Liver Transplantation Dilip Chakravarty K, WC Lee, YY Jan, YC Chain, Po-Huang Lee
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History of Liver TransplantationCHAPTER 1

 
INTRODUCTION
Translations in Sanskrit written in 12th century BC reveal a legend about a Hindu God who transplanted the head of an elephant (xenograft) onto a boy whom the God had wrongly beheaded.1 However, this was lacking an immunological explanation for xenotransplantation. The earliest reports on transplantation related to allotransplantation were experimental. In 600 BC, an Indian surgeon, Sushruta, supposedly used skin flaps to replace cut-off noses (the nose was often cut-off as a punishment).2 In 255 BC, a famous Chinese surgeon, Pien Ch'iao, successfully exchanged the hearts of 2 soldiers Ying and Yang. This was considered to be first reference of general anesthesia; to perform surgery.3
In the 2nd century AD the concept of transplantation was first evoked by a Chinese surgeon, Hua-To, who replaced sick organs by healthy organs while making it clear that his purpose was to cure patients.4 In the 3rd century AD, in Rome, Italy, two Syrian doctors, Cosmas and Damian amputated the cancerous leg of a sacristan suffering from gas gangrene and replaced it with the leg of a dead black man.5,6 In the 16th century, an Italian surgeon, Gaspare Tagliacozzi, took up and improved the nose graft techniques of Susrata.7 He noted the difficulties associated with transplantation.
In 1902, Emerich Ullmann performed the first experimental kidney transplantation in dogs in Vienna. A few years later, in 1906, Mathieu Jaboulay, professor of surgery in Lyon, France, connected the renal vessels of a sheep and a pig kidney, respectively, to the brachial vessels of two patients who were dying of renal failure. Both kidneys failed to work. But these were the first transplants, albeit xenografts, that had been placed in humans. The first cadaveric kidney transplant was performed in 1936 in an attempt to treat renal failure after mercury poisoning, but the patient died after 2 days.8 Later on 23rd Dec 1954, first successful kidney transplantation was performed between 2 identical twins, who was dying of renal disease. The surgery was performed at the Peter Bent Brigham Hospital in Boston by Joseph Murray, John Merrill, Hartwell Harrison and their team. The operation was successful and renal function was restored in the recipient, and the donor suffered no adverse effects. This was the first successful transplantation, performed against a background of failure.9,10
 
HISTORY OF LIVER TRANSPLANTATION
Liver transplantation was first attempted in dogs by Welch in Albany in 1955 and Cannon in California in 1956. In the late 1950s and early 1960s two centers, Starzl working in Denver11 and Moore in Boston were interested in the technique of transplanting the liver, which was clearly going to be a formidable undertaking. Both had realized that dogs would not tolerate clamping of the vena cava and portal vein that is necessary to take out and transplant the liver.12 On 1st March, 1963, Thomas E Starzl (Figure 1.1) in Denver, University of Colorado Health Sciences Center (UCHSC), USA had performed the first human liver transplantation in the world in a 3 years old child with biliary atresia and received the liver from another child who died from brain tumor. But they could not complete the surgery and patient died due to uncontrolled hemorrhage.13 The second liver transplantation in man was performed on 5th May, 1963. Patient died on the 22nd postoperative day due to pulmonary embolism but with a normal liver. Starzl therefore decided to have a moratorium on clinical application of liver transplantation that lasted until 1967 when he started his main program. The first long term survival was achieved in 1967 by Starzl in Denver, Colorado, USA.14,15 Despite the developments in surgical techniques, liver transplantation remained experimental till 1970 with 1 yr patient survival rate around 25%.2
zoom view
Figure 1.1: Prof Thomas E Starzl (World's 1st Liver transplantation) [Contributed and reproduced with permission of Terry Mangan, UPMC, USA]
By the end of summer 1967, the Denver experience included 11 liver transplantations. Eight of the patients had undergone orthotopic liver transplantation, and three had been provided with an auxiliary liver. Early immuno-suppressive therapy consisted of azathioprine and prednisolone, but rejection was usually rapid. None of these patients had recovered their health; the longest survival was 34 days. In the same year, a chamber for the preservation of the liver was developed in Denver. The system included perfusion of the liver with diluted blood under hypothermia and hyperbaric oxygenation. When dog livers were placed in the chamber, it was found that the livers could be preserved for 8 hours.16 At the same time, Denver group set out to prepare antihuman anti-lymphocyte globulin (ALG).
