Organ transplantation

Organ transplantation
Intervention

Reenactment of the first heart transplant, performed in South Africa in 1967.
ICD-10-PCS 0?Y
MeSH D016377

Organ transplantation is the moving of an organ from one body to another or from a donor site to another location on the person's own body, to replace the recipient's damaged or absent organ. Organs and/or tissues that are transplanted within the same person's body are called autografts. Transplants that are recently performed between two subjects of the same species are called allografts. Allografts can either be from a living or cadaveric source.

Organs that can be transplanted are the heart, kidneys, liver, lungs, pancreas, intestine, and thymus. Tissues include bones, tendons (both referred to as musculoskeletal grafts), cornea, skin, heart valves, nerves and veins. Worldwide, the kidneys are the most commonly transplanted organs, followed by the liver and then the heart. Cornea and musculoskeletal grafts are the most commonly transplanted tissues; these outnumber organ transplants by more than tenfold.

Organ donors may be living, brain dead, or dead via circulatory death.[1] Tissue may be recovered from donors who die of circulatory death, as well as of brain death – up to 24 hours past the cessation of heartbeat. Unlike organs, most tissues (with the exception of corneas) can be preserved and stored for up to five years, meaning they can be "banked". Transplantation raises a number of bioethical issues, including the definition of death, when and how consent should be given for an organ to be transplanted, and payment for organs for transplantation.[2][3] Other ethical issues include transplantation tourism and more broadly the socio-economic context in which organ procurement or transplantation may occur. A particular problem is organ trafficking.[4] Some organs, such as the brain, cannot be transplanted.

Transplantation medicine is one of the most challenging and complex areas of modern medicine. Some of the key areas for medical management are the problems of transplant rejection, during which the body has an immune response to the transplanted organ, possibly leading to transplant failure and the need to immediately remove the organ from the recipient. When possible, transplant rejection can be reduced through serotyping to determine the most appropriate donor-recipient match and through the use of immunosuppressant drugs.[5]

Types of transplant

Autograft

Main article: Autotransplantation

Autografts are the transplant of tissue to the same person. Sometimes this is done with surplus tissue, tissue that can regenerate, or tissues more desperately needed elsewhere (examples include skin grafts, vein extraction for CABG, etc.). Sometimes an autograft is done to remove the tissue and then treat it or the person before returning it (examples include stem cell autograft and storing blood in advance of surgery). In a rotationplasty, a distal joint is used to replace a more proximal one; typically a foot or ankle joint is used to replace a knee joint. The person's foot is severed and reversed, the knee removed, and the tibia joined with the femur.

Allograft and allotransplantation

Main article: Allotransplantation

An allograft is a transplant of an organ or tissue between two genetically non-identical members of the same species. Most human tissue and organ transplants are allografts. Due to the genetic difference between the organ and the recipient, the recipient's immune system will identify the organ as foreign and attempt to destroy it, causing transplant rejection. The risk of transplant rejection can be estimated by measuring the Panel reactive antibody level.

Isograft

A subset of allografts in which organs or tissues are transplanted from a donor to a genetically identical recipient (such as an identical twin). Isografts are differentiated from other types of transplants because while they are anatomically identical to allografts, they do not trigger an immune response. One study was used on rats where kidney isografts were transplanted into them to study the functionality.[6]

Xenograft and xenotransplantation

Main article: Xenotransplantation

A transplant of organs or tissue from one species to another. An example is porcine heart valve transplant, which is quite common and successful. Another example is attempted piscine-primate (fish to non-human primate) transplant of islet (i.e. pancreatic or insular tissue) tissue. The latter research study was intended to pave the way for potential human use if successful. However, xenotransplantion is often an extremely dangerous type of transplant because of the increased risk of non-compatibility, rejection, and disease carried in the tissue.

