Thomas E. Starzl Transplantation Institute, University of Pittsburgh
Progress in kidney xenotransplantation
1Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, United States
The number of patients waiting for a kidney donorcontinues to grow, while rates of donation and transplantation stagnate. Xenotransplantation (XTx) offers the possibility of overcoming the chronic shortage of human donors.
Significant progress in life-supporting kidney xenograft survival in nonhuman primates (NHPs) has been associated largely with the increasing availability of pigs with genetic modifications that protect the pig tissues from the primate immune response and correct molecular incompatibilities. The availability of α1,3-galactosyltransferase gene-knockout (GTKO) pigs expressing one or more human complement-regulatory proteins (e.g., CD46, CD55, or CD59) has largely prevented hyperacute and acute vascular rejection
However, other issues have become more prominent, such as the development of thrombotic microangiopathy and/or systemic consumptive coagulopathy, that are related to several factors. Activation of the graft endothelial cells by anti-nonGal antibody, complement, and innate immune cells results in a procoagulant state, which is exacerbated by discrepancies in coagulation-anticoagulation factors between the two species.
Grafts from pigs expressing one or more human coagulation-regulatory proteins (e.g., thrombomodulin [TBM], endothelial protein C receptor [EPCR], tissue factor pathway inhibitor [TFPI], CD39) provide some protection from this problem. Coagulation and inflammatory and immune responses appear to have a complex interrelationship, but other genetic modifications and/or anti-inflammatory agents may protect the graft from the effects of inflammation.
Immunosuppressive regimens have contributed to progress. Costimulation blockade with anti-CD154 mAb therapy has contributed to prolongation of kidney xenograft survival, although it is not clinically available because of its thrombogenic properties. An anti-CD40 mAb-based regimen is likely to be equally successful, but blockade of the CD28/B7 pathway alone would appear to be inadequate.
Hypoalbuminemia and proteinuria were uniformly documented in the early studies of pig kidney XTx, but whether these resulted from the immune response (endothelial cell activation by antibody, complement, innate cells, and/or platelets) or from physiological incompatibility between the species, or both, remained uncertain.
Before 2014, the longest survival of a life-supporting kidney graft was 90 days, though graft survival >30 days was unusual. Recently this has been extended to >125 days by two groups. The Emory group transplanted kidneys from GTKO/CD55 pigs in rhesus monkeys with low titers of anti-pig antibodies under an anti-CD154mAb-based regimen. The Pittsburgh group reported survival of a GTKO/CD46/CD55/TBM/EPCR/ CD39 pig kidney in a baboon immunosuppressed with an anti-CD40mAb-baased regimen, without features of a consumptive coagulopathy or a protein-losing nephropathy.
In conclusion, overcoming the immune, coagulation, and inflammatory responses by the development of precise genetic modification of the donor pig, along with effective clinically-applicable immunosuppressive and anticoagulant/anti-inflammatory therapy is advancing the field towards clinical trials.
08:00 - 09:00
|Progress in Solid Organ Xenotransplantation||Progress in Kidney Xenotransplantation||Room 109|
11:00 - 12:30
|Inflammation & Coagulation||Effect of pig genetic modification on human platelet aggregation in response to pig vascular endothelial cells||Room 109|
15:30 - 17:00
|Solid Organ Xenotransplantation (1)||Factors contributing to pig kidney graft survival in a baboon for >4 months||Room 109|
17:30 - 18:30
|Joint Poster Session||Regulation of the inflammatory response by human thrombomodulin transgenic pigs in xenotransplantation.||Main Foyer 1 & 2|