Clinical and molecular correlation defines activity of physiological pathways in life-sustaining kidney xenotransplantation

Daniel J. Firl, Grace Lassiter, Takayuki Hirose, Robert Policastro, Ashley D’Attilio, James F. Markmann, Tatsuo Kawai and Katherine C. Hall ()
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Daniel J. Firl: Center for Transplantation Sciences, Massachusetts General Hospital
Grace Lassiter: Center for Transplantation Sciences, Massachusetts General Hospital
Takayuki Hirose: Center for Transplantation Sciences, Massachusetts General Hospital
Robert Policastro: eGenesis Inc
Ashley D’Attilio: Center for Transplantation Sciences, Massachusetts General Hospital
James F. Markmann: Center for Transplantation Sciences, Massachusetts General Hospital
Tatsuo Kawai: Center for Transplantation Sciences, Massachusetts General Hospital
Katherine C. Hall: eGenesis Inc

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Porcine kidney xenotransplantation is accelerating towards clinical translation. However, despite the demonstrated ability of porcine kidneys to remove metabolic waste products, questions remain about their ability to faithfully recapitulate renal endocrine functions after transplantation. Here we analyze xenograft growth and function of two kidney dependent endocrine pathways in seventeen cynomolgus macaques after kidney xenotransplantation from gene edited Yucatan minipigs. Xenograft growth, the renin-angiotensinogen aldosterone-system, and the calcium-vitamin D-parathyroid hormone axis are assessed using clinical chemistries data, renin activity and beta-C-terminal-telopeptide assays, kidney graft RNA-sequencing and serial ultrasonography. We demonstrate that xenografts transplanted from minipigs show only modest growth and do not substantially contribute to recipient RAAS pathway activity. However, parathyroid hormone-independent hypercalcemia and hypophosphatemia are observed, suggesting a need for close monitoring and timely intervention during human testing. Further study of these phenotypes is warranted in designing prospective clinical trials.

Date: 2023
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DOI: 10.1038/s41467-023-38465-x

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