Domino transplants

In people with cystic fibrosis, where both lungs need to be replaced, it is a technically easier operation with a higher rate of success to replace both the heart and lungs of the recipient with those of the donor. As the recipient's original heart is usually healthy, it can then be transplanted into a second recipient in need of a heart transplant.[7] Another example of this situation occurs with a special form of liver transplant in which the recipient suffers from familial amyloidotic polyneuropathy, a disease where the liver slowly produces a protein that damages other organs. The recipient's liver can then be transplanted into an older person for whom the effects of the disease will not necessarily contribute significantly to mortality.[8]

This term also refers to a series of living donor transplants in which one donor donates to the highest recipient on the waiting list and the transplant center utilizes that donation to facilitate multiple transplants. These other transplants are otherwise impossible due to blood type or antibody barriers to transplantation. The "Good Samaritan" kidney is transplanted into one of the other recipients, whose donor in turn donates his or her kidney to an unrelated recipient. Depending on the person on the waiting list, this has sometimes been repeated for up to six pairs, with the final donor donating to the person at the top of the list. This method allows all organ recipients to get a transplant even if their living donor is not a match to them. This further benefits people below any of these recipients on waiting lists, as they move closer to the top of the list for a deceased-donor organ. Johns Hopkins Medical Center in Baltimore and Northwestern University's Northwestern Memorial Hospital have received significant attention for pioneering transplants of this kind.[9][10]

In February 2012, the last link in a record 60-person domino chain of 30 kidney transplants was completed.[11][12]

ABO-incompatible transplants

Because very young children (generally under 12 months, but often as old as 24 months,[13]) do not have a well-developed immune system,[14] it is possible for them to receive organs from otherwise incompatible donors. This is known as ABO-incompatible (ABOi) transplantation. Graft survival and peoples mortality is approximately the same between ABOi and ABO-compatible (ABOc) recipients.[15] While focus has been on infant heart transplants, the principles generally apply to other forms of solid organ transplantation.[13]

The most important factors are that the recipient not have produced isohemagglutinins, and that they have low levels of T cell-independent antigens.[14][16] United Network for Organ Sharing (UNOS) regulations allow for ABOi transplantation in children under two years of age if isohemagglutinin titers are 1:4 or below,[17][18] and if there is no matching ABOc recipient.[17][18][19] Studies have shown that the period under which a recipient may undergo ABOi transplantation may be prolonged by exposure to nonself A and B antigens.[20] Furthermore, should the recipient (for example, type B-positive with a type AB-positive graft) require eventual retransplantation, the recipient may receive a new organ of either blood type.[13][18]

Limited success has been achieved in ABO-incompatible heart transplants in adults,[21] though this requires that the adult recipients have low levels of anti-A or anti-B antibodies.[21] Kidney transplantation is more successful, with similar long-term graft survival rates to ABOc transplants.[18]

Transplantation in obese individuals

Until recently, people labeled as obese were not considered appropriate candidates for renal transplantation. In 2009, the physicians at the University of Illinois Medical Center performed the first robotic kidney transplantation in an obese recipient and have continued to transplant people with Body Mass Index (BMI)’s over 35 using robotic surgery. As of January 2014, over 100 people that would otherwise be turned down because of their weight have successfully been transplanted.[22] [23]

Organs and tissues transplanted

Chest

Abdomen

Tissues, cells and fluids

Types of donor

Organ donors may be living or may have died of brain death or circulatory death. Most deceased donors are those who have been pronounced brain dead. Brain dead means the cessation of brain function, typically after receiving an injury (either traumatic or pathological) to the brain, or otherwise cutting off blood circulation to the brain (drowning, suffocation, etc.). Breathing is maintained via artificial sources, which, in turn, maintains heartbeat. Once brain death has been declared the person can be considered for organ donation. Criteria for brain death vary. Because less than 3% of all deaths in the U.S. are the result of brain death, the overwhelming majority of deaths are ineligible for organ donation, resulting in severe shortages.

Organ donation is possible after cardiac death in some situations, primarily when the person is severely brain injured and not expected to survive without artificial breathing and mechanical support. Independent of any decision to donate, a person's next-of-kin may decide to end artificial support. If the person is expected to expire within a short period of time after support is withdrawn, arrangements can be made to withdraw that support in an operating room to allow quick recovery of the organs after circulatory death has occurred.