In July 1967, a 2½ yrs old child underwent orthotopic liver transplantation on (23rd July, 1967). The donor liver had been maintained for 3 hours in the preservation chamber. The early postoperative function was satisfactory. Postoperatively, antilymphocyte globulin (ALG) was given for several months in combination with azathioprine, and prednisolone. During the following 2 months, two more infants, both suffering from biliary atresia, underwent orthotopic liver transplantation. The protocol was the same as that for the first child. These three children were the first to achieve extended survival after liver transplantation.17 In 1969, Starzl published a monograph on liver transplantation, and by that time 25 patients had been treated in Denver and a number of the patients had survived for more than 1 year.18
Thomas E Starzl's pioneering efforts in organ transplantation for four decades have resulted in clinically proven treatments for patients with end-staged organ failure, who were previously doomed to death. His contributions to immunosuppression, organ procurement, organ preservation, tissue matching, surgical transplant technology, and the team approach to organ transplantation paved the way for the acceptance of heart, lung, pancreas, intestinal, liver, and kidney transplantation.
TABLE 1.1   Historical milestones of liver transplantation15,23–27,66,69
Year
Type of liver transplantation
Surgeon and Country
1963
1st Liver transplantation (biliary atresia)
Starzl TE, Denver, Colorado, USA
1964
1st Liver transplantation in Asia from non-heartbeating donor (biliary atresia)
Nakayama, Chiba Univ., Japan
1967
1st Successful liver transplantation
Starzl TE Denver, Colorado, USA
1968
1st Long-term survival (1 yr) of child
Denver, Colorado, USA
1968
1st Liver transplantation in Europe
Roy Y Calne, Cambridge, Europe
1983
NIH Consensus Conference declares liver transplantation is justified in the treatment of ESLD
1984
1st Reduced-size liver transplantation
Bismuth H, Univ Paris Sud, France
1987
1st LDLT in a child
Raia S, Univ. of São Paulo Brazil
1987
Introduction of University of Wisconsin Solution
1988
1st Split Liver transplantation (2nd Feb.)
Pichlmayr R, Germany
1989
1st Successful LDLT in child
Strong RW, Brisbane, Australia
1989
1st LDLT in Asia (Biliary atresia)
Nagasue, Japan
1993
1st Adult to adult LDLT
Makuuchi, Tokyo Univ., Japan
1997
1st Split Liver transplantation in Asia
Chen CL, Chang Gung Univ, Taiwan
2000
1st Dual graft transplantation
Lee SG, Ulsan Univ., Korea
2001
UNOS/OPTN Board of Directors approve MELD and PELD scoring system for organ allocation in liver transplantation
2002
MELD and PELD Scoring system becomes effective
2007
1st Dual graft transplantation in Europe
Broering DC, H-E Univ, Germany
3
TABLE 1.2   Details of the initial 7 orthotopic liver transplants in the world13,15,18–21,23,70
No
Survival (Days)
Cause of death
Center
1.
0
Uncontrolled hemorrhage
Denver
2.
22
Sepsis and pulmonary embolism
Denver
3.
7.5
Sepsis and pulmonary embolism
Denver
4.
6.5
Pulm. edema, hepatic failure, and pulm. embolism
Denver
5.
11
Hepatic failure, pneumonitis, and liver abscess
Boston
6.
23
Peritonitis, sepsis, and hepatic failure
Denver
7.
0
Hemorrhage
Paris
Starzl combined the marginally effective drugs, azathioprine and prednisolone, in a strategy (1962-63) that made kidney transplantation a viable option for treatment of end-stage renal disease.
Dr Starzl introduced the first major innovation in hypothermia, when canine liver allografts were cooled by infusion of chilled fluids into the vascular bed of hepatic allografts via the portal vein.21 In the initial stages of liver transplantation, 1-year survival rates were below 30% due to various limitations related to surgical technique, ineffective immunosuppression, and inadequate postoperative care. But results later improved drastically.
