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Original ArticleFree Preview

Results of Two Cases of Pig-to-Human Kidney Xenotransplantation

List of authors.
  • Robert A. Montgomery, M.D., D.Phil.,
  • Jeffrey M. Stern, M.D.,
  • Bonnie E. Lonze, M.D., Ph.D.,
  • Vasishta S. Tatapudi, M.D.,
  • Massimo Mangiola, Ph.D.,
  • Ming Wu, M.D.,
  • Elaina Weldon, M.S.N., A.C.N.P.-B.C.,
  • Nikki Lawson, R.N.,
  • Cecilia Deterville, M.S.,
  • Rebecca A. Dieter, Pharm.D., B.C.P.S.,
  • Brigitte Sullivan, M.B.A.,
  • Gabriella Boulton, B.A.,
  • Brendan Parent, J.D.,
  • Greta Piper, M.D.,
  • Philip Sommer, M.D.,
  • Samantha Cawthon, B.S.,
  • Erin Duggan, M.D.,
  • David Ayares, Ph.D.,
  • Amy Dandro, M.S.,
  • Ana Fazio-Kroll, Ph.D.,
  • Maria Kokkinaki, Ph.D.,
  • Lars Burdorf, M.D., Ph.D.,
  • Marc Lorber, M.D.,
  • Jef D. Boeke, Ph.D.,
  • Harvey Pass, M.D.,
  • Brendan Keating, Ph.D.,
  • Adam Griesemer, M.D.,
  • Nicole M. Ali, M.D.,
  • Sapna A. Mehta, M.D.,
  • and Zoe A. Stewart, M.D., Ph.D.

Abstract

Background

Xenografts from genetically modified pigs have become one of the most promising solutions to the dearth of human organs available for transplantation. The challenge in this model has been hyperacute rejection. To avoid this, pigs have been bred with a knockout of the alpha-1,3-galactosyltransferase gene and with subcapsular autologous thymic tissue.

Methods

We transplanted kidneys from these genetically modified pigs into two brain-dead human recipients whose circulatory and respiratory activity was maintained on ventilators for the duration of the study. We performed serial biopsies and monitored the urine output and kinetic estimated glomerular filtration rate (eGFR) to assess renal function and xenograft rejection.

Results

The xenograft in both recipients began to make urine within moments after reperfusion. Over the 54-hour study, the kinetic eGFR increased from 23 ml per minute per 1.73 m2 of body-surface area before transplantation to 62 ml per minute per 1.73 m2 after transplantation in Recipient 1 and from 55 to 109 ml per minute per 1.73 m2 in Recipient 2. In both recipients, the creatinine level, which had been at a steady state, decreased after implantation of the xenograft, from 1.97 to 0.82 mg per deciliter in Recipient 1 and from 1.10 to 0.57 mg per deciliter in Recipient 2. The transplanted kidneys remained pink and well-perfused, continuing to make urine throughout the study. Biopsies that were performed at 6, 24, 48, and 54 hours revealed no signs of hyperacute or antibody-mediated rejection. Hourly urine output with the xenograft was more than double the output with the native kidneys.

Conclusions

Genetically modified kidney xenografts from pigs remained viable and functioning in brain-dead human recipients for 54 hours, without signs of hyperacute rejection. (Funded by Lung Biotechnology.)

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Funding and Disclosures

Supported by Lung Biotechnology, a wholly owned subsidiary of United Therapeutics.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank David Sachs, M.D., Megan Sykes, M.D., and Kazuhiko Yamada, M.D., Ph.D., who conducted pioneering work on the preclinical development of the thymokidney; Alice F.-X. Liang, Ph.D., Chris Petzold, M.S., and Joseph Sall, B.S., of the New York University (NYU) Microscopy Laboratory, for consultation and timely preparation of the electron microscopy images; Estefania Gallego, B.S., of the NYU Center for Biospecimen Research and Development; Navneet Narula, M.D., for preparation, staining, and interpretation of the thymus histologic tests; Chandra Goparaju, Ph.D., for work with messenger RNA samples and data analysis; John Beagle, B.S., and Thomas K. Adams, D.V.M., of the Revivicor surgical team, who performed the thymokidney operation (subcapsular pig thymic autograft) and helped with the kidney procurements; and Jay Fishman, M.D., for help in designing the zoonosis surveillance protocol.

Author Affiliations

From the New York University (NYU) Langone Transplant Institute (R.A.M., J.M.S., B.E.L., V.S.T., M.M., E.W., N.L., C.D., R.A.D., B.S., G.B., G.P., N.M.A., S.A.M., Z.A.S.), the Departments of Pathology (M.W.), Anesthesia (P.S.), Biochemistry and Molecular Pharmacology (J.D.B.), and Cardiothoracic Surgery (H.P.), and the Institute for Systems Genetics (J.D.B.), NYU Langone Health, the Department of Population Health, Division of Medical Ethics (B.P.), NYU Grossman School of Medicine (S.C.), and the Columbia Center for Translational Immunology and the Department of Surgery, Columbia University (E.D., A.G.) — all in New York; Revivicor, Blacksburg, VA (D.A., A.D., A.F.-K., M.K., L.B.); United Therapeutics, Silver Spring, MD (M.L.); and the Department of Surgery, University of Pennsylvania, Philadelphia (B.K.).

Dr. Montgomery can be contacted at or at NYU Langone Health, 550 First Ave., New York, NY 10016.

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