Advances in organ preservation, immunosuppression, and surgical procedures have resulted in improved outcomes and survival rates. However, regarding organ transplant in different communities, these advances raise major ethical, policy, and religious issues.
Transplant progress in Iran, in relation to the rest of the world, has been slow at times and quick during others. Between 1988 and 1993, there was a rapid surge in experiments with tissue transplant in Iran, and the Shiraz Organ Transplantation Center, established in 1988, rose to become a pioneer of the most significant improvements, a leading center for organ transplant, and the only center for liver transplant in Iran.
In this article, we review milestones in the development of a successful organ transplant program and implementation of legislation in Iran. The Shiraz model of transplant is a new program that attempts to overcome the problems of organ shortage. We provide a description of the Iranian model of transplant and its restrictions and examine the most promising future trends in this exciting field.
Key words : Transplantation, Kidney, Liver, Donation, Xenograft
History of Transplant in Shiraz
Regarding the history of transplant in Iran, Shiraz is the most important city. Ideas of implanting organs from animals into human, known as xenotransplantation, date back to the sixth century BC, to Achaemenidae (the Achaemenian dynasty), as evidenced by engravings in Persepolis (an ancient city located near Shiraz) (Figure 1) of mythologic chimeras with a human head, the body of a lion, and the wings of an eagle (1). This chimera represents a superhuman creature with the intelligence of a human being, the power of a lion, and the freedom of the eagle.
Professor Mohammad Sanadizadeh performed the first kidney transplant in Iran from a living-related donor in 1967 in Shiraz (2). The Shiraz Organ Transplantation Center, established by Professor Seyed Ali Malek-Hosseini in 1988, uses the Iran transplant model of renal transplant (3). The first successful heart transplant was performed in Shiraz in 1993 by Professor Mohammad Ali Sanjarian at Saa’di Hospital in Shiraz (personal communication). Professor Malek-Hosseini performed the first liver transplant from a deceased donor at the Shiraz Organ Transplantation Center in 1993 (4).
The reduced-size liver transplant and the split-liver transplant paved the way for the living-donor liver transplant, the most viable alternative to the significant shortage of organs for liver transplant (5,6). In Iran, first attempts were made in pediatric recipients beginning in 1998 at the Shiraz Organ Transplantation Center (7).
Because of the difficulty in finding size-matched hepatic grafts, the donor shortage has been even worse for children (8). Prior to instituting the living-donor liver transplant procedure for infants at the Shiraz Organ Transplantation Center, morality rates for infants awaiting liver transplants approached 61%. With the rapid acceptance of the living-donor liver transplant procedure, mortality decreased to less than 31% in 2006 (9). Although the first living-donor liver transplant was performed in 1993, owing to technical problems leading to graft loss, the procedure has only recently emerged as a clinical liver transplant alternative at the Shiraz Organ Transplantation Center. By November 2006, the Shiraz Organ Transplantation Center had performed 19 living-related liver transplants (17 left lobes and 2 right lobes) (10).
The first split liver transplant in Iran was performed at the Shiraz Organ Transplantation Center in January 2004. By 2006, the Shiraz Organ Transplantation Center had performed 10 split liver transplants, demonstrating that patient survival after split liver transplant is not significantly different from that of whole-organ orthotopic liver transplant (10). For the first time in Iran, between April 2006 and August 2006, the Shiraz Organ Transplantation Center performed a simultaneous kidney-pancreas transplant in 5 patients with type 1 diabetes mellitus and end-stage renal disease (11).
Iranian Model of Renal Transplant
Until 1975, transplanted kidneys were all from living-related donors. The Dialysis and Transplant Committee at the Blood Transfusion Organization, under the Ministry of Health and Medical Education of Iran, established an agreement with Eurotransplant to transfer deceased-donor kidneys to Iran and because of this, 10 kidney transplants were performed (12). By 1980, 112 renal transplants had been performed. Unfortunately, because a deceased organ donation program had not been established, this rapid success in organ transplant was not matched by a parallel increase in the supply of organs available for transplant (13). Since 1980, because of the limited renal transplant activity in Iran, the Ministry of Health, using government funds, began to allow dialysis patients to be transplanted abroad. Any dialysis patient who had a letter of acceptance from a transplant unit abroad was accepted, and all travel and transplant expenses were paid by the government. As a result, the many dialysis patients awaiting transplant created a long transplant waiting list at the Ministry of Health. Between 1980 and 1985, more than 400 of these patients traveled to Europe and the United States to receive their renal transplants. The majority of these transplants were performed in the United Kingdom from living-related donors (14). In 1985, the high cost of renal transplant abroad and the increasing number of patients on the renal transplant waiting list prompted health authorities to establish renal transplant in Iran (13).
