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Clinical Pig Kidney Xenotransplantation: How Close Are We?

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Clinical Pig Kidney Xenotransplantation: How Close Are We? REVIEW www.jasn.org Clinical Pig Kidney Xenotransplantation: How Close Are We? David K. C. Cooper,1 Hidetaka Hara ,1 Hayato Iwase,1 Takayuki Yamamoto,1 Abhijit Jagdale,1 Vineeta Kumar,2 Roslyn Bernstein Mannon,2 Michael J. Hanaway,1 Douglas J. Anderson ,1 and Devin E. Eckhoff1 1Division of Transplantation, Department of Surgery and 2Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama ABSTRACT Patients with ESKD who would benefit from a kidney transplant face a critical and Here we review advances in the ex- continuing shortage of kidneys from deceased human donors. As a result, such perimental laboratory and consider patients wait a median of 3.9 years to receive a donor kidney, by which time approx- which patients might ethically be offered imately 35% of transplant candidates have died while waiting or have been removed the opportunity of receiving a pig kid- from the waiting list. Those of blood group B or O may experience a significantly ney, either to reduce the length of time longer waiting period. This problem could be resolved if kidneys from genetically that they need be supported by chronic engineered pigs offered an alternative with an acceptable clinical outcome. At- dialysis before undergoing allotrans- tempts to accomplish this have followed two major paths: deletion of pig xenoanti- plantation or as a means of permanent gens, as well as insertion of “protective” human transgenes to counter the human support. The state of the science is suf- immune response. Pigs with up to nine genetic manipulations are now available. In ficiently advanced to indicate that clini- nonhuman primates, administering novel agents that block the CD40/CD154 cos- cal trials of pig kidney transplantation timulation pathway, such as an anti-CD40 mAb, suppresses the adaptive immune are likely to be initiated within the next response, leading to pig kidney graft survival of many months without features of 2 years. rejection (experiments were terminated for infectious complications). In the ab- sence of innate and adaptive immune responses, the transplanted pig kidneys have generally displayed excellent function. A clinical trial is anticipated within 2 years. HISTORICAL ASPECTS OF KIDNEY We suggest that it would be ethical to offer a pig kidney transplant to selected XENOTRANSPLANTATION 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 Several attempts were made to trans- genetically engineered to control the adaptive immune response, thus enabling plant NHP kidneys into patients with exogenous immunosuppressive therapy to be significantly reduced or eliminated. ESKD, with little or no success.7–9 When Reemtsma et al. transplanted JASN 31: ccc–ccc, 2020. doi: https://doi.org/10.1681/ASN.2019070651 chimpanzee kidneys into six patients in 1963, although most of them succumbed from either rejection or infection within 8 weeks, one patient led an active life for There is a continuing shortage of de- The lack of donor kidneys could be 9 months, returning to work as a ceased human donor kidneys for trans- resolved if kidneys from genetically en- plantation in patients with ESKD.1–3 gineered pigs offered an alternative with The overall survival of patients on an acceptable clinical outcome. The po- chronic hemodialysis is 78% at 1 year, tential advantages of xenotransplanta- Published online ahead of print. Publication date 57% at 3 years, and only 42% at 5 years tion are several (Table 1). The results of available at www.jasn.org. (Figure 1).4 Forty percent of waitlisted genetically engineered pig kidney trans- Correspondence: Dr. David K. C. Cooper, Division patients are likely to die within 5 plantation in nonhuman primates of Transplantation, Department of Surgery, ZRB 701, 1720 2nd Avenue South, University of Ala- 4,5 fi years. Importantly, in one analysis, (NHPs) have improved signi cantly in bama at Birmingham, Birmingham, AL 35294. most of those who died on the waitlist recent years (Figure 2), sufficiently to Email: [email protected] had been excellent candidates at the encourage consideration for initial clin- Copyright © 2020 by the American Society of time of listing.6 ical trials. Nephrology JASN 31: ccc–ccc,2020 ISSN : 1046-6673/3101-ccc 1 REVIEW www.jasn.org e.g., human decay-accelerating factor (hCD55) or membrane cofactor protein (CD46), that protected against the recip- ient NHP complement cascade. When the first hCD55 transgenic pigs were in- troduced,17,18 pig kidney graft survival was significantly increased, but graft fail- ure still occurred from delayed anti- body-mediated rejection.19 In 2004, Cozzi and colleagues reported graft survival for a