Tissue may be recovered from donors who die of either brain or circulatory death. In general, tissues may be recovered from donors up to 24 hours past the cessation of heartbeat. In contrast to organs, most tissues (with the exception of corneas) can be preserved and stored for up to five years, meaning they can be "banked." Also, more than 60 grafts may be obtained from a single tissue donor. Because of these three factors—the ability to recover from a non-heart beating donor, the ability to bank tissue, and the number of grafts available from each donor—tissue transplants are much more common than organ transplants. The American Association of Tissue Banks estimates that more than one million tissue transplants take place in the United States each year.

Living donor

In living donors, the donor remains alive and donates a renewable tissue, cell, or fluid (e.g., blood, skin), or donates an organ or part of an organ in which the remaining organ can regenerate or take on the workload of the rest of the organ (primarily single kidney donation, partial donation of liver, lung lobe, small bowel). Regenerative medicine may one day allow for laboratory-grown organs, using person's own cells via stem cells, or healthy cells extracted from the failing organs.

Deceased donor

Deceased donors (formerly cadaveric) are people who have been declared brain-dead and whose organs are kept viable by ventilators or other mechanical mechanisms until they can be excised for transplantation. Apart from brain-stem dead donors, who have formed the majority of deceased donors for the last 20 years, there is increasing use of donation-after-circulatory-death-donors (formerly non-heart-beating donors) to increase the potential pool of donors as demand for transplants continues to grow. Prior to the recognition of brain death in the 1980s, all deceased organ donors had died of circulatory death. These organs have inferior outcomes to organs from a brain-dead donor;[25] however, given the scarcity of suitable organs and the number of people who die waiting, any potentially suitable organ must be considered.

Allocation of organs

In most countries there is a shortage of suitable organs for transplantation. Countries often have formal systems in place to manage the process of determining who is an organ donor and in what order organ recipients receive available organs.

The overwhelming majority of deceased-donor organs in the United States are allocated by federal contract to the Organ Procurement and Transplantation Network (OPTN), held since it was created by the Organ Transplant Act of 1984 by the United Network for Organ Sharing or UNOS. (UNOS does not handle donor cornea tissue; corneal donor tissue is usually handled by various eye banks.) Individual regional organ procurement organizations (OPOs), all members of the OPTN, are responsible for the identification of suitable donors and collection of the donated organs. UNOS then allocates organs based on the method considered most fair by the scientific leadership in the field. The allocation methodology varies somewhat by organ, and changes periodically. For example, liver allocation is based partially on MELD score (Model of End-Stage Liver Disease), an empirical score based on lab values indicative of the sickness of the person from liver disease. In 1984, the National Organ Transplant Act (NOTA) was passed which gave way to the Organ Procurement and Transplantation Network that maintains the organ registry and ensures equitable allocation of organs. The Scientific Registry of Transplant Recipients was also established to conduct ongoing studies into the evaluation and clinical status of organ transplants. In 2000 the Children’s Health Act passed and required NOTA to consider special issues around pediatric patients and organ allocation (Services).

Experiencing somewhat increased popularity, but still very rare, is directed or targeted donation, in which the family of a deceased donor (often honoring the wishes of the deceased) requests an organ be given to a specific person. If medically suitable, the allocation system is subverted, and the organ is given to that person. In the United States, there are various lengths of waiting times due to the different availabilities of organs in different UNOS regions. In other countries such as the UK, only medical factors and the position on the waiting list can affect who receives the organ.

One of the more publicized cases of this type was the 1994 Chester and Patti Szuber transplant. This was the first time that a parent had received a heart donated by one of their own children. Although the decision to accept the heart from his recently killed child was not an easy decision, the Szuber family agreed that giving Patti's heart to her father would have been something that she would have wanted.[26][27]

Access to organ transplantation is one reason for the growth of medical tourism.

