Historical perspectives in kidney transplantation: an updated review The present state of success in kidney transplantation, including its benefits to patients with end-stage renal failure, was achieved through relentless research, both in experimental animal models and human volunteers. Kidney transplantation has evolved during the past century thanks to various milestones in surgical techniques, immunology, immunosuppressive drugs, expansion of donor sources, organ preservation, transplant against immunological barriers (ABO blood group-incompatible and positive crossmatch transplants), and research on induction of tolerance, xenotransplants, and stem cell technology. Despite significant improvements in graft and patient survival, several issues still must be addressed to reduce the growing number of patients with kidney failure waiting to receive organs. This article provides an up-to-date review of the milestones in the history of kidney transplantation and highlights strategies to resolve current problems faced by patients and the transplant community. (Progress in Transplantation. 2015;25:64-69,76) ©2015 NATCO, The Organization for Transplant Professionals doi: http://dx.doi.org/10.7182/pit2015789
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idney transplant is the best type of renal replacement therapy for most patients with stage 5 chronic kidney disease because it improves patients’ quality of life and survival rate and is cost-effective.1 According to the World Health Organization,2 in 2012, a total of 77 818 kidney transplants were performed worldwide. The success achieved in kidney transplant has evolved during the past century thanks to major advances in surgical techniques for both donors and recipients, immunology, immunosuppressive drugs, and the selection of donor sources. The current success was achieved only through relentless research, both in experimental animal models and human volunteers. Despite significant improvement in survival rates for both grafts and patients, several issues still must be addressed to reduce the growing number of patients with kidney failure waiting to receive organs.3 This article provides an up-to-date review of the important milestones in the history of kidney transplantation and highlights the future strategies to resolve the current problems faced by patients and the transplant community.
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Badri Shrestha, MS, MD, FRCS, John Haylor, PhD, MPharm, Andrew Raftery, MD, FRCS Sheffield Kidney Institute, Sheffield, United Kingdom Corresponding author: Badri Shrestha, MS, MD, FRCS, FACS, Sheffield Kidney Institute, Herries Road, Sheffield, S5 7AU, United Kingdom (e-mail: [email protected]) To purchase electronic or print reprints, contact: The American Association of Critical-Care Nurses 101 Columbia, Aliso Viejo, CA 92656 Phone (800) 899-1712 (ext 532) or (949) 448-7370 (ext 532) Fax (949) 362-2049 E-mail [email protected]
Literature Search Strategy The literature search was carried out in PubMed and relevant websites by using the search terms kidney transplantation, history, milestones, experiments, and future. Relevant references were compiled by using EndNote software (X6.0.1; Bld 6599). Historical Myths and Milestones in Surgery The history of organ transplantation began in the medicine of mythology. Chimeric gods and heroes appear in a number of cultures. Probably the first and most famous is Ganesha, a child upon whom the Hindu god Shiva xenografted an elephant head.4 Skin autografts for rhinoplasty was used by an Indian surgeon Sushruta and are mentioned in Ayurveda in 800 BC.5 In 1767, John Hunter, the father of British “scientific surgery,” successfully transplanted a human tooth into a cock’s comb, which led him to believe that “transplantation is founded on a disposition in all living substances to unite when brought into contact with each other.”6
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Historical perspectives in kidney transplantation During the nineteenth century, experimental transplants were widespread and involved many different tissues in many animal species. Mathieu Jaboulay and Alexis Carrel of Lyon, France, acted as pioneers in the experimental field of vascular surgery and transplantation. Alexis Carrel popularized the triangular vascular anastomosis technique and performed experimental transplants of vessels, kidneys, thyroid glands, parathyroid glands, heart, ovary, and limbs. In recognition of his many contributions, he was awarded the Noble Prize in 1912.7,8 The first successful experimental kidney transplant was carried out by Emerich Ullman on March 7, 1902, in Vienna, where he autotransplanted a dog kidney from its normal position to the vessels of the neck, which resulted in some urine flow.9 After several years of experimentation, Ukrainian surgeon Yurii Voronoy performed the first human deceased kidney transplant in 1933 by anastomosing the renal vessels to the right femoral vessels in a young woman who had acute renal failure due to mercury poisoning. However, as the donor’s blood group was B and the recipient’s blood group was O, the kidney never functioned and the recipient died after 2 days.10 The first successful kidney transplant, between 2 monozygotic twins, was performed by Joseph Murray on December 23, 1954, at the Peter Bent Brigham Hospital in Boston, Massachusetts, when he transplanted a kidney between identical twin brothers Ronald and Richard Herrick. The recipient, Richard, survived for 8 years and the donor, Ronald, lived for an additional 56 years. Immunosuppression was not available, but in this instance, it was not needed. Dr Murray was awarded the Nobel Prize in medicine in 1990 for his work in transplantation.11 In the same year, David Hume advanced human kidney transplantation in Boston, performing the first successful deceased transplant. He noted accelerated atherosclerosis in the allograft vessels during the postmortem examination. He also reported recurrent disease in the allograft and demonstrated the possibility of controlling intractable hypertension by performing a bilateral nephrectomy.12 The shortage of organ donors, together with the exponential increase in the number of patients with renal failure who are in need of organs, has led to deaths of patients on the transplant waiting list. The donor pool has been expanded by extending the criteria for accepting kidneys that previously had been considered unsuitable for transplant. The criteria for brainstem death were defined and the donors were called donors after brain death (DBD).13,14 Potential donors in intensive care units who do not fulfill the criteria for DBD, but for whom treatment is considered futile, can have treatment withdrawn after opinions of their families have been sought. Once the heart Progress in Transplantation, Vol 25, No. 1, March 2015
has stopped, perfusion and retrieval of the organs are performed. These donors are called donors after circulatory death (DCD). The DCD transplant was initiated in Maastricht in 1995, at which point 4 categories were defined, which were further amended in 2003.15 In fact, before establishment of the criteria for DBD, all organ donors were DCD donors. Use of this source of organs from DCD donors has increased the kidney transplant rate significantly.16 The survival rates of renal grafts from DBD and DCD donors are comparable, although the delayed graft function rate was higher in grafts from DCD donors.17 Dual Kidney Transplant As a result of the shortage of kidneys for transplant, the increasing demand for transplantable grafts, and the increasing numbers of elderly patients, the use of kidneys from older donors has become widely accepted. Because of the reduced renal mass of older kidneys, there is an inherent risk of poor long-term outcome, but this risk has been balanced by transplanting both donor kidneys into a single recipient, known as dual kidney transplant. In 1998, Masson and colleagues were the first to transplant both adult donor kidneys unilaterally into the same iliac fossa.18 In 1 study,19 the 3-year graft survival rate after unilateral dual kidney transplant was 90.9%. Laparoscopic Donor Nephrectomy In order to avoid the disincentives of open nephrectomy, laparoscopic nephrectomy was introduced by Ratner et al in 1995 at Johns Hopkins Hospital. The laparoscopic approach led to significant reductions in postoperative pain, hospital stay, and convalescence time, improved cosmesis, and enhanced organ donation.20 In 1998, Wolf et al21 modified the standard total laparoscopic nephrectomy technique to hand-assisted transperitoneal nephrectomy and demonstrated similar donor and recipient outcomes for the 2 techniques. In 2004, Gill et al22 described single-port transumbilical live donor nephrectomy, which was called scarfree abdominal surgery via natural body orifices, now termed natural orifice transluminal endoscopic surgery (NOTES). In 2006, Renoult et al23 described robotassisted laparoscopic donor nephrectomy and reported low morbidity compared with open donor nephrectomy. Although both the operating time and the warm ischemia time were longer with the robot-assisted technique, no adverse effect on graft function was noted. Organ Preservation Kidneys must be preserved while allocation, transportation, tissue typing, crossmatching and preparation of the recipient are performed. Preservation by using cold storage in preservation solution at 0ºC to 4ºC has been successful in maintaining cellular
