Thomas E. Starzl Transplantation Institute, University of Pittsburgh
Factors contributing to pig kidney graft survival in a baboon for >4 months
Hayato Iwase1, Hong Liu 1, Martin Wijkstrom1, Huidong Zhou1, Hidetaka Hara 1, Jagjit Singh 1, Mohamed Ezzelarab1, Cassandra Long 1, Edwin Klein 1, Robert Wagner1, Carol Phelps 2, David Ayares2, Abhinav Humar1, David K.C. Cooper 1.
1Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, United States; 2Revivicor, Blacksburg, VA, United States
Background: When this experiment was carried out, the longest survival of a nonhuman primate with a life-supporting pig kidney xenograft was 90 days, though graft survival >30 days was unusual. The cause of failure was generally the development of consumptive coagulopathy and/or massive proteinuria.
Methods: A baboon received a kidney graft from an α1,3-galactosyltransferase gene-knockout pig transgenic for two human complement (CD46, CD55)- and three human coagulation (thrombomodulin, endothelial protein C receptor, CD39)- regulatory proteins. The baboon had a very high level of anti-nonGal pig IgM. Immunosuppressive therapy was induction with ATG + anti-CD20mAb + CVF and maintenance with anti-CD40mAb + rapamycin + corticosteroids. Anti-inflammatory therapy (anti-TNF-α and anti-IL-6R) was administered. No i.v. heparin was administered. Monitoring included blood cell counts, chemistry, coagulation parameters, and immunological assays (T and B cell counts, xenoreactive anti-nonGal IgM and IgG). The graft was examined microscopically at biopsy (day 103) and at necropsy.
Results: The baboon survived 136 days with a generally stable serum creatinine (0.6-1.6mg/dL) until termination. It developed no features of a consumptive coagulopathy (e.g., thrombocytopenia, decreased fibrinogen) or of a protein-losing nephropathy (serum albumin remained largely within normal range without the need for i.v. human albumin infusion). There was no evidence of an elicited anti-pig antibody response. However, an anastomotic stricture of the ureter slowly developed and, on day 103, surgical resection and reimplantation of the ureter was carried out. A kidney biopsy showed no histopathological abnormality, but some IgM, IgG, and C3 deposition. Thereafter, the serum creatinine remained slightly elevated. Throughout the post-transplant course, there was a gradual increase in size of the kidney. Termination of the experiment was related to septic shock (Myroides spp). By day 136 the kidney showed features of glomerular enlargement, thrombi, and mesangial expansion, with patchy interstitial hemorrhage.
Conclusions: The combination of (i) a graft from a specific genetically-engineered pig, (ii) an effective immunosuppressive regimen, and (iii) anti-inflammatory agents prevented immune injury, a protein-losing nephropathy, and coagulation dysfunction for >4 months. The exact roles of each contributory factor require further investigation, but it is significant to the field to report a 50% extension in life-supporting xenograft function in the non-human primate model.
08:00 - 09:00
|Progress in Solid Organ Xenotransplantation||Progress in Kidney Xenotransplantation||Room 109|
11:00 - 12:30
|Inflammation & Coagulation||Effect of pig genetic modification on human platelet aggregation in response to pig vascular endothelial cells||Room 109|
15:30 - 17:00
|Solid Organ Xenotransplantation (1)||Factors contributing to pig kidney graft survival in a baboon for >4 months||Room 109|
17:30 - 18:30
|Joint Poster Session||Regulation of the inflammatory response by human thrombomodulin transgenic pigs in xenotransplantation.||Main Foyer 1 & 2|