Reasons for donation and ethical issues

Living related donors

Living related donors donate to family members or friends in whom they have an emotional investment. The risk of surgery is offset by the psychological benefit of not losing someone related to them, or not seeing them suffer the ill effects of waiting on a list.

Paired exchange

Diagram of an exchange between otherwise incompatible pairs

A "paired-exchange" is a technique of matching willing living donors to compatible recipients using serotyping. For example, a spouse may be willing to donate a kidney to their partner but cannot since there is not a biological match. The willing spouse's kidney is donated to a matching recipient who also has an incompatible but willing spouse. The second donor must match the first recipient to complete the pair exchange. Typically the surgeries are scheduled simultaneously in case one of the donors decides to back out and the couples are kept anonymous from each other until after the transplant.

Paired exchange programs were popularized in the New England Journal of Medicine article "Ethics of a paired-kidney-exchange program" in 1997 by L.F. Ross.[28] It was also proposed by Felix T. Rapport[29] in 1986 as part of his initial proposals for live-donor transplants "The case for a living emotionally related international kidney donor exchange registry" in Transplant Proceedings.[30] A paired exchange is the simplest case of a much larger exchange registry program where willing donors are matched with any number of compatible recipients.[31] Transplant exchange programs have been suggested as early as 1970: "A cooperative kidney typing and exchange program."[32]

The first pair exchange transplant in the U.S. was in 2001 at Johns Hopkins Hospital.[33] The first complex multihospital kidney exchange involving 12 people was performed in February 2009 by The Johns Hopkins Hospital, Barnes-Jewish Hospital in St. Louis and Integris Baptist Medical Center in Oklahoma City.[34] Another 12-person multihospital kidney exchange was performed four weeks later by Saint Barnabas Medical Center in Livingston, New Jersey, Newark Beth Israel Medical Center and New York-Presbyterian Hospital.[35] Surgical teams led by Johns Hopkins continue to pioneer in this field by having more complex chain of exchange such as eight-way multihospital kidney exchange.[36] In December 2009, a 13 organ 13 recipient matched kidney exchange took place, coordinated through Georgetown University Hospital and Washington Hospital Center, Washington DC.[37]

Paired-donor exchange, led by work in the New England Program for Kidney Exchange as well as at Johns Hopkins University and the Ohio OPOs may more efficiently allocate organs and lead to more transplants.

Good Samaritan

Good Samaritan or "altruistic" donation is giving a donation to someone not well-known to the donor. Some people choose to do this out of a need to donate. Some donate to the next person on the list; others use some method of choosing a recipient based on criteria important to them. Web sites are being developed that facilitate such donation. It has been featured in recent television journalism that over half of the members of the Jesus Christians, an Australian religious group, have donated kidneys in such a fashion.[38]

Financial compensation

See also: Organ theft and Organ trade

Now monetary compensation for organ donors is being legalized in Australia, and strictly only in the case of kidney transplant in the case of Singapore (minimal reimbursement is offered in the case of other forms of organ harvesting by Singapore. Kidney disease organizations in both countries have expressed their support.[39][40]

In compensated donation, donors get money or other compensation in exchange for their organs. This practice is common in some parts of the world, whether legal or not, and is one of the many factors driving medical tourism.[41]

In the illegal black market the donors may not get sufficient after-operation care,[42] the price of a kidney may be above $160,000,[43] middlemen take most of the money, the operation is more dangerous to both the donor and receiver, and the receiver often gets hepatitis or HIV.[44] In legal markets of Iran[45] the price of a kidney is $2,000 to $4,000.[44][46][47]

An article by Gary Becker and Julio Elias on "Introducing Incentives in the market for Live and Cadaveric Organ Donations"[48] said that a free market could help solve the problem of a scarcity in organ transplants. Their economic modeling was able to estimate the price tag for human kidneys ($15,000) and human livers ($32,000).

In the United States, The National Organ Transplant Act of 1984 made organ sales illegal. In the United Kingdom, the Human Organ Transplants Act 1989 first made organ sales illegal, and has been superseded by the Human Tissue Act 2004.

