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Kidney transplantation in adults: Xenotransplantation

Kidney transplantation in adults: Xenotransplantation
Literature review current through: Jan 2024.
This topic last updated: Jul 28, 2022.

INTRODUCTION — The transplantation of cells, tissues, and organs between individuals of different species is called xenotransplantation. The clinical application of xenotransplantation has been a goal of transplant clinicians since the beginning of the twentieth century. Kidneys of animals were used during the first attempts at clinical transplantation because it was not readily apparent how human kidneys could be ethically retrieved [1]. Today, the shortage of human kidneys available for transplantation impels ongoing consideration of xenotransplantation.

The shortage of human kidneys for transplantation makes kidney transplantation unavailable for some and significantly increases waiting time for others. The increasing prevalence of end-stage kidney disease with age makes these challenges worse over time. Other approaches to kidney replacement, such as implantable devices, cell or stem cell therapies, and organogenesis are being explored [2]; however, xenotransplantation could provide the most widely available and cost-effective approach [3-5]. Additional benefits may include the ability to prevent the recurrence of some infectious diseases (as animal organs are not susceptible to certain viruses, such as Epstein-Barr virus and hepatitis B and C) and the ability to introduce extrinsic genetic material for therapeutic purposes [4].

Despite these possible benefits, xenotransplantation remains a matter of controversy. This controversy stems from the ongoing challenge of overcoming the immune hurdles to xenografting with attendant need for more intense immunosuppression and the theoretical possibility that a xenograft may pose risks to public health by the introduction of infectious agents. The implantation of pig kidneys into recently deceased recipients [6,7] and the transplantation of a porcine heart into a living recipient with severe cardiac failure [8] suggest that xenotransplantation of the kidney is approaching clinical application. A review of xenotransplantation and pertinent challenges is presented in this topic review.

SOURCES OF XENOGRAFTS — The most obvious animal to use as a source of xenografts is one that is genetically close to humans, such as the chimpanzee. In the early 1960s, a series of transplants of chimpanzee kidneys into patients with kidney failure were performed [9]. These transplants functioned for up to nine months; arguably some were successful, the recipients having died from intercurrent disease and not rejection.

Baboon livers were reported to function for months in two patients with hepatic failure [10]. As with some of the chimpanzee kidney transplants, intercurrent illness rather than intrinsic failure of the livers resulted in patient death.

Despite these "successes," nonhuman primates are not considered potential sources of xenografts because nonhuman primates are scarce and may harbor deadly viruses. Instead, lower mammals, particularly pigs, are preferred because they are available in unlimited numbers and because the pig can be genetically engineered to lower some biological hurdles. Additional benefits are that porcine kidneys are appropriately sized for humans and have only a limited risk of transferring infectious agents (as discussed below).

Using technologies described below, swine kidneys have survived and functioned more than a year and heterotopic hearts more than two years in nonhuman primates [11]. Swine tissues, such as islets and hepatocytes, have functioned months longer. This progress encourages some to conclude that clinical application is imminent; however, further progress is needed to make xenografts comparable to allografts or preferable to dialysis for treatment of kidney failure.

Xenotransplantation might also be used in conjunction with organogenesis to generate functioning kidneys. With this strategy, animal fetal cells committed to a renal lineage, particularly metanephroi, are isolated and transplanted into an appropriate recipient [12,13]. Limited studies suggest that developing metanephroi surgically placed into the omentum of cross-species hosts (eg, pig to rodent) differentiate, grow, become vascularized, and exhibit excretory behavior.

In still more advanced strategies, human stem cells might be generated from the person needing treatment and introduced as "reverse xenografts" in a fetal animal host, in which the cells grow into renal primordia [14,15]. After development begins, the primordial kidney could be harvested and transferred back to the person from whom the stem cells were generated [2,15,16]. Alternatively, human stem cells might be seeded on the decellularized matrix of an animal kidney to generate an "engineered" human organ.

BARRIERS TO XENOTRANSPLANTATION — The hurdles to successful application of xenotransplantation include the following:

Immunological responses of the recipient against the graft

Physiological limitations of the graft

Infection

Ethical considerations

Although the following section addresses kidney xenotransplantation, this discussion also largely applies to cardiac, liver, and lung xenotransplantation.

Immunologic reactions — Without genetic manipulation and/or severe immune modulation, a pig organ transplanted into a human would succumb because of the following reactions (figure 1) [4].

