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Genetically-Edited Porcine Kidneys Have Sufficient Tissue Integrity for Use in Xenotransplantation
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Douglas J. Anderson1, *Maggie Jones-Carr
1, *Jackson Perry
1, *Vineeta Kumar
2, *Paige Porrett
1, *Jayme E. Locke
11Surgery, University of Alabama at Birmingham, Birmingham, AL; 2Medicine, University of Alabama at Birmingham, Birmingham, AL
Objective: We sought to determine if porcine kidney xenografts had sufficient tissue integrity to support ongoing function in a human recipient.
Background: Kidney transplantation remains the best available treatment for patients with end-stage kidney disease. Xenotransplantation is a potential solution to the shortage of donor organs. Previous experience in the non-human primate (NHP) model raised concerns about poor tissue integrity of the porcine ureter leading to necrosis and anastomotic leak, post-transplant growth of the porcine kidney creating compression of the graft, and whether pig vasculature could withstand human systolic pressures. We therefore sought to address these knowledge gaps by leveraging a novel pre-clinical human model, the brain-dead decedent or Parsons Model, to answer these key safety questions.
Methods: Kidneys recovered from porcine donors with 10 gene edits (10-GE), including growth hormone receptor knockout (GHRKO), were transplanted across a negative crossmatch and under the cover of standard immunosuppression into brain dead recipients not eligible for organ donation. Recipients underwent bilateral native nephrectomies prior to transplant and were then observed for 3-7 days after xenotransplantation. Vital signs including blood pressure were recorded at least hourly. Xenograft tissue integrity was assessed with serial biopsies, visual inspection of vascular and ureteral anastomoses, and volume measurements.
Results: Three decedents underwent xenotransplantation. Following implantation, the kidneys developed subcapsular hematomas requiring incision of the kidney capsule. Blood pressures were maintained in a physiologic range for humans (median MAP (Interquartile range): Decedent#1: 108.5mmHg (97-114), Decedent#2: 74mmHg (71-78), and Decedent#3: 95mmHg (88-99), without macroscopic evidence of bleeding or aneurysm formation. Serial needle biopsies were taken from the kidneys without apparent loss of tissue integrity such as parenchymal fracture or intractable bleeding, despite the lack of a kidney capsule. At study completion there were no visually apparent issues with the ureteric anastomoses or urine leaks. In one case with 7d follow-up, the left and right kidneys increased in volume by 25% and 26%, respectively, despite GHRKO. In this recipient, human growth hormone levels remained very low (<0.1 ng/ml) while insulin-like growth factor 1 levels were 34-50 ng/ml.
Conclusions: The findings of this study suggest kidneys recovered from 10-GE porcine donors have sufficient tissue integrity to tolerate transplantation into a human recipient. There was no evidence of anastomotic complications and the kidneys tolerated needle biopsy without issue. Kidney growth, possibly driven by parallel pathways to the growth hormone receptor, remains a concern post-xenotransplantation.
Figure: A) Post-transplant mean arterial pressures in 3 decedents. B) Demonstration of subcapsular hematoma on the transplanted porcine kidney. C) The transplanted ureters remained viable and without anastomotic leak D) Kidney volume increased. IGF-1 levels were stable at lower than physiologic levels.
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