Xenotransplantation and the kidney
- Jeffrey L Platt, MD
Jeffrey L Platt, MD
- Professor of Surgery and Microbiology and Immunology
- University of Michigan
- Section Editor
- Daniel C Brennan, MD, FACP
Daniel C Brennan, MD, FACP
- Editor-in-Chief — Nephrology
- Section Editor — Renal Transplantation
- Professor of Medicine
- Medical Director and Co-Director of the Comprehensive Transplant Center, Department of Internal Medicine, Division of Nephrology
- Johns Hopkins Medical School
The transplantation of cells, tissues, and organs between individuals of different species is referred to as 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 . 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 renal disease makes these challenges worse. Other approaches to renal replacement, such as implantable devices, cell or stem cell therapies, and organogenesis are being explored ; 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 hepatitis B and C) and the ability to introduce extrinsic genetic material for therapeutic purposes .
Despite these possible benefits, xenotransplantation remains a matter of controversy. This controversy stems from the ongoing challenge of overcoming the immune hurdles to xenografting and the theoretical possibility that a xenograft may pose risks to public health by the introduction of infectious agents. A review of xenotransplantation and these 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 renal failure were performed . These transplants functioned for up to nine months; in some cases, the cause of transplant failure and patient death was intercurrent disease and not rejection.
More recently, baboon livers functioned for months after transplantation into two patients with hepatic failure . As with some of the chimpanzee kidney transplants, intercurrent illness rather than intrinsic failure of the livers resulted in patient death.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Jaboulay M. De reins au pli du coude par soutures arterielles et veineuses. Lyon Med 1906; 107:575.
- Cascalho M, Platt JL. Xenotransplantation and other means of organ replacement. Nat Rev Immunol 2001; 1:154.
- White DJ. Genetic engineering of pigs to provide organs for xenotransplantation. Curr Opin Organ Transplant 2006; 11:160.
- Platt JL. New directions for organ transplantation. Nature 1998; 392:11.
- Pierson RN 3rd. Current status of xenotransplantation. JAMA 2009; 301:967.
- REEMTSMA K, MCCRACKEN BH, SCHLEGEL JU, et al. RENAL HETEROTRANSPLANTATION IN MAN. Ann Surg 1964; 160:384.
- Starzl TE, Fung J, Tzakis A, et al. Baboon-to-human liver transplantation. Lancet 1993; 341:65.
- Ekser B, Cooper DK, Tector AJ. The need for xenotransplantation as a source of organs and cells for clinical transplantation. Int J Surg 2015; 23:199.
- Hammerman MR. Xenotransplantation of developing kidneys. Am J Physiol Renal Physiol 2002; 283:F601.
- Rogers SA, Talcott M, Hammerman MR. Transplantation of pig metanephroi. ASAIO J 2003; 49:48.
- Cascalho M, Platt JL. New technologies for organ replacement and augmentation. Mayo Clin Proc 2005; 80:370.
- Yokoo T, Fukui A, Matsumoto K, Okabe M. Stem cells and kidney organogenesis. Front Biosci 2008; 13:2814.
- Cascalho M, Platt JL. Emerging strategies in kidney transplantation. In: Chronic Kidney Disease, Dialysys, and Transplantation, 3, Himmelfarb J, Sayegh MH (Eds), Elsevier, Philadelphia 2010.
- Parker W, Bruno D, Holzknecht ZE, Platt JL. Characterization and affinity isolation of xenoreactive human natural antibodies. J Immunol 1994; 153:3791.
- Brauer RB, Baldwin WM 3rd, Daha MR, et al. Use of C6-deficient rats to evaluate the mechanism of hyperacute rejection of discordant cardiac xenografts. J Immunol 1993; 151:7240.
- Saadi S, Platt JL. Transient perturbation of endothelial integrity induced by natural antibodies and complement. J Exp Med 1995; 181:21.
- Crikis S, Cowan PJ, d'Apice AJ. Intravascular thrombosis in discordant xenotransplantation. Transplantation 2006; 82:1119.
- Schmelzle M, Schulte Esch J 2nd, Robson SC. Coagulation, platelet activation and thrombosis in xenotransplantation. Curr Opin Organ Transplant 2010; 15:212.
- Sablinski T, Latinne D, Gianello P, et al. Xenotransplantation of pig kidneys to nonhuman primates: I. Development of the model. Xenotransplantation 1995; 2:264.