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Shrestha et al integrity and graft function. Collins in 1969 introduced the first static cold storage solution, which was modified by the Eurotransplant Foundation in 1976 by eliminating magnesium, yielding what is popularly known as Euro-Collins solution. Continuous research by Belzer and Southard24 in 1988 led to the development of the University of Wisconsin solution, which showed a significant reduction in delayed graft function (23% vs 33%; P = .003) and improved 1-year graft survival (88.2% vs 82.55; P = .04), compared with Euro-Collins solution.25 Machine Perfusion Versus Cold Static Storage Belzer and colleagues26 developed the hypothermic perfusion machine in 1967 and were able to preserve canine kidneys for 72 hours. Machine perfusion generates a controlled continuous or pulsatile recirculating flow of the preservation solution at 0ºC to 4ºC, thereby promoting a complete washout of the blood and metabolites and subsequent tissue equilibration with preservation solution. Overall experimental and clinical data suggest that machine perfusion improves renal preservation and reduces delayed graft function, but any differences in the incidence of primary nonfunction, acute rejection, long-term renal function, and patient survival have yet to be demonstrated.27 Simultaneous Pancreas and Kidney Transplant for Diabetes and Renal Failure Insulin-dependent diabetes mellitus of longer than 20 years leads to poor quality of life, renal failure, premature death, and considerable health care costs. The first successful pancreatic transplant was performed in 1966 by Kelly and Lillehei, simultaneous with a kidney transplant, in a uremic diabetic patient at the University of Minnesota.28 The current indication for pancreatic transplant is brittle diabetes with frequent episodes of diabetic ketoacidosis and unawareness of hypoglycemia. An analysis of 18 159 pancreatic transplants from the International Pancreas Transplant Registry, performed from July 25, 1978, to December 31, 2005, showed an improvement not only in short-term but also in long-term graft function. Most recent 5-year, 10-year, and 20-year graft function for transplants with the appropriate follow-up time were 80%, 68%, and 45%, respectively, for simultaneous pancreas/kidney transplants; 62%, 46%, and 16%, respectively, for pancreatic transplants after a kidney transplant; and 59%, 39%, and 12%, respectively, for pancreatic transplants alone.29 Milestones in Immunology The experimental evidence for the concept of transplant immunology was provided by the pioneering work of Sir Peter Medawar, professor of zoology in Glasgow, between 1943 and 1944, together with
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plastic surgeon Thomas Gibson, by demonstrating that a second skin graft in the same animal was rejected more readily than the first. 30,31 The “second stage phenomenon” or “second set of reaction” was due to “active immunization” from the first graft. The role of lymphocytes in the rejection process was demonstrated much later after the development of hybridoma technology.32 The importance of a humoral component in hyperacute rejection was emphasized by Kissmeyer-Nielsen et al33 in 1966, who described the destructive effects of preformed antibodies on the allograft. The development of crossmatching has considerably reduced the incidence of this dramatic complication. Lafferty and Cunningham, in 1975, described the “2 signal hypothesis” showing a physiological relationship between Tcell subsets: a first humoral signal generated by antigen-presenting elements to helper-inducer T cells (CD4+) and a second humoral signal, the cytokines (interleukin 2, interferon γ, tumor necrosis factors α and β), from these cells to the effector T and B cells.34 The human major histocompatibility complex or human leukocyte antigen (HLA) includes class I, class II, and other poorly defined loci on the short arm of autosomal chromosome 6, which have been extensively elucidated during the past 5 decades. 35 The HLA-A, HLA-B, and HLA-C antigens are known as class I antigens comprising 2 chains, the heavy chain, which is polymorphic, and a nonvariable light-chain 2 microglobulin. The class I antigens are normally expressed on all nucleated cells including all B lymphocytes and resting and activated T cells to present antigens to CD8+ cells to trigger cytotoxic activity. The DR, DQ, and DP antigens are known as class II antigens, which are also glycoproteins comprising α and β chains, and are confined mainly to the endothelium and dendritic cells in nonlymphoid tissues and on B lymphocytes and activated T cells in lymphoid tissues.36 Zinkernagel and Doherty in 1974 proposed the Tcell restriction hypothesis according to which the class I and II glycoproteins serve as scaffolds for the binding and presentation of peptide fragments of the antigen and for T cells to recognize foreign markers only when presented with the histocompatibility antigen.37 The matching of HLA antigens between donors and recipients aims to avoid rejection, but this is seldom possible because of the existence of polymorphism and cross-reactivity between subtypes despite “epitope matching” using monoclonal antibody and DNA sequencing techniques.38 Successful initiation of an immune response depends on 2 major signals being delivered to T cells, leading to their activation. First, antigen-specific recognition occurs through engagement of the T-cell receptor with processed foreign antigen in the context of a self major histocompatibility complex class II molecule. A second
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Historical perspectives in kidney transplantation signal, termed co-stimulatory signal, serves to lower the activation threshold of the T cells, where the pathway involves interaction between the CD40 and CD80/CD86 (B7) cognate ligands in the antigenpresenting cells and CD154 (CD40L) and CD28 in the T-lymphocyte cell membrane. This results in intracellular signaling cascades leading to interleukin 2 gene transcription and its protein synthesis. Interleukin 2 binds to its receptor CD25 and stimulates proliferation of T cells.39 Milestones in Immunosuppression Total body irradiation was the first method of immunosuppression used in human clinical practice and was based on the principle of the destruction of blood cells in bone marrow and lymphoid tissue responsible for rejection.40 The adverse effects of total body irradiation, such as nausea, vomiting, diarrhea, hair loss, bone marrow suppression, and infections made this form of treatment less favorable. The modern era of pharmacological immunosuppression was initiated by Schwartz and Dameshek41 in 1959 by documenting that the antiproliferative drug 6-mercaptopurine dampened antibody production and prolonged survival of rabbit skin allograft. The imidazole derivative of 6-mercaptopurine, azathioprine, was used by Sir Roy Calne and colleagues42 in 1960, prolonging the survival of canine kidney transplants from 7.5 to 23.7 days. Zukoski et al43 of Texas documented the benefit of corticosteroid therapy, first in a canine model and then in humans. From 1966 to 1978, “conventional” therapy consisting of azathioprine and highdose prednisolone was used but was complicated by bone marrow aplasia, gastrointestinal perforation, and fungal infections. Subsequently, attention was focused on the T cells. Antilymphocyte sera produced in 1899 by Russian zoologist Metchnikoff were used 70 years later in rodent models by Levey and Medawar.44 Polyclonal antilymphocyte preparations were introduced into clinical transplant by Starzl et al,45 which led to a broad degree of T-cell inactivation with increased overall graft success rate. Simultaneously, agents that inhibit T-cell activation were explored. Cyclosporine, a calcineurin inhibitor, inhibits the activation cascade necessary for interleukin 2 synthesis, required for the maturation of the cytotoxic T-cell precursor to mature cytotoxic T cells. Cyclosporine was isolated in 1969 from a soil fungus Tolypocladium inflatum (Gams), and its immunosuppressive action in transplant was elucidated by Jean F. Borel. 4 6 , 4 7 Clinical trials of cyclosporine in kidney transplant began in Cambridge in 1978, and cyclosporine was introduced into immunosuppression regimen protocols worldwide in 1982.48,49 With the discovery of cell hybridization techniques, OKT3, an anti-CD3 monoclonal antibody was produced,