In 2007, two major European conferences recommended against the sale of organs.[49]

Recent development of web sites and personal advertisements for organs among listed candidates has raised the stakes when it comes to the selling of organs, and have also sparked significant ethical debates over directed donation, "good-Samaritan" donation, and the current U.S. organ allocation policy. Bioethicist Jacob M. Appel has argued that organ solicitation on billboards and the internet may actually increase the overall supply of organs.[50]

Two books, Kidney for Sale By Owner by Mark Cherry (Georgetown University Press, 2005); and Stakes and Kidneys: Why markets in human body parts are morally imperative by James Stacey Taylor: (Ashgate Press, 2005); advocate using markets to increase the supply of organs available for transplantation. In a 2004 journal article Economist Alex Tabarrok argues that allowing organ sales, and elimination of organ donor lists will increase supply, lower costs and diminish social anxiety towards organ markets.[51]

Iran has had a legal market for kidneys since 1988.[52] The donor is paid approximately US$1200 by the government and also usually receives additional funds from either the recipient or local charities.[46][53] The Economist[54] and the Ayn Rand Institute[55] approve and advocate a legal market elsewhere. They argued that if 0.06% of Americans between 19 and 65 were to sell one kidney, the national waiting list would disappear (which, the Economist wrote, happened in Iran). The Economist argued that donating kidneys is no more risky than surrogate motherhood, which can be done legally for pay in most countries.

In Pakistan, 40 percent to 50 percent of the residents of some villages have only one kidney because they have sold the other for a transplant into a wealthy person, probably from another country, said Dr. Farhat Moazam of Pakistan, at a World Health Organization conference. Pakistani donors are offered $2,500 for a kidney but receive only about half of that because middlemen take so much.[56] In Chennai, southern India, poor fishermen and their families sold kidneys after their livelihoods were destroyed by the Indian Ocean tsunami on 26 December 2004. About 100 people, mostly women, sold their kidneys for 40,000–60,000 rupees ($900–$1,350).[57] Thilakavathy Agatheesh, 30, who sold a kidney in May 2005 for 40,000 rupees said, "I used to earn some money selling fish but now the post-surgery stomach cramps prevent me from going to work." Most kidney sellers say that selling their kidney was a mistake.[58]

In Cyprus in 2010 police closed a fertility clinic under charges of trafficking in human eggs. The Petra Clinic, as it was known locally, imported women from Ukraine and Russia for egg harvesting and sold the genetic material to foreign fertility tourists.[59] This sort of reproductive trafficking violates laws in the European Union. In 2010 Scott Carney reported for the Pulitzer Center on Crisis Reporting and the magazine Fast Company explored illicit fertility networks in Spain, the United States and Israel.[60][61]

Forced donation

There have been concerns that certain authorities are harvesting organs from people deem undesirable, such as prison populations. The World Medical Association stated that prisoners and other individuals in custody are not in a position to give consent freely, and therefore their organs must not be used for transplantation.[62]

According to the Chinese Deputy Minister of Health, Huang Jiefu,[63] approximately 95% of all organs used for transplantation are from executed prisoners. The lack of public organ donation program in China is used as a justification for this practice.

In July 2006, the Kilgour-Matas report[64] stated, "the source of 41,500 transplants for the six year period 2000 to 2005 is unexplained" and "we believe that there has been and continues today to be large scale organ seizures from unwilling Falun Gong practitioners".[64] Investigative journalist Ethan Gutmann estimates 65,000 Falun Gong practitioners were killed for their organs from 2000 to 2008.[65][66] However 2016 reports updated the death toll of the 15-year period since the persecution of Falun Gong began putting the death toll at 150 thousand[67] to 1.5 million.[68][69]

In December 2006, after not getting assurances from the Chinese government about allegations relating to Chinese prisoners, the two major organ transplant hospitals in Queensland, Australia stopped transplant training for Chinese surgeons and banned joint research programs into organ transplantation with China.[70]

