First clinical‐grade porcine kidney xenotransplant using a human decedent model

@article{Porrett2022FirstCP,
  title={First clinical‐grade porcine kidney xenotransplant using a human decedent model},
  author={Paige M. Porrett and Babak J. Orandi and Vineeta Kumar and Julie A. Houp and Douglas J Anderson and A Cozette Killian and Vera Hauptfeld-Dolejsek and Dominque E Martin and Sara Macedon and Natalie Budd and Katie Stegner and Amy S. Dandro and Maria Kokkinaki and Kasinath V Kuravi and Rhiannon D. Reed and Huma Fatima and John Killian and Gavin Baker and Jackson Perry and Emma D Wright and Matthew D Cheung and Elise N. Erman and Karl Kraebber and Tracy L. Gamblin and Linda Guy and James F. George and David Ayares and Jayme E. Locke},
  journal={American Journal of Transplantation},
  year={2022},
  volume={22},
  pages={1037 - 1053}
}
A radical solution is needed for the organ supply crisis, and the domestic pig is a promising organ source. In preparation for a clinical trial of xenotransplantation, we developed an in vivo pre‐clinical human model to test safety and feasibility tenets established in animal models. After performance of a novel, prospective compatible crossmatch, we performed bilateral native nephrectomies in a human brain‐dead decedent and subsequently transplanted two kidneys from a pig genetically… 
A model of pig-to-human kidney transplantation
  • S. Allison
  • Medicine, Biology
    Nature Reviews Nephrology
  • 2022
TLDR
How pig-to-human transplantation can be implemented in a safe and systematic fashion with potential to help thousands, rather than just one specific individual is demonstrated, as well as several notable firsts.
Kidney xenotransplantation in a brain‐dead donor: Glass half‐full or half‐empty?
  • L. Riella, J. Markmann, R. Pierson
  • Medicine, Biology
    American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
  • 2022
TLDR
The reported case demonstrates the surgical feasibility of intra-abdominal bilateral sequential kidney xenotransplantation and suggests the next step should be to transplant GE pig kidneys into dialysis- dependent, otherwise stable ESKD patients with no living donor and on the bottom of the waiting list.
Xenotransplantation: A New Era
TLDR
This review serves as a brief discussion of the recent progress in xenotransplantation research, particularly as it concerns utilization of porcine heart, renal, and liver xenografts in clinical practice.
Pig‐to‐human kidney transplantation using brain‐dead donors as recipients: One giant leap, or only one small step for transplantkind?
TLDR
This study demonstrated the outstanding achievement in this research area and revealed remaining gaps to move xenotransplantation to the clinic, as their pro‐inflammatory and pro‐coagulant environment will limit the assessment of kidney function, infection and rejection risk post‐transplant, in particular antibody‐mediated rejection.
Ethical considerations during a pioneering surgical procedure: porcine cardiac xenotransplantation.
TLDR
The patient was denied candidacy for durable mechanical circulatory support and heart transplantation as a result of non-adherence to medical advice and the role of regulatory bodies during performance of the first human porcine cardiac xenotransplantation is focused on.
The science of xenotransplantation for nephrologists
TLDR
Overall, it appears that critical physiologic, immunologic and technical barriers to implementation of clinical trials in humans have been overcome.
Letter to the editor in response to: Measuring success in pig to non‐human‐primate renal xenotransplantation: Systematic review and comparative outcomes analysis of 1051 life sustaining NHP renal allo‐ and xeno‐transplants by Firl and Markmann
TLDR
A systematic review of allo- and xeno- kidney transplantation outcomes in pre- clinical NHP models found that NHP- allotransplantation survival was superior to that of xenotrans transplantation; however, adjusting for the use of genetically modified donors reduced this gap.
Current status of xenotransplantation research and the strategies for preventing xenograft rejection
TLDR
This review comprehensively discussed the mechanism of these immunological rejections and summarized the strategies for preventing them, such as generation of gene knock out donors by different genome editing tools and the use of immunosuppressive regimens.
Long-term Transplant Function After Thrombolytic Treatment Ex Vivo of Donated Kidneys Retrieved 4 to 5 Hours After Circulatory Death.
TLDR
The present method salvages kidneys from extended unontrolled donation after circulatory death using thrombolytic treatment while preserving histology and enabling transplantation after ex vivo reconditioning, with clinically acceptable late function after 3 mo, as measured by creatinine and iohexol clearance.
...
...

References

SHOWING 1-10 OF 44 REFERENCES
Pathologic characteristics of transplanted kidney xenografts.
TLDR
The success of pig-to-primate xenotransplantation may necessitate immune tolerance to inhibit acute humoral and cellular xenograft rejection.
Justification of specific genetic modifications in pigs for clinical organ xenotransplantation
TLDR
It is suggested that a pig with nine genetic modifications will provide organs that would function for a clinically valuable period of time, for example, >12 months, after transplantation into patients with end‐stage organ failure.
Microbiological safety of the first clinical pig islet xenotransplantation trial in New Zealand
TLDR
The first clinical trial of (alginate‐encapsulated) porcine islet cell transplantation in New Zealand, which was approved by the New Zealand Government as an open‐label phase I/IIa safety/efficacy trial, offers the possibility to analyze microbiological safety in a prospective clinical study.
Transplanting organs from pigs to humans
TLDR
The potential and limitations of modifications of pigs genetically and how the engineering of the graft can be leveraged to alter the host immune response so that all types of immune attack are avoided are discussed.
LIFE-SUPPORTING KIDNEY XENOTRANSPLANTATION FROM GENETICALLY-ENGINEERED PIGS IN BABOONS: A COMPARISON OF TWO IMMUNOSUPPRESSIVE REGIMENS.
TLDR
Recognizing that the pig donors in each group differed in some genetic modifications, these data indicate that maintenance immunosuppression including anti-CD40 mAb may be important to prevent pig kidney graft failure.
Gene-edited Pigs for Xenotransplantation
TLDR
Humans express antibodies to both of these antigens, but also to N-glycolylneuraminic acid (Neu5Gc), and are thus anticipated to elicit a similar response to pig organs transplanted into non-human primates.
Long‐term follow‐up for the microbiological safety of clinical microencapsulated neonatal porcine islet transplantation
TLDR
Microbiological safety was demonstrated for microencapsulated neonatal porcine islet xenotransplantation from 5‐7 years post‐transplantation consistent with earlier reports.
Anti-C5 Antibody Tesidolumab Reduces Early Antibody-mediated Rejection and Prolongs Survival in Renal Xenotransplantation
TLDR
Inhibition of the C5 complement subunit prolongs renal xenotransplant survival in a pig to non-human primate model and reduces early graft loss secondary to antibody-mediated rejection.
Why was PERV not transmitted during preclinical and clinical xenotransplantation trials and after inoculation of animals?
TLDR
The data indicate that PERVs were not transmitted because they were not released from the transplant or were inhibited by intracellular restriction factors and innate immunity in the recipient.
Marked prolongation of porcine renal xenograft survival in baboons through the use of α1,3-galactosyltransferase gene-knockout donors and the cotransplantation of vascularized thymic tissue
TLDR
Life-supporting pig-to-baboon renal xenograft survivals of up to 83 d with normal creatinine levels are achieved using α-1,3-galactosyltransferase knockout donors and a tolerance induction approach.
...
...