Hyperacute rejection — Hyperacute rejection may arise in transplanted organs, whether human to human or across species. It is not observed with transplanted tissue or cells, such as pancreatic islets or hepatocytes. This severe reaction may occur within minutes to hours and would be observed in many, if not most, pig kidneys transplanted into unmodified human patients. (See "Kidney transplantation in adults: Evaluation and diagnosis of acute kidney allograft dysfunction".)

Hyperacute rejection is characterized by the aggregation of platelets, formation of platelet thrombi, and the presence of interstitial hemorrhage in the recently transplanted organ. The dissolution of graft blood vessels and accumulation of neutrophils is sometimes, but not invariably, observed.

Hyperacute rejection of pig organs by primates is triggered by the binding to endothelium of "xenoreactive natural antibodies." These antibodies predominately recognize Gal alpha1-3Gal, a sugar expressed by lower mammals such as pigs, but not by humans, apes, or Old World Monkeys. The anti-Gal alpha1-3Gal antibodies are believed to be similar to the isohemagglutinins that recognize blood groups A and B [17].

Binding of xenoreactive natural or elicited antibodies to xenograft endothelium activates complement and attracts leukocytes, which together cause hyperacute rejection. Xenografts appear to be particularly susceptible to hyperacute rejection because porcine complement regulatory proteins fail to dampen the activation of human complement in xenogeneic blood vessels. (See "Regulators and receptors of the complement system".)

Most evidence suggests that hyperacute rejection is caused by the accumulation of terminal complement complexes (C5b-9) on endothelial surfaces [18]. Deposition of terminal complement complexes causes an alteration in the shape of endothelium, which brings platelets into contact with underlying matrix, thereby triggering aggregation and thrombosis [19-21].

Although hyperacute rejection is arguably the most severe of all known immune pathologies, it can be prevented by one or more of the following strategies:

Depleting xenoreactive antibodies from the recipient's circulation [22].

Inhibiting complement activation [23]. This can be achieved by the administration of cobra venom factor (which depletes C3), soluble complement receptor type 1 (which inhibits the critical convertase enzymes of the complement cascade [24]), or anti-C5 antibodies (which inhibit the assembly of terminal complement complexes [25]).

Expressing the human complement regulatory proteins, decay accelerating factor (hCD55) or membrane cofactor protein (hCD46), in the animal organ [26]. Expression of these proteins can be achieved by making transgenic animals in which the genes for the human proteins are integrated into the porcine genome [27]. The use of transgenic organs as a means of preventing hyperacute rejection was first described by the author [28], and the application to the kidney was first described by Cozzi [29]. In both of these studies and in many subsequently published, transgenic porcine organs transplanted into baboons continued to function without evidence of structural damage well beyond the period when hyperacute rejection usually occurs (24 hours). Protection may be further enhanced with a triple transgenic animal that expresses hCD46, hCD55, and hCD59 [30].

Eradicating antigenic targets of xenoreactive antibodies. The most important target is Gal(alpha)1-3Gal, which can be eradicated by knocking out (alpha)1,3 galactosyltransferase, the enzyme that catalyzes synthesis of that sugar, in cloned pigs [31-35]. The transplantation of such kidneys into baboons has allowed the survival of kidney xenografts for months [34,36].

Acute vascular or antibody-mediated rejection — Also known as antibody-mediated rejection, acute vascular rejection of xenografts can occur if hyperacute rejection is averted. Acute vascular rejection is recognized as the major hurdle to clinical application of xenotransplantation. Acute vascular rejection is characterized by severe endothelial thickening, injury, ischemia, and thrombosis, with thrombi consisting of fibrin and platelets. (See "Kidney transplantation in adults: Clinical features and diagnosis of acute kidney allograft rejection".)

Although a variety of factors have been implicated, acute vascular rejection is triggered by binding of antibodies to graft blood vessels, leading to activation of complement and/or attachment of leukocytes. Depletion of xenoreactive antibodies from xenograft recipients or suppression of antibody synthesis by immunosuppressive agents can avert or delay the occurrence of acute vascular rejection [37,38].

Some antibodies that cause acute vascular rejection are specific for Gal alpha1-3Gal [26,39] and others elicited by other components of xenograft endothelium can cause this process.

Although acute vascular rejection has been prevented in a few cases of pig-to-primate xenotransplantation, it remains the main therapeutic challenge. Among the approaches to preventing acute vascular rejection are the induction of immunological tolerance, genetic engineering to eliminate antigen besides Gal alpha1-3Gal, and induction of accommodation to help transplants resist injury.