In May 2008, two United Nations Special Rapporteurs reiterated their requests for "the Chinese government to fully explain the allegation of taking vital organs from Falun Gong practitioners and the source of organs for the sudden increase in organ transplants that has been going on in China since the year 2000".[71]

People in other parts of the world are responding to this availability of organs, and a number of individuals (including U.S. and Japanese citizens) have elected to travel to China or India as medical tourists to receive organ transplants which may have been sourced in what might be considered elsewhere to be unethical manner.[72][73][74]

Usage

Some estimates of the number of transplants performed in various regions of the world have been derived from the Global Burden of Disease Study.[75]

Transplantation of organs in different regions in 2000[76][77]
Kidney

(pmp*)

 Liver

(pmp)

 Heart

(pmp)

United States 52 19 8
Europe 27 10 4
Africa 11 3.5 1
Asia 3 0.3 0.03
Latin America 13 1.6 0.5
*All numbers per million population

According to the Council of Europe, Spain through the Spanish Transplant Organization shows the highest worldwide rate of 35.1[78][79] donors per million population in 2005 and 33.8[80] in 2006. In 2011, it was 35.3.[81]

In addition to the citizens waiting for organ transplants in the U.S. and other developed nations, there are long waiting lists in the rest of the world. More than 2 million people need organ transplants in China, 50,000 waiting in Latin America (90% of which are waiting for kidneys), as well as thousands more in the less documented continent of Africa. Donor bases vary in developing nations.

In Latin America the donor rate is 40–100 per million per year, similar to that of developed countries. However, in Uruguay, Cuba, and Chile, 90% of organ transplants came from cadaveric donors. Cadaveric donors represent 35% of donors in Saudi Arabia. There is continuous effort to increase the utilization of cadaveric donors in Asia, however the popularity of living, single kidney donors in India yields India a cadaveric donor prevalence of less than 1 pmp.

Traditionally, Muslims believe body desecration in life or death to be forbidden, and thus many reject organ transplant.[82] However most Muslim authorities nowadays accept the practice if another life will be saved.[83] As an example, it may be assumed in countries such as Singapore with a cosmopolitan populace that includes Muslims, a special Majlis Ugama Islam Singapura governing body is formed to look after the interests of Singapore's Muslim community over issues that includes their burial arrangements.

Organ transplantation in Singapore being thus optional for Muslims, is generally overseen by the National Organ Transplant Unit of the Ministry of Health (Singapore).[84] Due to a diversity in mindsets and religious viewpoints, while Muslims on this island are generally not expected to donate their organs even upon death, youths in Singapore are educated on the Human Organ Transplant Act at the age of 18 which is around the age of military conscription. The Organ Donor Registry maintains two types of information, firstly people of Singapore that donate their organs or bodies for transplantation, research or education upon their death, under the Medical (Therapy, Education and Research) Act (MTERA),[85] and secondly people that object to the removal of kidneys, liver, heart and corneas upon death for the purpose of transplantation, under the Human Organ Transplant Act (HOTA).[86] The Live On social awareness movement is also formed to educate Singaporeans on organ donation.[87]

Organ transplantation in China has taken place since the 1960s, and China has one of the largest transplant programmes in the world, peaking at over 13,000 transplants a year by 2004.[88] Organ donation, however, is against Chinese tradition and culture,[89][90] and involuntary organ donation is illegal under Chinese law.[91] China's transplant programme attracted the attention of international news media in the 1990s due to ethical concerns about the organs and tissue removed from the corpses of executed criminals being commercially traded for transplants.[92][93] In 2006 it became clear that about 41,500 organs had been sourced from Falun Gong practitioners in China since 2000.[64] With regard to organ transplantation in Israel, there is a severe organ shortage due to religious objections by some rabbis who oppose all organ donations and others who advocate that a rabbi participate in all decision making regarding a particular donor. One third of all heart transplants performed on Israelis are done in the Peoples' Republic of China; others are done in Europe. Dr. Jacob Lavee, head of the heart-transplant unit, Sheba Medical Center, Tel Aviv, believes that "transplant tourism" is unethical and Israeli insurers should not pay for it. The organization HODS (Halachic Organ Donor Society) is working to increase knowledge and participation in organ donation among Jews throughout the world.[94]

Transplantation rates also differ based on race, sex, and income. A study done with people beginning long term dialysis showed that the sociodemographic barriers to renal transplantation present themselves even before patients are on the transplant list.[95] For example, different groups express definite interest and complete pretransplant workup at different rates. Previous efforts to create fair transplantation policies had focused on people currently on the transplantation waiting list.