Till now, 8 patients have survived for more than 30 years after liver transplantation worldwide and 6 of them are from the Denver series.22 The longest survivor has had her new liver for 38 years. This patient was only 3 years old at the time of transplantation. Carl Groth reported that a total of 8 patients transplanted with livers from nonheart-beating donors have by now survived for more than 20 years in Stockholm.23
One of Starzl's early experimental animals survived for many years after the immunosuppressant had been stopped.28 In Cambridge, Roy Y Calne (Figure 1.2) and team were fascinated with the immunological studies of orthotopic liver transplantation and decided to follow Starzl with clinical application in April 1968.29 Clane performed 1st OLT on May 2, 1968, in Addenbrookes Hospital, Europe. In any immunosuppressed patient with an organ graft, there is a danger of sepsis, or infection, and this was in fact the cause of failure in many of the early cases performed in Cambridge.
Starzl wrote in Annals of Surgery (1994):30 Once a seam is opened in the fabric of the finished transplant product by rejection or by the drugs used to control it—whether this be in the graft vasculature, drainage system or any other components of the operation—the deadly handmaid of sepsis……………‥is close by.
zoom view
Figure 1.2: Sir Roy Yorke Calne (Introduced cyclosporine, 1st liver transplantation in Europe, and World's 1st combined heart, lung and liver transplantation) (Reproduced with permission from Sir Roy Y Calne)
 
CONCEPT OF LIVING DONOR LIVER TRANSPLANTATION (LDLT)
Silvano Raia (Figure 1.3) in San Paolo, Brazil, introduced the concept of a living donor transplant to a child.31 The first attempt was performed in December, 1988 without success (the child died on the 6th postoperative day during hemodialysis). The second one was performed in July, 21st, 1989 and the girl survived for 4.5 months and died probably due to CMV infection. His efforts were not successful but were followed up shortly afterward by cases done in Brisbane, Australia by Russell Strong with success.32
4
zoom view
Figure 1.3: Prof Silvano Raia. Professor emeritus at the Faculty of Medicine of the University of San Paulo, San Paulo, Brazil (World's first Living Donor Liver Transplantation in a child)(Contributed and reproduced with permission of Dr. Sergio Mies, Sao Paulo Medical School - USP, Liver Unit, Instituto Dante Pazzanese de Cardiologia, São Paulo–SP, Brazil)
This provided an opportunity to develop liver transplantation in Japan by Makuuchi M and Tanaka K33 that previously had been impossible due to the law on organ donation and reluctance of the public to donate organs. However, parents would frequently offer a lobe of a liver for their child. The Japanese became the most experienced and skillful exponents of this technique in the world, although there was also enthusiasm for it in other centers particularly in the United States.
As results improved and FK506 (tacrolimus) became available as another calcineurin inhibitor like cyclosporine, but with certain advantages in therapeutic index for liver transplants, the criteria of selection for living donors widened to people who are not necessarily parents of a child, but more distant relatives or even friends. Then, adult-to-adult living donation was popularized in Hong Kong by ST Fan whose excellent techniques showed that good results could be obtained either using the right or left lobe, depending on the size of the donor and recipient.34 In Taiwan, first successful deceased donor liver transplantation was performed in March 1984 by CL Chen and his team.
 
ADULT-TO-ADULT LDLT
Initially adult-to-adult liver transplantation was considered as hazardous to the donor. The exact mortality is not known but it has been calculated to be around 0.1-1% either due to complications or inappropriate donor selection with small residual volume or a fatty liver leading to hepatic failure after surgery. But the techniques of LDLT are refined with gaining experience the morbidity and mortality rates are less and risk of the donor can be balanced against the benefits of the recipient.
 
SPLIT LIVER
First split liver transplantation was done on 2nd Feb. 1988 by Rudolf Pichlmayr (Figure 1.4), Germany, later many studies have been reported and is an option to increase the donor pool in carefully selected deceased donor. In Asia, Chen CL from Taiwan performed the first split liver transplantation in May 1997, followed by KC Tan in July 1997 in Singapore.65 Initially, split liver was used for one adult and one pediatric patient, but in the present transplantation scenario, split liver for 2 adults is the subject of interest.
zoom view
Figure 1.4: Prof Rudolf Pichlmayr (1932-1997) (First split liver transplantation)(Contributed and reproduced with permission of S. Karger AG, Medical and Scientific Publishers, Allschwilerstrasse, Basel, Switzerland)
5
 
DOMINOS
1st domino transplantation was introduced in 1997 to increase the donor pool. But this is popular in few countries—Portugal, Japan, and in Sweden, where metabolic diseases like Familial amyloid polyneuropathy was seen. Few cases were also done in Spain, UK and USA.