Since 1980, Iran has been involved in the imposed war with Iraq, and because of unilateral sanctions against Iran and also the costs of the war, acquiring supplies and equipments for dialysis has become increasingly difficult. Dialysis patients have been dying because of the burdens imposed by the war’s expenses and the sanctions imposed on Iran. Although the imposed war was a restricting event, it had some valuable benefits too because it trained skilled surgeons and taught them independence. Owing to strong cultural and religious barriers to deceased-donor transplant, the only solution for this lack of organs was to establish living-unrelated donations, which would enhance organ availability and reduce the number of problems associated with dialysis. Therefore, a controlled, living-unrelated–donor renal transplant program called the Iranian Model of Kidney Transplant was adopted in 1988 by Professor Iraj Fazel (15). Since that time, however, there have been fears about unethical organ trade in Iran.
Historically, money has been the driving force in purchasing healthcare worldwide. Even so, there are many who do not agree that healthy individuals should be allowed to pay for organs or that they should be allowed to sell one of their kidneys while alive. Despite ethical dilemmas and discussions, organ sales in Third World countries occur all the time, and all attempts to rely solely on altruism to meet the demand for transplantable donor organs have failed and will continue to fail because the dilemma regarding organ availability will always be: to buy or to die (16-18).
Kidneys are the subject of a quietly growing global drama. In the United States, ailing, rich patients are buying kidneys from the poor and desperate in burgeoning black markets. Clandestine kidney sellers get little medical follow-up, buyers often catch hepatitis or HIV, and both endure the consequences of slapdash surgery. As long as some people are determined to obtain kidneys and others are desperate enough to sell them, the trade will be impossible to stop. It makes better sense to regulate the business than to drive it underground (19).
In the face of all this, most countries are staying with the worst of all possible policy options. Governments place the onus on their citizens to volunteer organs. A few European countries, including Spain, increase the supply slightly by presuming citizens' consent to have their organs transplanted when they die unless specified otherwise. Whether or not such presumed consent is morally right, it does not solve the supply problem, in Spain or elsewhere (19). On the other hand, if just 0.06% of healthy Americans aged between 19 and 65 years donated 1 kidney, the country would have no waiting list (19), which is now about 74 128 patients (20). The only way to encourage this is to legalize the sale of kidneys. Although organ donors are currently deprived of legitimate compensation in many places worldwide, there is an international push toward acceptance of a regulated market for human organs. Providing incentives to increase people’s willingness to donate organs and compensating living-unrelated donors are receiving increased global attention (21). This is already occurring in the United States: the State of Pennsylvania will pay $300 to families of deceased organ donors to help cover funeral expenses (22).
In Iran, the initiative to provide compensation to living-unrelated kidney donors began in 1997. The so-called “sacrifice gift” is given as a reward from the Society and Charity Foundation to compensate the donor’s altruistic donation for saving a life. The acceptance and regulation of living-unrelated kidney donation in 1988 provided the foundation for this initiative. Under the living-unrelated donor program, the Charity Foundation of Special Diseases, a nongovernmental organization, is responsible for providing financial compensation as a social gift to unrelated kidney donors in a fixed amount of ten million rials (USD $1090) (23).
It was hoped that a living-unrelated kidney transplant program would decrease waiting list mortality rates and improve the quality of life for patients undergoing dialysis. Before implementing living-unrelated donation, only 30% of patients on the waiting list for a transplant received kidneys from living-related donors. As a result of procuring kidneys from living-unrelated donors, the waiting list for a kidney transplant in Iran was eliminated in 1999 (13).