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which successfully reversed steroid-resistant rejection, although serious and even lethal adverse reactions due to cytokine release are occasionally evident.50 Like cyclosporine, tacrolimus is a calcineurin inhibitor, isolated from Streptomyces tsukubaensis, but 100 times more potent. In combination with other drugs, tacrolimus has led to significant reduction of acute rejection and thereby prolonged allograft survival.51,52 A meta-analysis comparing tacrolimus with cyclosporine showed significant reduction in acute rejection (relative risk, 0.69) and graft loss (relative risk, 0.56) when tacrolimus was used, although the incidence of new-onset diabetes increased significantly (relative risk, 1.86).53 Subsequently, mycophenolate mofetil, an antiproliferative agent54; sirolimus, an mTOR inhibitor55; interleukin 2 receptor inhibitors such as basiliximab and daclizumab56; anti-CD52 monoclonal antibody such as alemtuzumab (Campath-1H)57; and a chimeric anti-CD20 monoclonal antibody, rituximab58 were introduced. FTY-720, a sphingosine-1-phosphate analogue that interferes with cell traffic between lymphoid organs and blood without impairing T- and B-cell activation, proliferation, and effector function, was tested in clinical trials, but abandoned because of its adverse effects on visual function.59 Currently, proteasome inhibitor (bortezomib), Jak3 inhibitor (tasocitinib), protein kinase C inhibitor (sotrastaurin), anti-C5 monoclonal antibody (eculizumab), anti-leukocyte function action inhibitors (natalizumab and efalizumab), and tumor necrosis factor α inhibitor (infliximab) are under investigation.60 ABO-Incompatible and Positive Crossmatch Transplant The first attempt at ABO-incompatible kidney transplant was reported in 1955 by Chung et al, 61 where 8 of 10 ABO-incompatible kidney allografts did not work successfully within the first few postoperative days. In 1987, Alexandre et al62 introduced an effective desensitization protocol to achieve success in ABO-incompatible living donor kidney transplant. This protocol included repeated plasmapheresis before transplant as a strategy not only to reduce the titers of anti-A or anti-B antibodies, but also to decrease antilymphocyte globulin–based induction. A 1-year graft survival of 75% and recipient survival of 88% were achieved in the 23 recipients.63,64 These efforts regarding ABO-incompatible kidney transplant were significantly expanded in Japan because of the near absence of deceased donors and the paucity (0.15%) of living A2 donors. The largest number of ABOincompatible kidney transplants since 1989, more than 1000 cases, have been performed in Japan, but such transplants were not performed in Europe and the United States until the early 2000s.65 Kidneys from A2 or A2B donors were transplanted into blood group B
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Shrestha et al or O recipients in the United States in 1986, resulting in a 10-year graft survival of 72% for B recipients of those kidneys compared with a 69% 10-year graft survival for B recipients of B kidneys.66 Patients who have anti-HLA antibodies as a consequence of failed previous transplants, pregnancy, or blood transfusions demonstrate positive crossmatch with heightened risk of hyperacute rejection and graft loss. A desensitization protocol consisting of plasmapheresis and a low-dose intravenous immunoglobulin (cytomegalovirus immune globulin) was first used in 1998 at Johns Hopkins Hospital in crossmatchincompatible living-donor kidney transplant candidates.67 Alternatives to desensitisation for ABO-incompatible and positive-crossmatch patients include (1) being placed on the deceased donor transplant waiting list or (2) entering into a paired-exchange living donor program. The paired kidney exchange, also known as kidney swap, has been successfully adopted in the United States, United Kingdom, and several other countries, and is used when a living donor is either blood group incompatible or the crossmatch is positive. Paired kidney exchange has increased the transplant opportunity for highly sensitized patients.68 Current Problems and Future Directions The introduction of cyclosporine resulted in significant improvement in the short- and long-term survival of kidney transplants. An analysis of 93 934 kidney transplants performed in the United States between 1988 and 1996 showed a significant increase in 1-year graft survival for both living donor (88.8% to 93.9%) and deceased donor (75.7% to 87.7%) kidney transplants.69 However, despite a significant reduction in acute rejection, chronic allograft nephropathy and death with functioning grafts remain the leading causes of late loss of renal grafts.70 Organ shortage remains a major hurdle in kidney transplant, leading to a continuous increase in the number of recipients on the transplant waiting list. This problem is being addressed by improving public and professional education programs; by use of non–heartbeating, marginal, and living-unrelated donors; and by the introduction of presumed consent.3 Strategies to modify factors such as calcineurin inhibitor nephrotoxicity, infections (cytomegalovirus, BK virus, and urinary tract infections), malignant neoplasms, and nonadherence are paramount in reducing loss of kidney transplants in the long term.71 In the future, a number of avenues must be explored. The first is the induction of tolerance to an organ allograft. Transplanting donor bone marrow to condition recipients leads to a state of mixed chimerism, where the recipient and donor hematopoietic cells coexist. This process induces tolerance, allowing
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successful withdrawal of long-term immunosuppression in both animal and human models after transplant.72,73 The development of stem cell technology, including nuclear replacement technology, may lead to development of tissue-engineered organs in the future.74 Belatacept is effective in reducing chronic allograft nephropathy by induction of tolerance by blocking co-stimulation.75 Another major endeavor is in the area of xenotransplants. Transplanting organs from animal sources, xenotransplants, remains in the experimental stage. Hyperacute rejection due to the presence of galactoseα1,3-galactose (Gal) antibodies in humans against the Gal-αl,3-Gal antigen present in the pig organs,76,77 is the major barrier to xenotransplant. This barrier is being overcome by breeding transgenic pigs that express human decay accelerating factor on their vascular endothelium. 78 Alternatively, the production of cloned α-1,3-Gal knockout pigs, through elimination of the gene that encodes for the α1,3-galactosyl transferase enzyme necessary for the generation of the α-Gal epitope, may prevent complement activation and hyperacute rejection.79 Xenozoonoses derived from the transfer of porcine endogenous retrovirus are the major risk of xenotransplants. Xenotransplant is not allowed clinically and remains in the experimental stage.80 Other strategies used are the establishment of xenogenic tolerance through mixed chimerism81 and thymic transplant.82 Finally, the development of stem cell technology, including nuclear replacement technology, holds out the hope of producing successful transplants of tissues, such as insulin-producing beta cells, and perhaps tissue-engineered organs.83 Despite continuing research, several factors that are present in donors and recipients, both before and after kidney transplant, influence the long-term outcomes and continue to remain a challenge to successful transplants.71 Financial Disclosures None reported. References 1. Shrestha A, Shrestha A, Basarab-Horwath C, McKane W, Shrestha B, Raftery A. Quality of life following live donor renal transplantation: a single centre experience. Ann Transplant. 2010;15(2):5-10. 2. Kidney Transplant Activity in 2012 in 84 Countries. World Health Organisation. http://issuu.com/o-n-t/docs/2012ad. Accessed August 25, 2014. 3. Shrestha BM. Strategies for reducing the renal transplant waiting list: a review. Exp Clin Transplant. 2009;7(3):173-179. 4. Kahan BD. Ganesha: the primeval Hindu xenograft. Transplant Proc. 1989;21(3 suppl 1):1-8. 5. Bhishagratna KKL. Sushruta Samhita: An English Translation of the Susruta Samhita. Bhishagratna KL, ed. 1907. 6. Hunter J, Palmer JF. The Complete Works of John Hunter, F.R.S. Philadelphia, PA: Haswell, Harrington, and Haswell; 1841:57. 7. Carrel A. La technique operatoire des anastomosis vasculaires, et la transplantation des visceres. Lyon Med. 1902;98:859-864.
