Clinical and molecular correlation defines activity of physiological pathways in life-sustaining kidney xenotransplantation
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....
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38465-x |
| _version_ | 1797801388661538816 |
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| author | Daniel J. Firl Grace Lassiter Takayuki Hirose Robert Policastro Ashley D’Attilio James F. Markmann Tatsuo Kawai Katherine C. Hall |
| author_facet | Daniel J. Firl Grace Lassiter Takayuki Hirose Robert Policastro Ashley D’Attilio James F. Markmann Tatsuo Kawai Katherine C. Hall |
| author_sort | Daniel J. Firl |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T04:49:43Z |
| format | Article |
| id | doaj.art-a3b4cf5831c441c8a2d3baadd8bd157d |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T04:49:43Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-a3b4cf5831c441c8a2d3baadd8bd157d2023-06-18T11:18:33ZengNature PortfolioNature Communications2041-17232023-06-0114111510.1038/s41467-023-38465-xClinical and molecular correlation defines activity of physiological pathways in life-sustaining kidney xenotransplantationDaniel J. Firl0Grace Lassiter1Takayuki Hirose2Robert Policastro3Ashley D’Attilio4James F. Markmann5Tatsuo Kawai6Katherine C. Hall7Center for Transplantation Sciences, Massachusetts General HospitalCenter for Transplantation Sciences, Massachusetts General HospitalCenter for Transplantation Sciences, Massachusetts General HospitaleGenesis IncCenter for Transplantation Sciences, Massachusetts General HospitalCenter for Transplantation Sciences, Massachusetts General HospitalCenter for Transplantation Sciences, Massachusetts General HospitaleGenesis IncAbstract 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.https://doi.org/10.1038/s41467-023-38465-x |
| spellingShingle | Daniel J. Firl Grace Lassiter Takayuki Hirose Robert Policastro Ashley D’Attilio James F. Markmann Tatsuo Kawai Katherine C. Hall Clinical and molecular correlation defines activity of physiological pathways in life-sustaining kidney xenotransplantation Nature Communications |
| title | Clinical and molecular correlation defines activity of physiological pathways in life-sustaining kidney xenotransplantation |
| title_full | Clinical and molecular correlation defines activity of physiological pathways in life-sustaining kidney xenotransplantation |
| title_fullStr | Clinical and molecular correlation defines activity of physiological pathways in life-sustaining kidney xenotransplantation |
| title_full_unstemmed | Clinical and molecular correlation defines activity of physiological pathways in life-sustaining kidney xenotransplantation |
| title_short | Clinical and molecular correlation defines activity of physiological pathways in life-sustaining kidney xenotransplantation |
| title_sort | clinical and molecular correlation defines activity of physiological pathways in life sustaining kidney xenotransplantation |
| url | https://doi.org/10.1038/s41467-023-38465-x |
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