According to the program protocol, a complete medical examination of the potential donor (including screening for serious contagious diseases such as hepatitis B and HIV infection, as well as a psychosocial evaluation and donor-recipient tissue matching) is performed prior to the procurement operation in all cases. The screening program and health check protocols have been set up to ensure the donors’ safety. The practice also rules out the possibility that persons with poor organs may try to cover up medical problems to participate in the program (21). While the risk of dying from renting out a womb is 6 times higher than that from selling a kidney, some countries still allow people to buy babies from surrogate mothers (19). To decrease the complication rate of kidney donation and make this procedure more acceptable for all persons, Professor Naser Simfroush developed a laparoscopic living-donor nephrectomy that has been used for more than 750 living kidney donors (24). The total cost of living-unrelated donor kidney transplant in Iran is USD $2047 (USD $374 for the donor and USD $1673 for the recipient). Compared with other countries, kidney transplants today are less expensive in Iran (25). There is no fee for a renal transplant incurred by the patient; the government pays all hospital charges (1). This program has removed the disparities for different socioeconomic classes in their access to organ transplants. In 1 study, 50.4% of recipients were poor, 36.2% were middle class, and 13.4% were wealthy (26).
In this model, many, but not all, of the ethical problems related to living-unrelated donor renal transplants have been prevented. For example, poorer persons who, prior to the model’s introduction, had been unable to afford transplants can now afford transplants (27). According to the available results, more men than women are living-unrelated donors. In studies from different cities in Iran, the male-to-female ratio in the donor group has varied from 3:1 to 9:1, and it is about 1.7:1 among recipients. Most living-unrelated donors are in their 30s or 40s, with a mean age of 28.8 ± 6.5 years. These data negate the possible violation and coercion of women or children to donate organs in Iran (27). In the Iranian model, if recipients have no living-related donors, they are referred to the Dialysis and Transplant Patients Association to find a suitable unrelated donor. All members of the Dialysis and Transplant Patients Association are themselves patients who are maintained on some sort of renal replacement therapy, either maintenance hemodialysis, or continuous ambulatory peritoneal dialysis, or they have undergone renal transplant. After the work-up, if the donor is found to be suitable, they will be referred to one of the transplant units (13).
By implementing various control measures, the Iranian model has officially banned trade in organs; the procurement system and the model work to prevent the development of organized organ trade such as exists in other countries. Iran, with its well-equipped transplant centers and qualified transplant surgeons, is attractive to patients from neighboring countries as a regional transplant hub (21). A thoughtful and effective regulation that states that the “organ donor and recipient must be of the same nationality” (28) has helped prevent Iran from being seen as a haven for international organ traders. The regulation prohibits non-Iranian citizens from participating in the country’s living-unrelated transplant system and associated compensated donation program. In all cases, organ procurement takes place from a well-documented source through the official registration process. Organ transplant from an unknown origin is never performed (29,30).
Shiraz Model of Transplant
Despite positive results and opinions favoring the Iranian model, some criticisms have arisen as well. Owing to cultural reasons, the program has decreased the willingness of transplant candidates to get organs from their loved ones. One study showed that the living-unrelated donor program had an adverse effect on the number of living-related donors. In that study, 81% of recipients who received a graft from living-unrelated donors had a potential living-related donor, but owing to cultural reasons, it was not used (31). Most recipients are reluctant to impose any emotional or physical pressure on their families. Although a reward is given to living-related renal transplant donors as well as most recipients, even poor persons prefer to obtain an organ from unrelated donors (31).