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Historical perspectives in kidney transplantation 8. Jaboulay M. Greffew de reinsau pli du coude par soudures artereilles et veinuses. Lyon Med. 1906;107:575. 9. Ullman E. Experimentelle Nierentransplantation. Wien Klin Wochenschr. 1902;15:281. 10. Hamilton DN, Reid WA. Yu. Yu. Voronoy and the first human kidney allograft. Surg Gynecol Obstet. 1984;159(3):289-294. 11. Guild WR, Harrison JH, Merrill JP, Murray J. Successful homotransplantation of the kidney in an identical twin. Trans Am Clin Climatol Assoc. 1955-1956;67:167-173. 12. Hume DM, Merril JP, Miller BF, Thorn GW. Experiences with renal homotransplantation in man modified recipients. J Clin Invest. 1955;34(2):327-382. 13. Brain stem death and organ donation. BMJ. 1989;299(6712): 1282-1286. 14. Simpson A. Organ transplants. Brain stem death. Nurs Times. 1987;83(8):41-42. 15. Daemen JW, Kootstra G, Wijnen RM, Yin M, Heineman E. Nonheart-beating donors: the Maastricht experience. Clin Transpl. 1994:303-316. 16. Fieux F, Losser MR, Bourgeois E, et al. Kidney retrieval after sudden out of hospital refractory cardiac arrest: a cohort of uncontrolled non heart beating donors. Crit Care. 2009;13(4):R141. 17. Hashiani AA, Rajaeefard A, Hasanzadeh J, et al. Ten-year graft survival of deceased-donor kidney transplantation: a single-center experience. Ren Fail. 2010;32(4):440-447. 18. Masson D, Hefty T. A technique for the transplantation of 2 adult cadaver kidney grafts into 1 recipient. J Urol. 1998; 160(5):1779-1780. 19. Ekser B, Furian L, Broggiato A, et al. Technical aspects of unilateral dual kidney transplantation from expanded criteria donors: experience of 100 patients. Am J Transplant. 2010; 10(9):2000-2007. doi: 10.1111/j.1600-6143.2010.03188.x. 20. Ratner LE, Ciseck LJ, Moore RG, Cigarroa FG, Kaufman HS, Kavoussi LR. Laparoscopic live donor nephrectomy. Transplantation. 1995;60(9):1047-1049. 21. Wolf JS Jr, Tchetgen MB, Merion RM. Hand-assisted laparoscopic live donor nephrectomy. Urology. 1998;52(5):885-887. 22. Gill IS, Canes D, Aron M, et al. Single port transumbilical (ENOTES) donor nephrectomy. J Urol. 2008;180(2):637-641; discussion 641. 23. Renoult E, Hubert J, Ladriere M, et al. Robot-assisted laparoscopic and open live-donor nephrectomy: a comparison of donor morbidity and early renal allograft outcomes. Nephrol Dial Transplant. 2006;21(2):472-477. 24. Belzer FO, Southard JH. Principles of solid-organ preservation by cold storage. Transplantation. 1988;45(4):673-676. 25. Ploeg RJ, van Bockel JH, Langendijk PT, et al. Effect of preservation solution on results of cadaveric kidney transplantation. The European Multicentre Study Group. Lancet. 1992; 340(8812):129-137. 26. Belzer FO, Ashby BS, Gulyassy PF, Powell M. Successful seventeen-hour preservation and transplantation of humancadaver kidney. N Engl J Med. 1968;278(11):608-610. 27. O’Callaghan JM, Morgan RD, Knight SR, Morris PJ. Systematic review and meta-analysis of hypothermic machine perfusion versus static cold storage of kidney allografts on transplant outcomes. Br J Surg. 2013;100(8):991-1001. 28. Kelly WD, Lillehei RC, Merkel FK, Idezuki Y, Goetz FC. Allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy. Surgery. 1967;61(6):827-837. 29. Gruessner AC, Sutherland DE, Gruessner RW. Long-term outcome after pancreas transplantation. Curr Opin Organ Transplant. 2012;17(1):100-105. 30. Medawar PB. The behaviour and fate of skin autografts and skin homografts in rabbits: a report to the War Wounds Committee of the Medical Research Council. J Anat. 1944; 78(pt 5):176-199. 31. Medawar PB. A second study of the behaviour and fate of skin homografts in rabbits: a Report to the War Wounds Committee of the Medical Research Council. J Anat. 1945;79(pt 4): 157-176. 32. Kohler G, Hengartner H, Shulman MJ. Immunoglobulin production by lymphocyte hybridomas. Eur J Immunol. 1978;8(2): 82-88.
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33. Kissmeyer-Nielsen F, Olsen S, Petersen VP, Fjeldborg O. Hyperacute rejection of kidney allografts, associated with preexisting humoral antibodies against donor cells. Lancet. 1966; 2(7465):662-665. 34. Lafferty KJ, Cunningham AJ. A new analysis of allogeneic interactions. Aust J Exp Biol Med Sci. 1975;53(1):27-42. 35. Klein J, Figueroa F. Polymorphism of the mouse H-2 loci. Immunol Rev. 1981;60:23-57. 36. Dallman MJ, Mason DW. Induction of Ia antigens on murine epidermal cells during the rejection of skin allografts. Transplantation. 1983;36(2):222-224. 37. Zinkernagel RM. The Nobel Lectures in Immunology. The Nobel Prize for Physiology or Medicine, 1996. Cellular immune recognition and the biological role of major transplantation antigens. Scand J Immunol. 1997;46(5):421-436. 38. Fuller AA, Rodey GE, Parham P, Fuller TC. Epitope map of the HLA-B7 CREG using affinity-purified human alloantibody probes. Hum Immunol. 1990;28(3):306-325. 39. Croft M, Dubey C. Accessory molecule and costimulation requirements for CD4 T cell response. Crit Rev Immunol. 1997; 17(1):89-118. 40. Hamburger J. 11 Attempts at renal homotransplants in man after irradiation of the receiver [in Spanish]. Rev Med Chil. 1963;91:446-459. 41. Schwartz R, Dameshek W. The effects of 6-mercaptopurine on homograft reactions. J Clin Invest. 1960;39:952-958. 42. Calne RY, Alexandre GP, Murray JE. A study of the effects of drugs in prolonging survival of homologous renal transplants in dogs. Ann N Y Acad Sci. 1962;99:743-761. 43. Zukoski CF, Callaway JM, Rhea WG Jr. Prolonged acceptance of a canine renal allograft achieved with prednisolone. Transplantation. 1965;3:380-386. 44. Levey RH, Medawar PB. Mechanism of action of antilymphoid antisera. Surg Forum. 1966;17:247-249. 45. Starzl TE, Marchioro TL, Hutchinson DE, Porter KA, Cerilli GJ, Brettschneider L. The clinical use of antilymphocyte globulin in renal homotransplantation. Transplantation. 1967;5(4 suppl): 1100-1105. 46. Borel JF. Ciclosporin and its future. Prog Allergy. 1986;38:9-18. 47. Kahan BD. Cyclosporine: the agent and its actions. Transplant Proc. 1985;17(4 suppl 1):5-18. 48. Calne RY, Rolles K, White DJ, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet. 1979;2(8151): 1033-1036. 49. Calne RY, Thiru S, McMaster P, et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. 1978. J Am Soc Nephrol. 1998;9(9):1751-1756. 50. Cosimi AB, Burton RC, Colvin RB, et al. Treatment of acute renal allograft rejection with OKT3 monoclonal antibody. Transplantation. 1981;32(6):535-539. 51. Fung JJ. Tacrolimus and transplantation: a decade in review. Transplantation. 2004;77(9 suppl):S41-43. 52. Mayer AD, Dmitrewski J, Squifflet JP, et al. Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group. Transplantation. 1997;64(3):436-443. 53. Webster AC, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. BMJ. 2005;331(7520):810. 54. Mathew TH. A blinded, long-term, randomized multicenter study of mycophenolate mofetil in cadaveric renal transplantation: results at three years. Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation. 1998;65(11):1450-1454. 55. Kahan BD. Sirolimus: a ten-year perspective. Transplant Proc. 2004;36(1):71-75. 56. Webster AC, Playford EG, Higgins G, Chapman JR, Craig J. Interleukin 2 receptor antagonists for kidney transplant recipients. Cochrane Database Syst Rev. 2004;(1):CD003897.