Accommodation – When antibodies against a kidney transplant donor are removed from the circulation or temporarily prevented from causing the demise of the graft, the graft may undergo a process known as accommodation [27]. This was first described clinically in blood-group O recipients of blood-group A and B donor kidneys [40]. However, it is best characterized in xenografts [41,42].

Accommodation is sometimes associated with expression in the transplant of "protective" genes such as heme oxygenase-1 [43]. These genes inhibit cellular cytotoxicity, allowing other changes in cell and tissue physiology to mount broad resistance to injury and noxious substances and cytokines [41,44].

Whether accommodation can be achieved to a sufficient extent and with sufficient regularity to make xenotransplantation clinically acceptable is yet to be proven. However, accommodation has allowed kidney allotransplantation to cross ABO and human leukocyte antigen (HLA) barriers with success of ABO-incompatible kidney transplants approaching ABO-compatible transplants. (See "Kidney transplantation in adults: ABO-incompatible transplantation".)

Tolerance – A second approach to preventing acute vascular rejection is the induction of immunological tolerance, which is defined as specific nonresponsiveness to a foreign antigen or tissue. In general, immunological tolerance is the goal of all clinical transplantation. Because of the severe immune responses that would otherwise be uncontrollable, some investigators suggest that the successful application of xenotransplantation will ultimately depend upon the induction of tolerance.

Among the most promising approaches to inducing tolerance for xenotransplantation is the transplantation of donor bone marrow into recipients whose ability to mount acute immune responses is suppressed or eradicated [45-48]. Another possible approach is to inhibit "costimulation," leading to the inactivation of B cells and T cells. Which of these, or other, approaches may work between highly disparate species is still unknown. (See "Transplantation immunobiology".)

Genetic engineering – A third strategy to prevent acute vascular rejection is to genetically engineer the animal source so that the relevant antigens are not expressed, and inhibitors of complement, inflammation, coagulation, or other beneficial proteins are expressed. The ability to efficiently introduce multiple genetic changes into the germline places genetic engineering at the center of efforts to advance xenotransplantation toward clinical application [49]. Organ xenografts from pigs with multiple genetic changes have functioned for more than two years in nonhuman primates, although not without heavy immunosuppression. However, the failure of severe regimens of immunosuppression to establish permanent function and survival of xenografts might suggest a need for further genetic modification to improve the "acceptability" of animal organs in humans. On the other hand, the transplantation of swine organs into nonhuman primates does not perfectly model transplantation into humans, because human genes introduced into pigs could be less than perfectly compatible with nonhuman primates and because therapeutic agents were developed and optimized for humans and not for nonhuman primates.

Cellular rejection — Xenografts, like allografts, are susceptible to cellular rejection. Critical questions include the following:

Whether the cellular rejection of xenografts resembles the cellular rejection of allografts [50]. This is under active investigation.

Whether the process can be controlled by existing immunosuppressive therapies. Immunosuppression used for allotransplant rejection appears to prevent the cellular rejection of xenotransplants over periods of weeks to months [51] and limits production of large quantities of antibodies against xenogeneic antigens [52]. Nevertheless, some argue that immune responses to xenotransplantation may be so severe that tolerance will be needed [48].

Chronic rejection — The bane of kidney allografts is chronic rejection, and it is reasonable to assume chronic rejection will also afflict kidney xenografts. However, the ability to limit ischemic injury and potentially to control inflammation by genetic engineering could slow the development of chronic rejection, and the ready availability of animal organs makes it possible to replace a chronically rejected xenograft.

The cause of chronic rejection of allografts is often unclear, but antibodies directed against the graft are implicated [53]. To the extent that such antibodies contribute to the rejection of clinical xenografts, the approaches discussed above for acute vascular rejection might also be applied to chronic rejection. Whether accommodation can be sufficiently durable and whether it could have a detrimental long-term impact are unknown. (See "Kidney transplantation in adults: Chronic allograft nephropathy".)

Physiologic function — The main clinical imperative of xenotransplantation is the functional replacement of a failing organ or organ system. Kidney xenografts can maintain life in nonhuman primates, but whether all kidney functions could be manifested and correctly regulated by a kidney xenograft in a human remains to be determined.

It is unlikely that a kidney xenograft will function exactly like an allograft. Limited studies indicate pig kidneys can maintain normal or near-normal serum creatinine, electrolyte, acid-base, calcium, and phosphorus balance and normal blood pressure in baboons. However, some report that monkeys and baboons with kidney xenografts have hypophosphatemia [51,54]. It is unclear, however, whether this complication reflects intrinsic limitations of the xenogeneic kidneys or a complication of immunosuppressive therapy or rejection remains unclear.

