Clinical Pig Kidney Xenotransplantation: How Close Are We?

Abstract

Patients with ESKD who would benefit from a kidney transplant face a critical and continuing shortage of kidneys from deceased human donors. As a result, such patients wait a median of 3.9 years to receive a donor kidney, by which time approximately 35% of transplant candidates have died while waiting or have been removed from the waiting list. Those of blood group B or O may experience a significantly longer waiting period. This problem could be resolved if kidneys from genetically engineered pigs offered an alternative with an acceptable clinical outcome. Attempts to accomplish this have followed two major paths: deletion of pig xenoantigens, as well as insertion of “protective” human transgenes to counter the human immune response. Pigs with up to nine genetic manipulations are now available. In nonhuman primates, administering novel agents that block the CD40/CD154 costimulation pathway, such as an anti-CD40 mAb, suppresses the adaptive immune response, leading to pig kidney graft survival of many months without features of rejection (experiments were terminated for infectious complications). In the absence of innate and adaptive immune responses, the transplanted pig kidneys have generally displayed excellent function. A clinical trial is anticipated within 2 years. We suggest that it would be ethical to offer a pig kidney transplant to selected patients who have a life expectancy shorter than the time it would take for them to obtain a kidney from a deceased human donor. In the future, the pigs will also be genetically engineered to control the adaptive immune response, thus enabling exogenous immunosuppressive therapy to be significantly reduced or eliminated.

Evidence for GTKO/β4GalNT2KO Pigs as the Preferred Organ-source for Old World Nonhuman Primates as a Preclinical Model of Xenotransplantation

“…Selecting baboons that have a low or negative CDC to pig cells will be important in mimicking the pig-to-human model (as many humans have no or low antibody binding or CDC to TKO pig cells) (Figure S2, SDC, http://links.lww.com/TXD/A267 ). 15 …”

Neonatal Pig Sertoli Cells Survive Xenotransplantation by Creating an Immune Modulatory Environment Involving CD4 and CD8 Regulatory T Cells

“…Xenotransplantation could provide an unlimited supply of tissue for clinical transplantation, thereby providing the ultimate solution to the shortage of donors 1 . However, the aggressive cell-mediated immune rejection of xenografts is a major obstacle to clinical application 2 and most of the immune suppressive drugs used to extend the survival of xenografts are highly toxic with some not suitable for human use 3 – 7 .…”

Method used to establish a large animal model of drug-induced acute kidney injury

“…Because of their strong genetic, anatomical and physiological similarities with humans, mini pigs have advantages over rodent models as pharmacokinetic models. 12 Studies have shown that in many cases, mini pigs are more suitable for toxicology tests than dogs or monkeys. 13…”