- Platt JL. Complement inhibitors. In: Inflammation: Basic Principles and Clinical Correlates, 3rd ed, Gallin JI, Snyderman R, Fearon DT, et al (Eds), Lippincott-Raven, Philadelphia 1999.
- Pruitt SK, Kirk AD, Bollinger RR, et al. The effect of soluble complement receptor type 1 on hyperacute rejection of porcine xenografts. Transplantation 1994; 57:363.
- Kroshus TJ, Rollins SA, Dalmasso AP, et al. Complement inhibition with an anti-C5 monoclonal antibody prevents acute cardiac tissue injury in an ex vivo model of pig-to-human xenotransplantation. Transplantation 1995; 60:1194.
- Shimizu A, Yamada K, Yamamoto S, et al. Thrombotic microangiopathic glomerulopathy in human decay accelerating factor-transgenic swine-to-baboon kidney xenografts. J Am Soc Nephrol 2005; 16:2732.
- Platt JL, Vercellotti GM, Dalmasso AP, et al. Transplantation of discordant xenografts: a review of progress. Immunol Today 1990; 11:450.
- McCurry KR, Kooyman DL, Alvarado CG, et al. Human complement regulatory proteins protect swine-to-primate cardiac xenografts from humoral injury. Nat Med 1995; 1:423.
- Cozzi E, Yannoutsos N, Langford GA, et al. Effect of transgenic expresssion of human decay-accelerating factor on the inhibition of hyperacute rejection of pig organs. In: Xenotransplantation: The Transplantation of Organs and Issues Between Species, Springer, Berlin 1997. p.665.
- Zhou CY, McInnes E, Copeman L, et al. Transgenic pigs expressing human CD59, in combination with human membrane cofactor protein and human decay-accelerating factor. Xenotransplantation 2005; 12:142.
- Dai Y, Vaught TD, Boone J, et al. Targeted disruption of the alpha1,3-galactosyltransferase gene in cloned pigs. Nat Biotechnol 2002; 20:251.
- Lai L, Kolber-Simonds D, Park KW, et al. Production of alpha-1,3-galactosyltransferase knockout pigs by nuclear transfer cloning. Science 2002; 295:1089.
- Cooper DK. Clinical xenotransplantion--how close are we? Lancet 2003; 362:557.
- Yamada K, Yazawa K, Shimizu A, et al. Marked prolongation of porcine renal xenograft survival in baboons through the use of alpha1,3-galactosyltransferase gene-knockout donors and the cotransplantation of vascularized thymic tissue. Nat Med 2005; 11:32.
- Zhong R. Gal knockout and beyond. Am J Transplant 2007; 7:5.
- Higginbotham L, Mathews D, Breeden CA, et al. Pre-transplant antibody screening and anti-CD154 costimulation blockade promote long-term xenograft survival in a pig-to-primate kidney transplant model. Xenotransplantation 2015; 22:221.
- Lin SS, Weidner BC, Byrne GW, et al. The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants. J Clin Invest 1998; 101:1745.
- Lin Y, Vandeputte M, Waer M. Accommodation and T-independent B cell tolerance in rats with long term surviving hamster heart xenografts. J Immunol 1998; 160:369.
- Platt JL, Lin SS, McGregor CG. Acute vascular rejection. Xenotransplantation 1998; 5:169.
- Bannett AD, McAlack RF, Morris M, et al. ABO incompatible renal transplantation: a qualitative analysis of native endothelial tissue ABO antigens after transplantation. Transplant Proc 1989; 21:783.
- Koch CA, Khalpey ZI, Platt JL. Accommodation: preventing injury in transplantation and disease. J Immunol 2004; 172:5143.
- Dorling A. Transplant accommodation--are the lessons learned from xenotransplantation pertinent for clinical allotransplantation? Am J Transplant 2012; 12:545.
- Bach FH, Ferran C, Hechenleitner P, et al. Accommodation of vascularized xenografts: expression of "protective genes" by donor endothelial cells in a host Th2 cytokine environment. Nat Med 1997; 3:196.
- Vogt BA, Shanley TP, Croatt A, et al. Glomerular inflammation induces resistance to tubular injury in the rat. A novel form of acquired, heme oxygenase-dependent resistance to renal injury. J Clin Invest 1996; 98:2139.
- Ildstad ST, Sachs DH. Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts. Nature 1984; 307:168.
