Renal xenotransplantation: experimental progress and clinical prospects

Abstract

There are >100,000 patients waiting for kidney transplants in the United States and a vast need worldwide. Xenotransplantation, in the form of the transplantation of kidneys from genetically engineered pigs, offers the possibility of overcoming the chronic shortage of deceased and living human donors. These genetic manipulations can take the form of (i) knockout of pig genes that are responsible for the expression of antigens against which the primate (human or nonhuman primate) has natural "preformed" antibodies that bind and initiate complement-mediated destruction or (ii) the insertion of human transgenes that provide protection against the human complement, coagulation, or inflammatory responses. Between 1989 and 2015, pig kidney graft survival in nonhuman primates increased from 23 days to almost 10 months. There appear to be no clinically significant physiological incompatibilities in renal function between pigs and primates. The organ-source pigs will be housed in a biosecure environment, and thus the risk of transferring an exogenous potentially pathogenic microorganism will be less than that after allotransplantation. Although the risk associated with porcine endogenous retroviruses is considered small, techniques are now available whereby they could potentially be excluded from the pig. The US Food and Drug Administration suggests that xenotransplantation should be restricted to "patients with serious or life-threatening diseases for whom adequately safe and effective alternative therapies are not available." These might include those with (i) a high degree of allosensitization to human leukocyte antigens or (ii) rapid recurrence of primary disease in previous allografts. The potential psychosocial, regulatory, and legal aspects of clinical xenotransplantation are briefly discussed.

Keywords: allosensitization; clinical trial; genetically engineered xenotransplantation; kidney; pig.

Figure 1

(A) Keith Reemtsma, who carried out a series of chimpanzee kidney transplants in patients in renal failure the early 1960s. (B) Macroscopic appearances at necropsy of a pair of chimpanzee kidneys transplanted into a patient 9 months previously by Keith Reemtsma.

Figure 2

(A) Macroscopic appearance of a wild-type (genetically-unmodified) pig kidney transplanted into a baboon immediately after graft reperfusion. (B) The same kidney 5 minutes later after it had undergone hyperacute rejection. (Reproduced with permission from.)

Figure 3

Human IgM and IgG antibody binding to pig and human aortic endothelial cells (AECs) by flow cytometry. Human IgM (top) and IgG (bottom) binding to GTKO/hCD46 pAECs was significantly decreased compared to wild-type (WT) pig AECs (*p<0.05), and was further decreased to GTKO/hCD46/NeuGcKO pig AECs (*p<0.05). There was significantly greater IgM binding to GTKO/hCD46/NeuGcKO pig AECs than human AECs (‡p<0.05), but there was no statistical significance in the extent of IgG binding between them.

Figure 4

Maximum life-supporting pig kidney graft survival after transplantation into nonhuman primates (by year). (WT = wild-type [i.e., genetically-unmodified] pig as source of kidney; CD55 = organ source pig genetically modified to express the human complement-regulatory protein CD55 [decay-accelerating factor]; GTKO = α1,3-galactosyltransferase gene-knockout pig that does not express the important Gal antigen that is a major target for primate anti-pig antibodies; GTKO/CD55 = GTKO pig expressing human CD55).