Monkeys with kidney xenografts also may develop a significant, nonhemolytic anemia [55]. The administration of erythropoietin returns the hemoglobin concentration to near-normal levels. Incompatibility of regulators of coagulation and platelet function might also increase the risk of thrombosis and might be addressed by genetic engineering of source animals.

Infection — The possibility of transferring an infectious agent from the xenotransplant to the recipient or community is one of the major hurdles to the clinical application of xenotransplantation [56,57]. Agents that cause pyogenic infections and influenza are among those that could infect a human if they were carried with a xenograft. However, nearly all (if not all) agents that are infectious for the pig can be excluded from potential xenograft donors by rigorous approaches to animal raising and isolation. In this way, a xenograft would probably be a less likely source of infection than a human allograft.

What cannot be excluded by these approaches are organisms that are endogenous to the porcine genome, such as endogenous retroviruses. The genome of all species contains retro-elements, and some have retroviruses capable of replicating and infecting.

The pig has a retrovirus known as porcine endogenous retrovirus (PERV), which is capable of infecting human cells in culture and murine cells in vivo [57,58]. Studies of human subjects to this point have failed to demonstrate that this virus can infect human cells in vivo, cause disease, or be transferred from one individual to another [59]; however, PERV is capable of infecting human cells that may fuse spontaneously with swine cells [60].

Various reasons for the limited infectivity of PERV have been hypothesized, including natural resistance of the human host [61]. In this author's judgment, clinical trials are required to determine whether this agent poses any risk for humans. If it proves to be a risk, genetic engineering has been successfully employed to inactivate at least some PERV inserts.

Additional potential human pathogens include herpesviruses, particularly porcine cytomegalovirus [57]. Tissue invasive disease due to this organism has been described in pig-to-primate xenotransplant models. Porcine cytomegalovirus, however, can be excluded from swine herds by early weaning of newborns [57].

Ethical considerations — The ethical aspects of xenotransplantation have been considered by various agencies, such as the Institute of Medicine in the United States [62], the Nuffield Council in Great Britain [63], and the International Xenotransplantation Association [64]. Although there are some individuals who oppose any use of animals for purposes such as xenotransplantation, these and other agencies have concluded that such opposition should not be public policy in societies that allow the use of animals as a source of food.

Of greater concern is the possibility that a xenograft may carry an infectious agent to the xenograft recipient and more broadly into society, thereby making the xenograft potentially a matter of public health. As indicated previously [4], there is no evidence that a porcine xenograft would introduce infectious agents distinct from those introduced through animal husbandry, slaughterhouses, and other agricultural activities unrelated to transplantation.

One potential exception is PERV, which apparently has not entered human populations [64]. However, there is no evidence that PERV can infect or spread among humans as a result of xenotransplantation or other types of exposure to pigs. Nevertheless, because there remains concern about this issue, agencies in various countries have formulated public policies for the regulation of xenotransplantation and the screening and evaluation of recipients [64].

POSSIBLE FUTURE INDICATIONS — If the biological hurdles to kidney xenotransplantation are overcome, the next critical question will be which patients with kidney disease would be most suitable to receive xenotransplants. This question is challenging because outcomes of xenotransplantation will be compared with outcomes of dialysis as well as allotransplantation. Xenotransplantation might be especially appealing because it is potentially available without the delay associated with use of kidneys from deceased donors and the intrusiveness of living donation. These advantages are likely to increase as populations age. The advantages may also include lower cost compared with other procedures [16,65]. In addition, xenotransplantation might be preferred in certain medical settings. However, preference for xenotransplantation over dialysis and/or allotransplantation will require advances that decrease the intensity of immunosuppression regimens currently considered essential for prolonged function and survival of organ xenografts in nonhuman primates [66].

Presensitized patients — Xenotransplants may be initially considered for a limited number of individuals who are presensitized to multiple potential donors and are therefore less likely to receive an allograft. Limited evidence suggests at least some anti-human leukocyte antigen (HLA) antibodies do not crossreact with porcine major histocompatibility antigens (SLA) [67,68]. (See "Kidney transplantation in adults: Prevention and treatment of antibody-mediated rejection".)

Infants — Kidney xenotransplantation might be considered for certain young infants. When dialysis is very difficult to perform and allografts are unavailable because of the mismatch in size between the adult human kidney and the infant, a temporary xenograft might be considered to allow the infant to grow to a size that is more optimal for allotransplantation. (See "Kidney transplantation in children: General principles".)