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Continued from page 69 57. Kirsch BM, Haidinger M, Zeyda M, et al. Alemtuzumab (Campath-1H) induction therapy and dendritic cells: impact on peripheral dendritic cell repertoire in renal allograft recipients. Transpl Immunol. 2006;16(3-4):254-257. 58. Tyden G, Kumlien G, Genberg H, Sandberg J, Lundgren T, Fehrman I. ABO-incompatible kidney transplantation and rituximab. Transplant Proc. 2005;37(8):3286-3287. 59. Budde K, Schmouder RL, Brunkhorst R, et al. First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients. J Am Soc Nephrol. 2002;13(4):1073-1083. 60. Durrbach A, Francois H, Beaudreuil S, Jacquet A, Charpentier B. Advances in immunosuppression for renal transplantation. Nat Rev Nephrol. 2010;6(3):160-167. 61. Chung BH, Lee JY, Kang SH, et al. Comparison of patient outcome according to renal replacement modality after renal allograft failure. Ren Fail. 2011;33(3):261-268. 62. Alexandre GP, Squifflet JP, De Bruyere M, et al. Present experiences in a series of 26 ABO-incompatible living donor renal allografts. Transplant Proc. 1987;19(6):4538-4542. 63. Sonnenday CJ, Warren DS, Cooper M, et al. Plasmapheresis, CMV hyperimmune globulin, and anti-CD20 allow ABOincompatible renal transplantation without splenectomy. Am J Transplant. 2004;4(8):1315-1322. 64. Warren DS, Zachary AA, Sonnenday CJ, et al. Successful renal transplantation across simultaneous ABO incompatible and positive crossmatch barriers. Am J Transplant. 2004; 4(4):561-568. 65. Ishida H, Tanabe K, Toma H, Akiba T. Therapeutic apheresis therapy for ABO-incompatible renal transplantations. Ther Apher Dial. 2003;7(6):520-528. 66. Bryan CF, Nelson PW, Shield CF 3rd, et al. Transplantation of A2 and A2B kidneys from deceased donors into B waiting list candidates increases their transplantation rate. Clin Transpl. 2004:127-133. 67. Montgomery RA, Zachary AA. Transplanting patients with a positive donor-specific crossmatch: a single center’s perspective. Pediatr Transplant. 2004;8(6):535-542. 68. Freitas MC. Kidney transplantation in the US: an analysis of the OPTN/UNOS registry. Clin Transpl. 2011:1-16. 69. Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med.
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2000;342(9):605-612. 70. Pascual M, Theruvath T, Kawai T, Tolkoff-Rubin N, Cosimi AB. Strategies to improve long-term outcomes after renal transplantation. N Engl J Med. 2002;346(8):580-590. 71. Shrestha BM, Haylor JL. Factors influencing long-term outcomes following renal transplantation: a review. JNMA J Nepal Med Assoc. 2007;46(167):136-142. 72. Pilat N, Wekerle T. Transplantation tolerance through mixed chimerism. Nat Rev Nephrol. 2010;6(10):594-605. 73. Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature. 1953;172(4379):603-606. 74. Terzic A, Edwards BS, McKee KC, Nelson TJ. Regenerative medicine: a reality of stem cell technology. Minn Med. 2011; 94(5):44-47. 75. Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med. 2005; 353(8):770-781. 76. Good AH, Cooper DK, Malcolm AJ, et al. Identification of carbohydrate structures that bind human antiporcine antibodies: implications for discordant xenografting in humans. Transplant Proc. 1992;24(2):559-562. 77. Cooper DK, Good AH, Koren E, et al. Identification of alphagalactosyl and other carbohydrate epitopes that are bound by human anti-pig antibodies: relevance to discordant xenografting in man. Transpl Immunol. 1993;1(3):198-205. 78. Cozzi E, White DJ. The generation of transgenic pigs as potential organ donors for humans. Nat Med. 1995;1(9):964-966. 79. Cooper DK, Koren E, Oriol R. Genetically engineered pigs. Lancet. 1993;342(8872):682-683. 80. Stoye JP, Le Tissier P, Takeuchi Y, Patience C, Weiss RA. Endogenous retroviruses: a potential problem for xenotransplantation? Ann N Y Acad Sci. 1998;862:67-74. 81. Sachs DH, Sykes M, Robson SC, Cooper DK. Xenotransplantation. Adv Immunol. 2001;79:129-223. 82. Zhao Y, Fishman JA, Sergio JJ, et al. Immune restoration by fetal pig thymus grafts in T cell-depleted, thymectomized mice. J Immunol. 1997;158(4):1641-1649. 83. Hacking SA, Kachouie NN, Lee WG, Khademhosseini A. Future approaches to organ regeneration: microscale environments, stem cell engineering, and self-assembly of living tissues. Stud Health Technol Inform. 2009;149:214-235.
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K
idney transplant is the best type of renal replacement therapy for most patients with stage 5 chronic kidney disease because it improves patients’ quality of life and survival rate and is cost-effective.1 According to the World Health Organization,2 in 2012, a total of 77 818 kidney transplants were performed worldwide. The success achieved in kidney transplant has evolved during the past century thanks to major advances in surgical techniques for both donors and recipients, immunology, immunosuppressive drugs, and the selection of donor sources. The current success was achieved only through relentless research, both in experimental animal models and human volunteers. Despite significant improvement in survival rates for both grafts and patients, several issues still must be addressed to reduce the growing number of patients with kidney failure waiting to receive organs.3 This article provides an up-to-date review of the important milestones in the history of kidney transplantation and highlights the future strategies to resolve the current problems faced by patients and the transplant community.