The Shiraz Model of Organ Transplant attempts to remove these problems by making structural revisions to the program. In April 1993, the Shiraz Organ Transplantation Center created the Southern Iran Network for Deceased Donor Organ Transplantation, which is an original, integrated approach to improving and emphasizing deceased organ donation over living-unrelated donation. This network monitors all patients listed for organ transplant across the country and is responsible for overseeing the procurement, allocation, and transplant of solid organs. This network covers 9 of most important provinces of Iran to offer the option of organ donation and coordinates deceased organ recovery and placement; it provides public education with the hope that every resident will become a donor (32). Consequently, the annual rate of organ transplant from deceased donors has increased from 0.3 per million of population in 2000 to 1.7 per million of population in 2004; living donations in 2004 were 22.9 per million (33). Since 2000, less than 1% of all kidney transplants in Iran have been from deceased donors. This percentage has increased to 10% currently (34). After training a liver transplant team in 1999 at King’s College in London, the Shiraz Organ Transplantation Center extended its work (35). Patients from Iran and other Persian Gulf countries requiring liver transplants are now referred to this center.
The strategy to increase deceased-organ donation is to have a recipient’s first-degree relatives evaluated, and then, if none is suitable for living-related donation, a living-unrelated donor candidate is selected. Transplant candidates should wait 6 months for a deceased-donor organ; if no deceased donor organ is found during this time, then a living-unrelated organ should be transplanted. This strategy has 3 benefits: it increases the number of deceased-donor and living-related donations; it decreases organ trafficking by decreasing the number of living-unrelated donors; and it increases compliance by requiring organ recipients to undergo a 6-month period of dialysis while waiting for the organ. Problems facing transplant candidates, prior to transplant, make the transplanted organ more valuable for them.
Studies at the Shiraz Organ Transplantation Center have shown that the most common cause of rejection in kidney transplant recipients is nonadherence to the immunosuppressive medication regimen (36). The Shiraz model has been used since 2003, and the preliminary results support the benefits of this program (3). To make the Shiraz model more ethically defensible, the Shiraz Organ Transplantation Center has adopted a policy of nondirected living-unrelated donation to prevent any direct monetary relationship between donors and recipients. According to this policy, individuals donate their kidneys to unknown recipients altruistically and receive compensation. To expand the donor pool, modifications have been made to the living-related donor/recipient relationship including using swap donation between incompatible living-related recipient/donor pairs and another pair who are compatible the donor and the recipient.
Between 1988 and 2004 there were 1200 renal transplants performed at the Shiraz Organ Transplantation Center, which included 168 deceased-donor (14% of donors) kidney transplants (3). The Shiraz Organ Transplantation Center is responsible for training the transplant coordinators for all centers. These coordinators are taught to advertise for deceased-donor donations by encouraging people to sign organ donation cards and urge families to consent to a donation if a family member dies (37). With 27 000 deaths per year related to motor vehicle accidents, Iran has a tragically plentiful supply of young corpses, and a deceased-donor program could alleviate the costs involved with a living-unrelated donation program and waiting lists (38). During just the first year after establishing this program, 55 000 organ donation cards were filled out. Today, more than 10% of the people living in Shiraz have filled out organ donation cards. The deceased organ donation consent number increased from 7 cases in 1998 to 12 cases in 1999. However, between 2000 and 2005, approximately 40 consents per year (or 243 consents) were granted (39). This itself is a reflection of excellent public awareness and humanistic motives, which undoubtedly are the result of having skilled transplant coordinators who can modify the attitudes of families, allowing well-informed families to make a decision and get on with the process of grieving. Our results show that activities to improve deceased-donor and living-related donations in Shiraz have been surprisingly effective in recent years (Figure 2). The 1- and 3-year patient survival rates for deceased-donor kidney transplants in Shiraz are 93% and 90.5%, respectively; while graft survival rates are 88% and 84% at 1 and 3 years, respectively. Although the success rate for transplant surgeries when clinicians in Iran first began performing them was not high, current data reflect a greater-than-90% survival rate, which is comparable to that of major centers throughout the world (3).
Barriers facing organ transplant
The economics of live kidney donations from the perspectives of the recipient and the healthcare provider have been well described: 1 kidney transplant is estimated to result in a net increase of 2 to 3.5 quality-adjusted life-years and a net healthcare savings of USD $100 000 (40). In many countries, there are economic barriers to donors that, in addition to being unfair, may limit rates of organ donation; these barriers must be addressed with a national policy (41). Eliminating barriers to donations is one way of increasing donations. It is the moral responsibility of those administering the procurement system to ensure that donors incur no economic detriment from donating (21).