Hyperoxaluria — Xenotransplantation might be explored as an interim procedure for patients with primary hyperoxaluria. Conventional transplant experience in these patients has been relatively disappointing because residual oxalate damages the transplant. A xenograft might be used as a temporary device to clear oxalate from selected patients. (See "Primary hyperoxaluria" and "Kidney transplantation in children: Complications".)

Human immunodeficiency virus infection — Human immunodeficiency virus (HIV)-positive patients with kidney failure may be candidates for xenotransplantation since many transplant centers exclude such patients (see "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient"). However, given the long-term survival of some HIV-positive patients with current therapy, a network of centers in the United States has been created where the feasibility of transplanting these patients is being evaluated in a systematic manner. Other transplant programs are considering the transplantation of HIV patients on an individual basis. (See "Kidney transplantation in adults: Kidney transplantation in patients with HIV".)

FUTURE APPROACH — Xenotransplantation may enter the clinic in a stepwise fashion. In the past:

Porcine livers have been used as devices for the treatment of fulminant hepatic failure.

Porcine skin has been used for the treatment of burns.

Porcine cells have been transplanted into patients with Parkinson disease and unremitting pain.

The transplantation of porcine hepatocytes or islet cells, which do not require removal of or full replacement of function of the autogenous organ, may be undertaken [69]. From these clinical activities, more precise information will emerge concerning the immune response to xenotransplantation and the risks of infection.

As a next step, bridge cardiac or kidney xenografts might be undertaken to provide temporary support for highly sensitized, extremely small, or surgically complex patients until an allotransplant or definitive treatment can be performed.

Bridge cardiac or kidney xenografts will provide important information about the manifestation and control of the vascular responses to xenotransplantation. Only when these responses are effectively controlled over a period of months is it likely that the porcine kidney will be used as a permanent xenogeneic transplant.

On January 7, 2022, a porcine heart was transplanted into a male with end-stage heart failure at the University of Maryland [8,70]. The heart, obtained from a pig genetically engineered to eliminate some antigens and control activation of complement, inflammation, and coagulation, functioned well up to seven weeks posttransplant. However, the transplant abruptly failed, and life support was withdrawn on the 60th day. At autopsy, the xenograft appeared grossly edematous, and histology revealed scattered myocyte necrosis, interstitial edema, and red cell extravasation, without clear evidence of rejection. As a potential prelude to kidney xenotransplantation, kidneys from similar pigs were engrafted in several deceased recipients, and various levels of function were reported [6,7].

SUMMARY AND RECOMMENDATIONS

General principles – The transplantation of cells, tissues, and organs between individuals of different species is referred to as xenotransplantation. The shortage of human kidneys for transplantation is severe, resulting in a heightened risk of morbidity and mortality and longer period of waiting for many in need of transplants. Xenotransplantation would eliminate this fundamental problem of clinical transplantation; however, implementation of xenotransplantation on a scale needed to efface the shortage of human kidneys will require development of less toxic regimens of immunosuppression. (See 'Introduction' above.)

Sources of xenografts – The most favored sources of xenografts are pigs genetically engineered to limit the impact of innate immunity and to overcome inherent incompatibility of major physiologic systems such as coagulation. Benefits of using pigs as sources of xenografts include potentially unlimited availability, suitability of organ size, limited scope of transmissible infection, and the possibility of using genetic engineering to address yet unforeseen barriers and improve outcomes. (See 'Sources of xenografts' above.)

Barriers to xenotransplantation – Although long-term survival and function of experimental xenografts have been repeatedly attained and a few clinical trials of xenotransplantation have begun, successful application of xenotransplantation of the kidney still must overcome some difficult hurdles. The most vexing hurdle to xenotransplantation remains the immunologic response of the recipient against the graft. The powerful immunologic reactions to xenografts impel use of intensive regimens of immunosuppression, and whether these can be made fully acceptable for widespread clinical application remains unclear. Also not fully clear is whether porcine kidney xenografts can provide all of the functions a human allograft can provide and whether yet unappreciated incompatibilities can be overcome by genetic engineering of the source or by medical treatment of the recipient. Although risks of infection associated with xenotransplantation appear manageable, uncertainty about these risks and other ethical considerations will likely remain unsettled until xenotransplantation achieves regular clinical application. (See 'Barriers to xenotransplantation' above.)

Possible future indications – If biologic hurdles are overcome, kidney xenotransplantation could be used for select populations. These may include presensitized individuals and young infants with kidney failure, among others. (See 'Possible future indications' above and 'Future approach' above.)

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Topic 7323 Version 20.0

References

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