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Badri Shrestha, MS, MD, FRCS, John Haylor, PhD, MPharm, Andrew Raftery, MD, FRCS Sheffield Kidney Institute, Sheffield, United Kingdom Corresponding author: Badri Shrestha, MS, MD, FRCS, FACS, Sheffield Kidney Institute, Herries Road, Sheffield, S5 7AU, United Kingdom (e-mail: [email protected]) To purchase electronic or print reprints, contact: The American Association of Critical-Care Nurses 101 Columbia, Aliso Viejo, CA 92656 Phone (800) 899-1712 (ext 532) or (949) 448-7370 (ext 532) Fax (949) 362-2049 E-mail [email protected]
Literature Search Strategy The literature search was carried out in PubMed and relevant websites by using the search terms kidney transplantation, history, milestones, experiments, and future. Relevant references were compiled by using EndNote software (X6.0.1; Bld 6599). Historical Myths and Milestones in Surgery The history of organ transplantation began in the medicine of mythology. Chimeric gods and heroes appear in a number of cultures. Probably the first and most famous is Ganesha, a child upon whom the Hindu god Shiva xenografted an elephant head.4 Skin autografts for rhinoplasty was used by an Indian surgeon Sushruta and are mentioned in Ayurveda in 800 BC.5 In 1767, John Hunter, the father of British “scientific surgery,” successfully transplanted a human tooth into a cock’s comb, which led him to believe that “transplantation is founded on a disposition in all living substances to unite when brought into contact with each other.”6
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Historical perspectives in kidney transplantation During the nineteenth century, experimental transplants were widespread and involved many different tissues in many animal species. Mathieu Jaboulay and Alexis Carrel of Lyon, France, acted as pioneers in the experimental field of vascular surgery and transplantation. Alexis Carrel popularized the triangular vascular anastomosis technique and performed experimental transplants of vessels, kidneys, thyroid glands, parathyroid glands, heart, ovary, and limbs. In recognition of his many contributions, he was awarded the Noble Prize in 1912.7,8 The first successful experimental kidney transplant was carried out by Emerich Ullman on March 7, 1902, in Vienna, where he autotransplanted a dog kidney from its normal position to the vessels of the neck, which resulted in some urine flow.9 After several years of experimentation, Ukrainian surgeon Yurii Voronoy performed the first human deceased kidney transplant in 1933 by anastomosing the renal vessels to the right femoral vessels in a young woman who had acute renal failure due to mercury poisoning. However, as the donor’s blood group was B and the recipient’s blood group was O, the kidney never functioned and the recipient died after 2 days.10 The first successful kidney transplant, between 2 monozygotic twins, was performed by Joseph Murray on December 23, 1954, at the Peter Bent Brigham Hospital in Boston, Massachusetts, when he transplanted a kidney between identical twin brothers Ronald and Richard Herrick. The recipient, Richard, survived for 8 years and the donor, Ronald, lived for an additional 56 years. Immunosuppression was not available, but in this instance, it was not needed. Dr Murray was awarded the Nobel Prize in medicine in 1990 for his work in transplantation.11 In the same year, David Hume advanced human kidney transplantation in Boston, performing the first successful deceased transplant. He noted accelerated atherosclerosis in the allograft vessels during the postmortem examination. He also reported recurrent disease in the allograft and demonstrated the possibility of controlling intractable hypertension by performing a bilateral nephrectomy.12 The shortage of organ donors, together with the exponential increase in the number of patients with renal failure who are in need of organs, has led to deaths of patients on the transplant waiting list. The donor pool has been expanded by extending the criteria for accepting kidneys that previously had been considered unsuitable for transplant. The criteria for brainstem death were defined and the donors were called donors after brain death (DBD).13,14 Potential donors in intensive care units who do not fulfill the criteria for DBD, but for whom treatment is considered futile, can have treatment withdrawn after opinions of their families have been sought. Once the heart Progress in Transplantation, Vol 25, No. 1, March 2015
has stopped, perfusion and retrieval of the organs are performed. These donors are called donors after circulatory death (DCD). The DCD transplant was initiated in Maastricht in 1995, at which point 4 categories were defined, which were further amended in 2003.15 In fact, before establishment of the criteria for DBD, all organ donors were DCD donors. Use of this source of organs from DCD donors has increased the kidney transplant rate significantly.16 The survival rates of renal grafts from DBD and DCD donors are comparable, although the delayed graft function rate was higher in grafts from DCD donors.17 Dual Kidney Transplant As a result of the shortage of kidneys for transplant, the increasing demand for transplantable grafts, and the increasing numbers of elderly patients, the use of kidneys from older donors has become widely accepted. Because of the reduced renal mass of older kidneys, there is an inherent risk of poor long-term outcome, but this risk has been balanced by transplanting both donor kidneys into a single recipient, known as dual kidney transplant. In 1998, Masson and colleagues were the first to transplant both adult donor kidneys unilaterally into the same iliac fossa.18 In 1 study,19 the 3-year graft survival rate after unilateral dual kidney transplant was 90.9%. Laparoscopic Donor Nephrectomy In order to avoid the disincentives of open nephrectomy, laparoscopic nephrectomy was introduced by Ratner et al in 1995 at Johns Hopkins Hospital. The laparoscopic approach led to significant reductions in postoperative pain, hospital stay, and convalescence time, improved cosmesis, and enhanced organ donation.20 In 1998, Wolf et al21 modified the standard total laparoscopic nephrectomy technique to hand-assisted transperitoneal nephrectomy and demonstrated similar donor and recipient outcomes for the 2 techniques. In 2004, Gill et al22 described single-port transumbilical live donor nephrectomy, which was called scarfree abdominal surgery via natural body orifices, now termed natural orifice transluminal endoscopic surgery (NOTES). In 2006, Renoult et al23 described robotassisted laparoscopic donor nephrectomy and reported low morbidity compared with open donor nephrectomy. Although both the operating time and the warm ischemia time were longer with the robot-assisted technique, no adverse effect on graft function was noted. Organ Preservation Kidneys must be preserved while allocation, transportation, tissue typing, crossmatching and preparation of the recipient are performed. Preservation by using cold storage in preservation solution at 0ºC to 4ºC has been successful in maintaining cellular
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Shrestha et al integrity and graft function. Collins in 1969 introduced the first static cold storage solution, which was modified by the Eurotransplant Foundation in 1976 by eliminating magnesium, yielding what is popularly known as Euro-Collins solution. Continuous research by Belzer and Southard24 in 1988 led to the development of the University of Wisconsin solution, which showed a significant reduction in delayed graft function (23% vs 33%; P = .003) and improved 1-year graft survival (88.2% vs 82.55; P = .04), compared with Euro-Collins solution.25 Machine Perfusion Versus Cold Static Storage Belzer and colleagues26 developed the hypothermic perfusion machine in 1967 and were able to preserve canine kidneys for 72 hours. Machine perfusion generates a controlled continuous or pulsatile recirculating flow of the preservation solution at 0ºC to 4ºC, thereby promoting a complete washout of the blood and metabolites and subsequent tissue equilibration with preservation solution. Overall experimental and clinical data suggest that machine perfusion improves renal preservation and reduces delayed graft function, but any differences in the incidence of primary nonfunction, acute rejection, long-term renal function, and patient survival have yet to be demonstrated.27 Simultaneous Pancreas and Kidney Transplant for Diabetes and Renal Failure Insulin-dependent diabetes mellitus of longer than 20 years leads to poor quality of life, renal failure, premature death, and considerable health care costs. The first successful pancreatic transplant was performed in 1966 by Kelly and Lillehei, simultaneous with a kidney transplant, in a uremic diabetic patient at the University of Minnesota.28 The current indication for pancreatic transplant is brittle diabetes with frequent episodes of diabetic ketoacidosis and unawareness of hypoglycemia. An analysis of 18 159 pancreatic transplants from the International Pancreas Transplant Registry, performed from July 25, 1978, to December 31, 2005, showed an improvement not only in short-term but also in long-term graft function. Most recent 5-year, 10-year, and 20-year graft function for transplants with the appropriate follow-up time were 80%, 68%, and 45%, respectively, for simultaneous pancreas/kidney transplants; 62%, 46%, and 16%, respectively, for pancreatic transplants after a kidney transplant; and 59%, 39%, and 12%, respectively, for pancreatic transplants alone.29 Milestones in Immunology The experimental evidence for the concept of transplant immunology was provided by the pioneering work of Sir Peter Medawar, professor of zoology in Glasgow, between 1943 and 1944, together with