History

Successful human allotransplants have a relatively long history of operative skills that were present long before the necessities for post-operative survival were discovered. Rejection and the side effects of preventing rejection (especially infection and nephropathy) were, are, and may always be the key problem.

Several apocryphal accounts of transplants exist well prior to the scientific understanding and advancements that would be necessary for them to have actually occurred. The Chinese physician Pien Chi'ao reportedly exchanged hearts between a man of strong spirit but weak will with one of a man of weak spirit but strong will in an attempt to achieve balance in each man. Roman Catholic accounts report the 3rd-century saints Damian and Cosmas as replacing the gangrenous or cancerous leg of the Roman deacon Justinian with the leg of a recently deceased Ethiopian.[96][97] Most accounts have the saints performing the transplant in the 4th century, many decades after their deaths; some accounts have them only instructing living surgeons who performed the procedure.

The more likely accounts of early transplants deal with skin transplantation. The first reasonable account is of the Indian surgeon Sushruta in the 2nd century BC, who used autografted skin transplantation in nose reconstruction, a rhinoplasty. Success or failure of these procedures is not well documented. Centuries later, the Italian surgeon Gasparo Tagliacozzi performed successful skin autografts; he also failed consistently with allografts, offering the first suggestion of rejection centuries before that mechanism could possibly be understood. He attributed it to the "force and power of individuality" in his 1596 work De Curtorum Chirurgia per Insitionem.

Alexis Carrel: 1912's Nobel Prize for his work on organ transplantation.

The first successful corneal allograft transplant was performed in 1837 in a gazelle model; the first successful human corneal transplant, a keratoplastic operation, was performed by Eduard Zirm at Olomouc Eye Clinic, now Czech Republic, in 1905. The first transplant in the modern sense – the implantation of organ tissue in order to replace an organ function – was a thyroid transplant in 1883. It was performed by the Swiss surgeon and later Nobel laureate Theodor Kocher. In the preceding decades Kocher had perfected the removal of excess thyroid tissue in cases of goiter to an extent that he was able to remove the whole organ without the person dying from the operation. Kocher carried out the total removal of the organ in some cases as a measure to prevent recurrent goiter. By 1883, the surgeon noticed that the complete removal of the organ leads to a complex of particular symptoms that we today have learned to associate with a lack of thyroid hormone. Kocher reversed these symptoms by implanting thyroid tissue to these people and thus performed the first organ transplant. In the following years Kocher and other surgeons used thyroid transplantation also to treat thyroid deficiency that appeared spontaneously, without a preceding organ removal. Thyroid transplantation became the model for a whole new therapeutic strategy: organ transplantation. After the example of the thyroid, other organs were transplanted in the decades around 1900. Some of these transplants were done in animals for purposes of research, where organ removal and transplantation became a successful strategy of investigating the function of organs. Kocher was awarded his Nobel Prize in 1909 for the discovery of the function of the thyroid gland. At the same time, organs were also transplanted for treating diseases in humans. The thyroid gland became the model for transplants of adrenal and parathyroid glands, pancreas, ovary, testicles and kidney. By 1900, the idea that one can successfully treat internal diseases by replacing a failed organ through transplantation had been generally accepted.[98] Pioneering work in the surgical technique of transplantation was made in the early 1900s by the French surgeon Alexis Carrel, with Charles Guthrie, with the transplantation of arteries or veins. Their skillful anastomosis operations and the new suturing techniques laid the groundwork for later transplant surgery and won Carrel the 1912 Nobel Prize in Physiology or Medicine. From 1902, Carrel performed transplant experiments on dogs. Surgically successful in moving kidneys, hearts, and spleens, he was one of the first to identify the problem of rejection, which remained insurmountable for decades. The discovery of transplant immunity by the German surgeon Georg Schöne, various strategies of matching donor and recipient, and the use of different agents for immune suppression did not result in substantial improvement so that organ transplantation was largely abandoned after WWI.[98]