 
ABO-INCOMPATIBLE (ABO-I) LDLT71
The first ABO-I LDLT was performed in November 1991 in Japan to overcome the organ shortage. As per the data of National Registry of the Japan Study Group for ABO-incompatible, 291 (155 children and 136 adults) ABO-I LDLTs have been performed till March 2006 in Japan from 28 institutions. ABO-incompatible LDLT is a standard practice in children (< 2 years), and plasmapharesis, local infusion and rituximab prophylaxis are promising in adults. In adult LDLT, it is exceptionally performed only as a rescue option in an emergent situation where suitable donor is not available.
 
DUAL GRAFTS
First Dual grafts reported by Lee SG and team from Korea in 2000.66 Several reports suggesting excellent results of this procedure have already been published.67–69
 
HISTORICAL REVIEW OF IMMUNOSUPPRESSION
 
IMMUNOSUPPRESSION DURING EARLIER TIMES
In 1944, Medawar reported that rejection is an immunological event; suppression of the immune system was shown to prolong skin and renal graft survival in animals.40
Immunosuppression in the early 1960s was first performed with total body irradiation,9 corticosteroid therapy,41,42 and later 6-mercaptopurine and its derivative azathioprine.43–45 In animal experiments and clinical trials, no single modality or combination provided complete control of rejection without lethal side effects.46–50 In 1963, Starzl discovered that azathioprine and prednisone had a synergistic effect in animals.51 When these two drugs were immediately applied in human kidney transplant recipients,52,53 the result was a revolution in clinical transplantation. Rejection could usually be reversed with prednisone, and the amount of drugs required could often be reduced with time.54
In 1967, at the University of Colorado, first clinical trials were performed with an antilymphocyte globulin prepared from sensitized horses65 and used as a supplement to azathioprine and prednisone. Most attempts at liver transplantation in 1967 and 1968 at the University of Colorado were initially successful, but all recipients eventually died. The first long-term survivor died of recurrent cancer at 400 days post-transplant.66,67 During the next 12 years, however, the one-year mortality rate never fell below 50%. In the meantime, other researchers around the world were also initiating attempts to transplant livers. At Cambridge University in England, Roy Calne began clinical trials in 1967.58 Rudolf Pichlmayr started a program in Hanover in 1972, and Henri Bismuth started in Paris in 1974. Nevertheless, liver transplantation remained an impractical procedure because of the high mortality rate.
TABLE 1.3   Historical review of rejection and immunosuppression35–39,55–57
Year
Events
1900
ABO blood grouping defined
1916
Immune properties of lymphocytes discovered
1944
Immunological basis of rejection discovered by Medawar
1948
Histocompatibility gene identified in the mice
1950
Histocompatibility complex identified in humans
1951
Lymphocyte sensitivity to radiation discovered
1952
Organic compounds used to prevent rejection
1959
Total body irradiation used to prevent rejection, survival of allografts used linked to HLA typing
1962
Clinical trials on Azathioprine
1964
Experimental transplantation between baboons and humans
1966
Animal experiments with antilymphocyte serum
1967
Antilymphocyte globulins used clinically in heart transplantation
1972
Immune properties of cyclosporine discovered
1972
Immune properties of cyclosporine discovered
1976
T cell inhibition of cyclosporine discovered
1978
Calne first introduced cyclosporine A in renal allografts
1979
FDA approves cyclosporine A for clinical use
1980
Combined cyclosporine and steroids used
1981
Klintmalm reported the nephrotoxicity of Cs A
1984
Immune properties of Tacrolimus discovered
1989
Tacrolimus introduced into clinical trials
1990
1st reports of MMF use in rejection
1993
OKT3 used for induction therapy Chimerism in organ transplantation discovered.
1996
Interleukin expression discovered
1998
Interleukin pathway blocked to prevent rejection
1999
Donor specific tolerance experiments.