The cost of a liver transplant in the United States is about USD $350 000 (20), but at the Shiraz Organ Transplantation Center this same cost is approximately USD $38 000, and health insurance does not cover all of it. Therefore, charity organizations such as the Fars Liver Foundation and the Ministry of Health pay some of the charges (about USD $32 000). Patients are left with the remainder of the charges (USD $6000).
Since 1980, owing to limited renal transplant activity in the country, the Ministry of Health began to allow dialysis patients to receive transplants abroad using governmental funds. All travel and transplant expenses are paid (14). However, this program developed 3 problems: first, the cost of organ transplants in Western countries was higher than it was in Iran. Second, it caused an outflux of financial resources from Iran. Third, and most important, were sociocultural problems. Patients were forced to go to another country with a different language, diet, and culture; they had the same problems regarding medical follow-up also. A portion of the funds from the Ministry of Health is now given to any active Iranian liver transplant center to cover some of the expenses of the transplant procedures (USD $6000 for each patient).
Dramatic improvements in organ transplant mean that patients must take expensive immunosuppressive medications for the rest of their lives. Health insurances currently cover most transplant procedures in Iran, but most insurance companies do not pay for outpatient immunosuppressive medications (42). Although the annual per capita income of most persons in Iran is approximately USD $2300 (43), the costs of mandatory immunosuppressive drugs such as mycophenolate mofetil and tacrolimus are USD $1700 and USD $8500, respectively, per year. Evidence suggests that poverty has become a major cause of noncompliance and allograft dysfunction among transplant recipients (44). A solution is needed. We believe that health insurance should cover the cost of all immunosuppressive therapies for all solid-organ transplant recipients who cannot afford to pay. Something must be done to ensure that transplants do not fail because people cannot afford to pay for their immunosuppressive medications.
Unilateral sanctions by the United States against Iran, which began after the takeover of the US embassy in Tehran (November 1979) (45), have limited the availability of vital medicines and medical devices for organ transplants in Iran. Especially, the availability of new immunosuppressive drugs, which are unquestionably more effective in controlling acute rejection and have potentially huge economic advantages regarding the costs of hospitalization and treatment of acute rejection episodes. Transplant in Iran has been slowed by political and financial obstacles, and patients are the casualties of these struggles. However, there are certain sociocultural beliefs and customs too that have slowed the process of transplant development in Iran. Important misconceptions and fears include fear of death, the belief that removing organs from a dead person violates the sanctity of the deceased, concerns about being dissected after death, the desire to be buried intact, a distain for the concept of organs inside another person, and inaccurate information regarding brain death.
Areas for improvement
The final goal of the Shiraz model to eliminate disparities in organ transplant between Iran and other developed countries, is not too far off. Since 2005, the Shiraz Organ Transplantation Center has been training liver transplant surgeons in an effort to increase the number of liver transplant centers and promote liver transplant in Iran. The Shiraz Organ Transplantation Center also began an integrated program for heart and lung transplant in 2006. Another large step in expanding the transplant program is the construction of the Avi-Cenna (Abou Ali Sina) Transplant Hospital in Sadra, a new town near Shiraz. This hospital hopefully will begin operating in 2009. It will offer the opportunity for transplant teams all over the Middle East to transfer graft organs between themselves and to increase cooperation. The hospital offers great promise for transplant medicine in Iran and other Persian Gulf countries (1).
Volume : 5
Issue : 2
Pages : 701 - 707
From the 1Shiraz Organ Transplant Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, and the 2Persian Network for Organ Transplantation, Shiraz, Iran, and the 3School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
Address reprint requests to: Alireza Mehdizadeh, PO Box: 91375-1471, Mashad, Iran
Phone: +98-915-510 31 08 +98-511-840 95 97
Fax: +98-511-851 75 05
Figure 1. Mythologic chimeras, creatures with a human head, a lion’s body, and an eagle’s wings. Carvings of these chimeras, which date back to the sixth century BC to Achaemenidae, remain to this day, in Persepolis, an ancient city near Shiraz.
Figure 2. Number of renal transplants performed at the Shiraz Organ Transplantation Center between 1988 and 2005.