Adams A. Late Renal Xenograft Failure Is Antibody-Mediated: Description of the Longest-Reported Survival in Pig-to-Primate Renal Xenotransplantation. Am J Transplant. 2016;16 (suppl 3).

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