 
CYCLOSPORINE ERA
Jean Borel in 1977 showed that the cyclic peptide cyclosporine A prolonged skin graft survival and inhibited immune reactions. Clinical trials with cyclosporine were conducted in cadaveric renal transplantation by Calne.59 The combination of cyclosporine with steroids was used in liver transplant trials by Starzl.606
The greatly improved results reported with cyclosporine A from 1981 to 1982 led to the historic NIH Consensus Development Conference in 1983,61 at which the world's four largest transplant centers presented their results. The conclusion, that liver transplantation was no longer to be considered an experimental procedure, was followed over the next few years by phenomenal increase in the number of liver transplants, transplant centers, and liver transplant candidates. In 1988, when Starzl reported the Pittsburgh experience with 1000 liver transplants with cyclosporine,62 the one-year patient survival rate had risen from 27% with azathioprine to 74% with cyclosporine.
 
TACROLIMUS ERA
In 1989, tacrolimus, another potent calcineurin inhibitor, was introduced in clinical practice in Pittsburgh.63,64 Tacrolimus was found to be effective in reducing the frequency of acute and chronic rejection in liver transplantation. Later these two calcineurin inhibitors, cyclosporine and tacrolimus, have become the primary immunosuppressive agents for transplantation of not only the liver but also other organs.
Recently, additional immunosuppressive agents with different mechanisms of action have become available such mycophenolate mofetil, sirolimus, etc. These agents are usually used in combination with lowered doses of a calcineurin inhibitor, to boost immunosuppression with additive or synergistic effects and to reduce the adverse effects of calcineurin inhibitors.
REFERENCES
  1. O'Flaherty WD. Hindu myths translated. Penguin Books Ltd  London,  England: 1975:261.
  1. Ray P, Gupta HN, Roy M. Susruta Samhita. A Scientific Synopsis. New Delhi: Indian National Science Academy,  1980.
  1. Kahan BD. Pien Ch'iao, the legendary exchange of hearts, traditional Chinese medicine, and the modern era of cyclosporine. Transplant Proc 1988;20:2.
  1. Kuss R, Bourget P. Une histoire illustreá e de la greffe d'organes. La grande aventure du sie” cle. [An illustrated history of organ transplantation: The great adventure of the century]. Laboratoires Sandoz,  Rueil-Malmaison,  France: 1992.
  1. Kahan BD. Cosmas and Damian revisited. Transplant Proc 1983;15:2211.
  1. Rinaldi E. The first homoplastic limb transplant according to the legend of Saint Cosmas and Saint Damian. Ital J Orthop Traumatol 1987;13:393.
  1. Zimbler MS. Gaspare Tagliacozzi (1545-1599): Renaissance surgeon. Arch Facial Plast Surg 2001;3:283.
  1. Hamilton DN, Reid WA, Yu Yu. Voronoy and the first human kidney allograft. Surg Gynecol Obstet 1984;159:289–94.
  1. Merrill JP, Murray JE, Harrison JH, Guild WR. Successful homotransplantation of the human kidney between identical twins JAMA 1956;160:277–82.
  1. Tilney NL. Transplant: from myth to reality. Yale University Press  New Haven,  Conn: 2003.
  1. Starzl TE, Kaupp HA Jr., Brock DR, et al. Reconstructive problems in canine liver homotransplantations with special reference to the postoperative role of hepatic venous flow. Surg Gynecol Obstet 1960;111:733–43.
  1. Moore FD, Wheelers HB, Demissianos HV, et al. Experimental whole organ transplantation of the liver and of the spleen. Ann Surg 1960;142:374–87.
  1. Starzl TE, Marchioro TL, Von Kaulla KN, Hermann G, Brittain RS, Waddel WR. Homotransplantation of the liver in humans. Surg Gynecol Obstet 1963;117:659–76.
  1. Starzl TE, Marchioro TL, Porter KA, Iwasaki Y, Cerilli GJ. The use of heterologous antilymphoid agents in canine renal and liver homotransplantations and in human renal homotrans-plantations. Surg Gynecol Obstet 1967;124:301–18.
  1. Starzl TE, Groth CG, Brettschneider L, et al. Extended survival in 3 cases of orthotopic homotransplantation of the human liver Surgery 1968;63:549.
  1. Brettschneider L, Daloze PM, Huguet C, et al. The use of combined preservation techniques for extended storage of orthotopic liver homografts. Surg Gynecol Obstet 1968;126:263.