- Ildstad ST, Vacchio MS, Markus PM, et al. Cross-species transplantation tolerance: rat bone marrow-derived cells can contribute to the ligand for negative selection of mouse T cell receptor V beta in chimeras tolerant to xenogeneic antigens (mouse + rat----mouse). J Exp Med 1992; 175:147.
- Li H, Ricordi C, Demetris AJ, et al. Mixed xenogeneic chimerism (mouse+rat-->mouse) to induce donor-specific tolerance to sequential or simultaneous islet xenografts. Transplantation 1994; 57:592.
- Sachs DH, Sablinski T. Tolerance across discordant xenogeneic barriers. Xenotransplantation 1995; 2:234.
- Mohiuddin MM, Singh AK, Corcoran PC, et al. Genetically engineered pigs and target-specific immunomodulation provide significant graft survival and hope for clinical cardiac xenotransplantation. J Thorac Cardiovasc Surg 2014; 148:1106.
- Sprangers B, Waer M, Billiau AD. Xenograft rejection and the innate immune system. Curr Opin Organ Transplant 2007; 12:142.
- Zaidi A, Schmoeckel M, Bhatti F, et al. Life-supporting pig-to-primate renal xenotransplantation using genetically modified donors. Transplantation 1998; 65:1584.
- McCurry KR, Parker W, Cotterell AH, et al. Humoral responses to pig-to-baboon cardiac transplantation: implications for the pathogenesis and treatment of acute vascular rejection and for accommodation. Hum Immunol 1997; 58:91.
- Hancock WW, Buelow R, Sayegh MH, Turka LA. Antibody-induced transplant arteriosclerosis is prevented by graft expression of anti-oxidant and anti-apoptotic genes. Nat Med 1998; 4:1392.
- Zaidi A, Bhatti F, Schmoeckel M, et al. Kidneys from HDAF transgenic pigs are physiologically compatible with primates. Transplant Proc 1998; 30:2465.
- Soin B, Smith KG, Zaidi A, et al. Physiological aspects of pig-to-primate renal xenotransplantation. Kidney Int 2001; 60:1592.
- Patience C, Stoye J. Infectious risk of clinical xenotransplantation. Curr Opin Organ Transplant 2004; 9:176.
- Fishman JA, Patience C. Xenotransplantation: infectious risk revisited. Am J Transplant 2004; 4:1383.
- Patience C, Takeuchi Y, Weiss RA. Infection of human cells by an endogenous retrovirus of pigs. Nat Med 1997; 3:282.
- Paradis K, Langford G, Long Z, et al. Search for cross-species transmission of porcine endogenous retrovirus in patients treated with living pig tissue. The XEN 111 Study Group. Science 1999; 285:1236.
- Ogle BM, Butters KA, Plummer TB, et al. Spontaneous fusion of cells between species yields transdifferentiation and retroviral transfer in vivo. FASEB J 2004; 18:548.
- Platt JL. Xenotransplantation. New risks, new gains. Nature 2000; 407:27, 29.
- Institute of Medicine. Xenotransplantation. National Academy Press, Washington, 1996.
- Animal-to-human transplants: the ethics of xenotransplantation. London: The Nuffield Council on Bioethics, 1996.
- Sykes M, d'Apice A, Sandrin M, IXA Ethics Committee. Position paper of the Ethics Committee of the International Xenotransplantation Association. Transplantation 2004; 78:1101.
- Platt JL, Cascalho M. New and old technologies for organ replacement. Curr Opin Organ Transplant 2013; 18:179.
- Cooper DK, Tseng YL, Saidman SL. Alloantibody and xenoantibody cross-reactivity in transplantation. Transplantation 2004; 77:1.
- Wong BS, Yamada K, Okumi M, et al. Allosensitization does not increase the risk of xenoreactivity to alpha1,3-galactosyltransferase gene-knockout miniature swine in patients on transplantation waiting lists. Transplantation 2006; 82:314.
- Rood PP, Cooper DK. Islet xenotransplantation: are we really ready for clinical trials? Am J Transplant 2006; 6:1269.
- SOURCES OF XENOGRAFTS
- BARRIERS TO XENOTRANSPLANTATION
- Immunologic reactions
- - Hyperacute rejection
- - Acute vascular rejection
- - Cellular rejection
- - Chronic rejection
- Physiologic function
- Ethical considerations
- POSSIBLE FUTURE INDICATIONS
- Presensitized patients
- Human immunodeficiency virus infection
- FUTURE APPROACH
- SUMMARY AND RECOMMENDATIONS