maximum of 90 days (Fig- ure 2), but the mean survival remained at 24 days.20 The identification of the major pig xenoantigen (Gal) against which humans and Old World NHPs (e.g.,ba- boons) have natural (preformed) anti- bodies21 enabled pigs to be bred in which expression of this antigen had been de- leted (GTKO pigs) (Table 2).22–24 The transplantation of kidneys from GTKO pigs into NHPs was associated with pro- longation of graft function, similar to Figure 1. Percentage survival of patients with ESKD by treatment modality in 2010 that achieved by the transplantation of (modified from reference 1, with permission, and on the basis of data from two sources: US Renal Data System [USRDS]4 and Orandi et al.5). CD55- or CD46-transgenic pig or- gans.25,26 The combination of GTKO and a human complement-regulatory schoolteacher, before dying relatively observed in some patients after kidney protein reduced early graft failure fur- suddenly from what was believed to be allotransplantation across the ABO- ther.27,28 an acute electrolyte disturbance.10 The blood group barrier or when sensitized In a GTKO/CD55 pig-to-rhesus transplantation of baboon or monkey to donor HLAs. It was soon clear that the monkey model of kidney transplanta- kidneys was less successful. 80 million years during which humans tion, Higginbotham et al. reported that It was not until the 1980s that it was (and NHPs) and pigs had been evolv- the selection of monkeys with low levels fully appreciated that, despite their phy- ing differently had resulted in a complex of anti-pig antibodies was associated logenetic closeness to humans, NHPs primate immune/inflammatory re- with prolonged graft survival (.4 were for a variety of reasons unlikely to sponse to a pig xenograft.14 However, months),29 as had Yamada et al.,25 provide a solution to the lack of organs importantly, xenotransplantation offers whereas a monkey with a high level of for kidney transplantation, and that pigs us the first real opportunity to modify antibodies rejected the graft within a might make preferable sources of or- the “donor” rather than just treat the week. However, the immunosuppressive gans.11–13 However, the transplantation recipient. regimen had to target the CD40/CD154 of an organ from a wildtype pig (i.e.,a When the genetic engineering of pigs T cell costimulation pathway, but genetically unmodified pig) was fol- was suggested in the early 1990s,15,16 the not the CD28-B7 (CD80/CD86) path- lowed by almost immediate graft rejec- initial approach was to introduce a hu- way, confirming the observations of tion (hyperacute rejection) (Figure 3), as man complement-regulatory protein, Iwase et al.30 Table 1. Advantages of xenotransplantation over allotransplantation Unlimited supply of “donor” organs. Organs available electively, even when required urgently. Avoids the detrimental effects of brain death on the donor organs. The “donors” will be free of all known infectious microorganisms. “Borderline” transplant candidates, i.e., those with health problems that may be detrimental to prolonged patient survival, e.g., poorly controlled diabetes, peripheral or cerebrovascular disease, will be more likely to be acceptable (as they will no longer be competing for scarce organs with other potential transplant candidates). Avoids the “cultural” barriers to deceased human organ donation, e.g., in countries such as Japan. 2 JASN JASN 31: ccc–ccc,2020 www.jasn.org REVIEW deletion of pig xenoantigens, and (2) insertion of “protective” human trans- genes.33 The introduction of more sophisticated techniques of genetic engi- neering has increased the speed and fa- cility with which genetic manipulations can be made, and has reduced the costs (Table 3). RECENT PROGRESS IN PIG-TO- NHP KIDNEY TRANSPLANTATION MODELS Figure 2. Reported maximum survivals of nonhuman primates with life-supporting pig kidney grafts, 1989–2017. Details can be found in Lambrigts et al.,19 and Cooper et al.73 In When conventional immunosuppressive some years, no results were reported. therapy was administered, graft survival was short, unless very high blood levels Furthermore, when post-transplant protein was documented (Figure 4)31 of the agents were maintained, which re- coagulation dysfunction became obvious, (reviewed in Wang et al.32). sulted in infectious complications. the importance of the additional expres- Subsequently, genetic engineering When novel agents that blocked the sion of a human coagulation-regulatory has followed these two major paths: (1) CD40/CD154 costimulation pathway, e.g., with an anti-CD154 mAb,34 the adaptive immune response was sup- A pressed, leading to prolonged graft sur- vival.25,35 Although anti-CD154 mAbs have been associated with thrombogenic complications, anti-CD40 mAbs, which appear almost
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