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plastic surgeon Thomas Gibson, by demonstrating that a second skin graft in the same animal was rejected more readily than the first. 30,31 The “second stage phenomenon” or “second set of reaction” was due to “active immunization” from the first graft. The role of lymphocytes in the rejection process was demonstrated much later after the development of hybridoma technology.32 The importance of a humoral component in hyperacute rejection was emphasized by Kissmeyer-Nielsen et al33 in 1966, who described the destructive effects of preformed antibodies on the allograft. The development of crossmatching has considerably reduced the incidence of this dramatic complication. Lafferty and Cunningham, in 1975, described the “2 signal hypothesis” showing a physiological relationship between Tcell subsets: a first humoral signal generated by antigen-presenting elements to helper-inducer T cells (CD4+) and a second humoral signal, the cytokines (interleukin 2, interferon γ, tumor necrosis factors α and β), from these cells to the effector T and B cells.34 The human major histocompatibility complex or human leukocyte antigen (HLA) includes class I, class II, and other poorly defined loci on the short arm of autosomal chromosome 6, which have been extensively elucidated during the past 5 decades. 35 The HLA-A, HLA-B, and HLA-C antigens are known as class I antigens comprising 2 chains, the heavy chain, which is polymorphic, and a nonvariable light-chain 2 microglobulin. The class I antigens are normally expressed on all nucleated cells including all B lymphocytes and resting and activated T cells to present antigens to CD8+ cells to trigger cytotoxic activity. The DR, DQ, and DP antigens are known as class II antigens, which are also glycoproteins comprising α and β chains, and are confined mainly to the endothelium and dendritic cells in nonlymphoid tissues and on B lymphocytes and activated T cells in lymphoid tissues.36 Zinkernagel and Doherty in 1974 proposed the Tcell restriction hypothesis according to which the class I and II glycoproteins serve as scaffolds for the binding and presentation of peptide fragments of the antigen and for T cells to recognize foreign markers only when presented with the histocompatibility antigen.37 The matching of HLA antigens between donors and recipients aims to avoid rejection, but this is seldom possible because of the existence of polymorphism and cross-reactivity between subtypes despite “epitope matching” using monoclonal antibody and DNA sequencing techniques.38 Successful initiation of an immune response depends on 2 major signals being delivered to T cells, leading to their activation. First, antigen-specific recognition occurs through engagement of the T-cell receptor with processed foreign antigen in the context of a self major histocompatibility complex class II molecule. A second
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Historical perspectives in kidney transplantation signal, termed co-stimulatory signal, serves to lower the activation threshold of the T cells, where the pathway involves interaction between the CD40 and CD80/CD86 (B7) cognate ligands in the antigenpresenting cells and CD154 (CD40L) and CD28 in the T-lymphocyte cell membrane. This results in intracellular signaling cascades leading to interleukin 2 gene transcription and its protein synthesis. Interleukin 2 binds to its receptor CD25 and stimulates proliferation of T cells.39 Milestones in Immunosuppression Total body irradiation was the first method of immunosuppression used in human clinical practice and was based on the principle of the destruction of blood cells in bone marrow and lymphoid tissue responsible for rejection.40 The adverse effects of total body irradiation, such as nausea, vomiting, diarrhea, hair loss, bone marrow suppression, and infections made this form of treatment less favorable. The modern era of pharmacological immunosuppression was initiated by Schwartz and Dameshek41 in 1959 by documenting that the antiproliferative drug 6-mercaptopurine dampened antibody production and prolonged survival of rabbit skin allograft. The imidazole derivative of 6-mercaptopurine, azathioprine, was used by Sir Roy Calne and colleagues42 in 1960, prolonging the survival of canine kidney transplants from 7.5 to 23.7 days. Zukoski et al43 of Texas documented the benefit of corticosteroid therapy, first in a canine model and then in humans. From 1966 to 1978, “conventional” therapy consisting of azathioprine and highdose prednisolone was used but was complicated by bone marrow aplasia, gastrointestinal perforation, and fungal infections. Subsequently, attention was focused on the T cells. Antilymphocyte sera produced in 1899 by Russian zoologist Metchnikoff were used 70 years later in rodent models by Levey and Medawar.44 Polyclonal antilymphocyte preparations were introduced into clinical transplant by Starzl et al,45 which led to a broad degree of T-cell inactivation with increased overall graft success rate. Simultaneously, agents that inhibit T-cell activation were explored. Cyclosporine, a calcineurin inhibitor, inhibits the activation cascade necessary for interleukin 2 synthesis, required for the maturation of the cytotoxic T-cell precursor to mature cytotoxic T cells. Cyclosporine was isolated in 1969 from a soil fungus Tolypocladium inflatum (Gams), and its immunosuppressive action in transplant was elucidated by Jean F. Borel. 4 6 , 4 7 Clinical trials of cyclosporine in kidney transplant began in Cambridge in 1978, and cyclosporine was introduced into immunosuppression regimen protocols worldwide in 1982.48,49 With the discovery of cell hybridization techniques, OKT3, an anti-CD3 monoclonal antibody was produced,
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which successfully reversed steroid-resistant rejection, although serious and even lethal adverse reactions due to cytokine release are occasionally evident.50 Like cyclosporine, tacrolimus is a calcineurin inhibitor, isolated from Streptomyces tsukubaensis, but 100 times more potent. In combination with other drugs, tacrolimus has led to significant reduction of acute rejection and thereby prolonged allograft survival.51,52 A meta-analysis comparing tacrolimus with cyclosporine showed significant reduction in acute rejection (relative risk, 0.69) and graft loss (relative risk, 0.56) when tacrolimus was used, although the incidence of new-onset diabetes increased significantly (relative risk, 1.86).53 Subsequently, mycophenolate mofetil, an antiproliferative agent54; sirolimus, an mTOR inhibitor55; interleukin 2 receptor inhibitors such as basiliximab and daclizumab56; anti-CD52 monoclonal antibody such as alemtuzumab (Campath-1H)57; and a chimeric anti-CD20 monoclonal antibody, rituximab58 were introduced. FTY-720, a sphingosine-1-phosphate analogue that interferes with cell traffic between lymphoid organs and blood without impairing T- and B-cell activation, proliferation, and effector function, was tested in clinical trials, but abandoned because of its adverse effects on visual function.59 Currently, proteasome inhibitor (bortezomib), Jak3 inhibitor (tasocitinib), protein kinase C inhibitor (sotrastaurin), anti-C5 monoclonal antibody (eculizumab), anti-leukocyte function action inhibitors (natalizumab and efalizumab), and tumor necrosis factor α inhibitor (infliximab) are under investigation.60 ABO-Incompatible and Positive Crossmatch Transplant The first attempt at ABO-incompatible kidney transplant was reported in 1955 by Chung et al, 61 where 8 of 10 ABO-incompatible kidney allografts did not work successfully within the first few postoperative days. In 1987, Alexandre et al62 introduced an effective desensitization protocol to achieve success in ABO-incompatible living donor kidney transplant. This protocol included repeated plasmapheresis before transplant as a strategy not only to reduce the titers of anti-A or anti-B antibodies, but also to decrease antilymphocyte globulin–based induction. A 1-year graft survival of 75% and recipient survival of 88% were achieved in the 23 recipients.63,64 These efforts regarding ABO-incompatible kidney transplant were significantly expanded in Japan because of the near absence of deceased donors and the paucity (0.15%) of living A2 donors. The largest number of ABOincompatible kidney transplants since 1989, more than 1000 cases, have been performed in Japan, but such transplants were not performed in Europe and the United States until the early 2000s.65 Kidneys from A2 or A2B donors were transplanted into blood group B