  1. Starzl TE, Groth CG, Brettschneider L, et al. Extended survival in 3 cases of orthotopic homotransplantation of the human liver Surgery 1968;63:549.
  1. Starzl TE. Experience in Hepatic Transplantation. Saunders  Philadelphia;  1969.
  1. Moore FD, Birtch AG, Dagher F, et al. Immunosuppression and vascular insufficiency in liver transplantation. Ann NY Acad Sci 1964;102:729.
  1. Demirleau Noureddine, Vignes, et al. Tentative d'homograffe hepatique (attempted hepatic homograft). Men Acad Chir (Paris) 1964;90:177.
  1. Starzl TE: Experience in hepatic transplantation. W.B. Saunders Company.  Philadelphia  1969.
  1. World Transplant Records. Liver. In Cecka JM, Terasaki PJ, (eds): Clinical Transplants 2005. Immunogenetics Center, UCLA  Los Angeles:  2006.
  1. CG Groth. Forty years of liver transplantation. Personal recollections. Transplantation Proceedings 2008;40:1127–29.
  1. Raia S, Nery J, Mies S. Lancet 1989;2:497.
  1. Strong RW, Lynch SV, Ong TH, Matsunami H, Koido Y, Balderson GA. Successful liver transplantation from a living donor to her son. N Engl J Med 1990;322:1505–07.
  1. Shimada M, Fuji M, Morine Y, et al. Living donor liver transplantation, present status and future prospective. Journal of medical investigations 2005;52:22–32.
  1. National Institute of Health. Hepatology 1984;4:107 S–110 S.
  1. Starzl TE. Experience in Hepatic Transplantation. WB Saunders  Philadelphia:  1969:45–48.
  1. Calne RY, Williams R. Liver transplantation in man. Observations on technique and organization in five cases. BMJ 1968;4:535–50.
  1. Todo S, Fung JJ, Starzl TE, Tzakis A, et al. Single center experience with primary orthotopic liver transplantation under FK506 immunosuppression. Ann Surg 1994;220:297–309.
  1. Raia S, Nery JR, Mies S. Liver transplantation from live donors. Lancet 1988;ii:497.
  1. Strong RW, Lynch SV, Ong TN, et al. Successful liver transplantation from a living donor to her son. N Engl J Med 1990;322:1505–07.
  1. 7 Tanaka K, Uemoto S, Tokunaga Y, et al. Surgical techniques and innovations in living related liver transplantation. Ann Surg 1993;217:82–91.
  1. Lo CM, Fan ST, Liu CL, et al. Adult-to-adult living donor transplantation using extended right lobe grafts. Ann Surg 1997;226:261.
  1. A De Vitto Dabbs, JH Dauber, LA Hoffman. Rejection after organ transplantation. A historical review. American journal of critical care 2000;10:419–29.
  1. Calne RY, White DJ, Thiru S, et al. Lancet 1978;2:1323.
  1. Klintmalm GB, Iwatsuki S, Starzl TE. Nephrotoxicity of cyclosporin A in liver and kidney transplant patients. Lancet 1981; 1:470.
  1. Klupp J, Bechstein WO, Platz KP, et al. Mycophenolate mofetil added to immunosuppression after liver transplantation– first results. Transpl Int 1997;10:223.
  1. Fisher RA, Ham JM, Marcos A, et al. A prospective randomized trial of mycophenolate mofetil with neoral or tacrolimus after orthotopic liver transplantation. Transplantation 1998;66:1616.
  1. Medawar PB. The behavior and fate of skin autografts and skin homografts in rabbits J Anat 1944;78:176.
  1. Dempster WJ, Lennox B, Boag JW. Prolongation of survival of skin homotransplants in the rabbit by irradiation of the host. Br J Exp Pathol 1950;31:670.
  1. Morgan JA. The influence of cortisone on the survival of homografts of skin in the rabbit. Surgery 1951;30:505.
  1. Meeker WR, Condie R, Weiner D, et al. Prolongation of skin homograft survival in rabbits by 6-mercaptopurine. Proc Soc Exp Biol Med 1959;102:459.
  1. Calne RY: The rejection of renal homografts: Inhibition in dogs by 6-mercaptopurine. Lancet 1960;1:417.
  1. Calne RY, Murray JE: Inhibition of the rejection of renal homografts in dogs by Burroughs Wellcome 57–332. Surg Forum 1961;12:118.
  1. Murray JE, Merrill JP, Dammin GJ, et al. Kidney transplantation in modified recipients. Ann Surg 1962;156:337.
  1. Murray JE, Merrill JP, Harrison JH, et al. Prolonged survival of human-kidney homografts by immunosuppressive drug therapy N Engl J Med 1963;268:1315.
  1. Woodruff MFA, Robson JS, Nolan B, et al. Homotransplantation of kidney in patients treated with preoperative administration of antimetabolite (Imuran). Lancet 1963;2:675.
  1. Groth CG. Landmarks in clinical renal transplantation. Surg Gynecol Obstet 1972;134:323.
  1. Hamburger J, Vaysse J, Crosnier J, et al. Renal homotransplantation in man after radiation of the recipient. Am J Med 1962;32:854.
  1. Marchioro TL, Axtell HK, LaVia MF, et al. The role of adrenocortical steroids in reversing established homograft rejection. Surgery 1964;55:412.
  1. Starzl TE, Marchioro TL, Waddell WR. The reversal of rejection human renal homografts with subsequent development of homograft tolerance. Surg Gynecol Obstet 1963;117:385.
  1. Starzl TE. Experience in Renal Transplantation. WB Saunders  Philadelphia:  1964.
  1. Starzl TE, Schroter GJP, Hartmann HM, et al. Long term (25 year) survival after renal homotransplantation-the world experience. Transplant Proc 1990;22:2361.
  1. Starzl TE, Marchioro TL, Porter KA, et al. The use of heterologous antilymphoid agents in canine renal and liver homotransplantation and in human renal homotransplantation. Surg Gynecol Obstet 1971;133:981.
  1. Starzl TE, Groth CG, Brettschneider F, et al. Orthotopic homotransplantation of the human liver. Ann Surg 1968; 168:392.
  1. Starzl TE, Iwatsuki S, Van Thiel DH, et al. Evolution of liver transplantation. Hepatology 1982;2:614.
  1. Calne RY, Williams R. Liver transplantation in man. I. Observations on technique and organization in five cases. Br Med J 1968;4:535.
  1. Calne RY, Rolles K, White DJG, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet 1979; 2:1033.
  1. Starzl TE, Klintmalm GBG, Porter KA, et al. Liver transplantation with the use of cyclosporin A and prednisone. N Engl J Med 1981;305:266.
  1. National Institutes of Health Consensus Development Conference Statement. Liver transplantation—June 20–23, 1983. Hepatology 1984;4:S107.
  1. Iwatsuki S, Starzl TE, Todo S, et al. Experience in 1,000 liver transplants under cyclosporine steroid therapy: a survival report. Transplant Proc 1998;20:498.
  1. Starzl TE, Todo S, Fung J, et al. FK506 for liver, kidney, and pancreas transplantation. Lancet 1989;2:1000.
  1. Todo S, Fung J, Starzl TE, et al. Liver, kidney, and thoracic organ transplantation under FK506. Ann Surg 1990;212:295.
  1. VH de Villa, CL Chen, YS Chen, et al. Split Liver Transplantation in Asia. Transplantation Proceedings 2001; 33:1502–03.
  1. Lee S, Hwang S, Park K, et al. An adult-to-adult living donor liver transplant using dual left lobe grafts. Surgery 2001;129:647–50.
  1. Lee SG, Hwang S, Park KM et al. Seventeen adult-to-adult living donor liver transplantations using dual grafts. Transplant Proc 2001;33:3461–63.
  1. Hwang S, Lee SG, Lee YJ et al. Lessons learned from 1,000 living donor liver transplantations in a single center: How to make living donations safe. Liver Transpl 2006;12:920–27.
  1. Broering DC, Walter J, Rogiers X. The first two cases of living donor liver transplantation using dual grafts in Europe. Liver Transpl 2007;13:149–53.
  1. Starzl TE. History of Liver and Other Splanchnic Organ Transplantation. In: Busutill RW, Klintmalm GB, eds. Transplantation of the Liver. Saunders;  Philadelphia,  Pa: 1996: 3–22 and www.emedicine.com
  1. Hiroto E, Satoshi T, Hironori H, et al. Present Status of ABO-Incompatible Living Donor Liver Transplantation in Japan. Hepatology 2008; 47(1):143–52.