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Shrestha et al or O recipients in the United States in 1986, resulting in a 10-year graft survival of 72% for B recipients of those kidneys compared with a 69% 10-year graft survival for B recipients of B kidneys.66 Patients who have anti-HLA antibodies as a consequence of failed previous transplants, pregnancy, or blood transfusions demonstrate positive crossmatch with heightened risk of hyperacute rejection and graft loss. A desensitization protocol consisting of plasmapheresis and a low-dose intravenous immunoglobulin (cytomegalovirus immune globulin) was first used in 1998 at Johns Hopkins Hospital in crossmatchincompatible living-donor kidney transplant candidates.67 Alternatives to desensitisation for ABO-incompatible and positive-crossmatch patients include (1) being placed on the deceased donor transplant waiting list or (2) entering into a paired-exchange living donor program. The paired kidney exchange, also known as kidney swap, has been successfully adopted in the United States, United Kingdom, and several other countries, and is used when a living donor is either blood group incompatible or the crossmatch is positive. Paired kidney exchange has increased the transplant opportunity for highly sensitized patients.68 Current Problems and Future Directions The introduction of cyclosporine resulted in significant improvement in the short- and long-term survival of kidney transplants. An analysis of 93 934 kidney transplants performed in the United States between 1988 and 1996 showed a significant increase in 1-year graft survival for both living donor (88.8% to 93.9%) and deceased donor (75.7% to 87.7%) kidney transplants.69 However, despite a significant reduction in acute rejection, chronic allograft nephropathy and death with functioning grafts remain the leading causes of late loss of renal grafts.70 Organ shortage remains a major hurdle in kidney transplant, leading to a continuous increase in the number of recipients on the transplant waiting list. This problem is being addressed by improving public and professional education programs; by use of non–heartbeating, marginal, and living-unrelated donors; and by the introduction of presumed consent.3 Strategies to modify factors such as calcineurin inhibitor nephrotoxicity, infections (cytomegalovirus, BK virus, and urinary tract infections), malignant neoplasms, and nonadherence are paramount in reducing loss of kidney transplants in the long term.71 In the future, a number of avenues must be explored. The first is the induction of tolerance to an organ allograft. Transplanting donor bone marrow to condition recipients leads to a state of mixed chimerism, where the recipient and donor hematopoietic cells coexist. This process induces tolerance, allowing
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successful withdrawal of long-term immunosuppression in both animal and human models after transplant.72,73 The development of stem cell technology, including nuclear replacement technology, may lead to development of tissue-engineered organs in the future.74 Belatacept is effective in reducing chronic allograft nephropathy by induction of tolerance by blocking co-stimulation.75 Another major endeavor is in the area of xenotransplants. Transplanting organs from animal sources, xenotransplants, remains in the experimental stage. Hyperacute rejection due to the presence of galactoseα1,3-galactose (Gal) antibodies in humans against the Gal-αl,3-Gal antigen present in the pig organs,76,77 is the major barrier to xenotransplant. This barrier is being overcome by breeding transgenic pigs that express human decay accelerating factor on their vascular endothelium. 78 Alternatively, the production of cloned α-1,3-Gal knockout pigs, through elimination of the gene that encodes for the α1,3-galactosyl transferase enzyme necessary for the generation of the α-Gal epitope, may prevent complement activation and hyperacute rejection.79 Xenozoonoses derived from the transfer of porcine endogenous retrovirus are the major risk of xenotransplants. Xenotransplant is not allowed clinically and remains in the experimental stage.80 Other strategies used are the establishment of xenogenic tolerance through mixed chimerism81 and thymic transplant.82 Finally, the development of stem cell technology, including nuclear replacement technology, holds out the hope of producing successful transplants of tissues, such as insulin-producing beta cells, and perhaps tissue-engineered organs.83 Despite continuing research, several factors that are present in donors and recipients, both before and after kidney transplant, influence the long-term outcomes and continue to remain a challenge to successful transplants.71 Financial Disclosures None reported. References 1. Shrestha A, Shrestha A, Basarab-Horwath C, McKane W, Shrestha B, Raftery A. Quality of life following live donor renal transplantation: a single centre experience. Ann Transplant. 2010;15(2):5-10. 2. Kidney Transplant Activity in 2012 in 84 Countries. World Health Organisation. http://issuu.com/o-n-t/docs/2012ad. Accessed August 25, 2014. 3. Shrestha BM. Strategies for reducing the renal transplant waiting list: a review. Exp Clin Transplant. 2009;7(3):173-179. 4. Kahan BD. Ganesha: the primeval Hindu xenograft. Transplant Proc. 1989;21(3 suppl 1):1-8. 5. Bhishagratna KKL. Sushruta Samhita: An English Translation of the Susruta Samhita. Bhishagratna KL, ed. 1907. 6. Hunter J, Palmer JF. The Complete Works of John Hunter, F.R.S. Philadelphia, PA: Haswell, Harrington, and Haswell; 1841:57. 7. Carrel A. La technique operatoire des anastomosis vasculaires, et la transplantation des visceres. Lyon Med. 1902;98:859-864.
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Historical perspectives in kidney transplantation 8. Jaboulay M. Greffew de reinsau pli du coude par soudures artereilles et veinuses. Lyon Med. 1906;107:575. 9. Ullman E. Experimentelle Nierentransplantation. Wien Klin Wochenschr. 1902;15:281. 10. Hamilton DN, Reid WA. Yu. Yu. Voronoy and the first human kidney allograft. Surg Gynecol Obstet. 1984;159(3):289-294. 11. Guild WR, Harrison JH, Merrill JP, Murray J. Successful homotransplantation of the kidney in an identical twin. Trans Am Clin Climatol Assoc. 1955-1956;67:167-173. 12. Hume DM, Merril JP, Miller BF, Thorn GW. Experiences with renal homotransplantation in man modified recipients. J Clin Invest. 1955;34(2):327-382. 13. Brain stem death and organ donation. BMJ. 1989;299(6712): 1282-1286. 14. Simpson A. Organ transplants. Brain stem death. Nurs Times. 1987;83(8):41-42. 15. Daemen JW, Kootstra G, Wijnen RM, Yin M, Heineman E. Nonheart-beating donors: the Maastricht experience. Clin Transpl. 1994:303-316. 16. Fieux F, Losser MR, Bourgeois E, et al. Kidney retrieval after sudden out of hospital refractory cardiac arrest: a cohort of uncontrolled non heart beating donors. Crit Care. 2009;13(4):R141. 17. Hashiani AA, Rajaeefard A, Hasanzadeh J, et al. Ten-year graft survival of deceased-donor kidney transplantation: a single-center experience. Ren Fail. 2010;32(4):440-447. 18. Masson D, Hefty T. A technique for the transplantation of 2 adult cadaver kidney grafts into 1 recipient. J Urol. 1998; 160(5):1779-1780. 19. Ekser B, Furian L, Broggiato A, et al. Technical aspects of unilateral dual kidney transplantation from expanded criteria donors: experience of 100 patients. Am J Transplant. 2010; 10(9):2000-2007. doi: 10.1111/j.1600-6143.2010.03188.x. 20. Ratner LE, Ciseck LJ, Moore RG, Cigarroa FG, Kaufman HS, Kavoussi LR. Laparoscopic live donor nephrectomy. Transplantation. 1995;60(9):1047-1049. 21. Wolf JS Jr, Tchetgen MB, Merion RM. Hand-assisted laparoscopic live donor nephrectomy. Urology. 1998;52(5):885-887. 22. Gill IS, Canes D, Aron M, et al. Single port transumbilical (ENOTES) donor nephrectomy. J Urol. 2008;180(2):637-641; discussion 641. 23. Renoult E, Hubert J, Ladriere M, et al. Robot-assisted laparoscopic and open live-donor nephrectomy: a comparison of donor morbidity and early renal allograft outcomes. Nephrol Dial Transplant. 2006;21(2):472-477. 24. Belzer FO, Southard JH. Principles of solid-organ preservation by cold storage. Transplantation. 1988;45(4):673-676. 25. Ploeg RJ, van Bockel JH, Langendijk PT, et al. Effect of preservation solution on results of cadaveric kidney transplantation. The European Multicentre Study Group. Lancet. 1992; 340(8812):129-137. 26. Belzer FO, Ashby BS, Gulyassy PF, Powell M. Successful seventeen-hour preservation and transplantation of humancadaver kidney. N Engl J Med. 1968;278(11):608-610. 27. O’Callaghan JM, Morgan RD, Knight SR, Morris PJ. Systematic review and meta-analysis of hypothermic machine perfusion versus static cold storage of kidney allografts on transplant outcomes. Br J Surg. 2013;100(8):991-1001. 28. Kelly WD, Lillehei RC, Merkel FK, Idezuki Y, Goetz FC. Allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy. Surgery. 1967;61(6):827-837. 29. Gruessner AC, Sutherland DE, Gruessner RW. Long-term outcome after pancreas transplantation. Curr Opin Organ Transplant. 2012;17(1):100-105. 30. Medawar PB. The behaviour and fate of skin autografts and skin homografts in rabbits: a report to the War Wounds Committee of the Medical Research Council. J Anat. 1944; 78(pt 5):176-199. 31. Medawar PB. A second study of the behaviour and fate of skin homografts in rabbits: a Report to the War Wounds Committee of the Medical Research Council. J Anat. 1945;79(pt 4): 157-176. 32. Kohler G, Hengartner H, Shulman MJ. Immunoglobulin production by lymphocyte hybridomas. Eur J Immunol. 1978;8(2): 82-88.
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