Major steps in skin transplantation occurred during the First World War, notably in the work of Harold Gillies at Aldershot. Among his advances was the tubed pedicle graft, which maintained a flesh connection from the donor site until the graft established its own blood flow. Gillies' assistant, Archibald McIndoe, carried on the work into the Second World War as reconstructive surgery. In 1962, the first successful replantation surgery was performed – re-attaching a severed limb and restoring (limited) function and feeling.

Transplant of a single gonad (testis) from a living donor was carried out in early July 1926 in Zaječar, Serbia, by a Russian emigré surgeon Dr. Peter Vasil'evič Kolesnikov. The donor was a convicted murderer, one Ilija Krajan, whose death sentence was commuted to 20 years imprisonment, and he was led to believe that it was done because he had donated his testis to an elderly medical doctor. Both the donor and the receiver survived, but charges were brought in a court of law by the public prosecutor against Dr. Kolesnikov, not for performing the operation, but for lying to the donor.[99]

The first attempted human deceased-donor transplant was performed by the Ukrainian surgeon Yuri Voronoy in the 1930s;[100][101] but failed due to Ischemia. Joseph Murray and J. Hartwell Harrison performed the first successful transplant, a kidney transplant between identical twins, in 1954, because no immunosuppression was necessary for genetically identical individuals.

In the late 1940s Peter Medawar, working for the National Institute for Medical Research, improved the understanding of rejection. Identifying the immune reactions in 1951, Medawar suggested that immunosuppressive drugs could be used. Cortisone had been recently discovered and the more effective azathioprine was identified in 1959, but it was not until the discovery of cyclosporine in 1970 that transplant surgery found a sufficiently powerful immunosuppressive.

Joseph Murray's success with the kidney led to attempts with other organs. There was a successful deceased-donor lung transplant into a lung cancer sufferer in June 1963 by James Hardy in Jackson, Mississippi. The person survived for eighteen days before dying of kidney failure. Thomas Starzl of Denver attempted a liver transplant in the same year, but he was not successful until 1967.

The heart was a major prize for transplant surgeons. But over and above rejection issues, the heart deteriorates within minutes of death, so any operation would have to be performed at great speed. The development of the heart-lung machine was also needed. Lung pioneer James Hardy attempted a human heart transplant in 1964, but when a premature failure of the recipient's heart caught Hardy with no human donor, he used a chimpanzee heart, which failed very quickly. The first success was achieved on 3 December 1967, by Christiaan Barnard in Cape Town, South Africa. Louis Washkansky, the recipient, survived for eighteen days amid what many saw as a distasteful publicity circus. The media interest prompted a spate of heart transplants. Over a hundred were performed in 1968–1969, but almost all the people died within 60 days. Barnard's second patient, Philip Blaiberg, lived for 19 months.

It was the advent of cyclosporine that altered transplants from research surgery to life-saving treatment. In 1968 surgical pioneer Denton Cooley performed 17 transplants, including the first heart-lung transplant. Fourteen of his patients were dead within six months. By 1984 two-thirds of all heart transplant patients survived for five years or more. With organ transplants becoming commonplace, limited only by donors, surgeons moved on to riskier fields, including multiple-organ transplants on humans and whole-body transplant research on animals. On 9 March 1981, the first successful heart-lung transplant took place at Stanford University Hospital. The head surgeon, Bruce Reitz, credited the patient's recovery to cyclosporine-A.

As the rising success rate of transplants and modern immunosuppression make transplants more common, the need for more organs has become critical. Transplants from living donors, especially relatives, have become increasingly common. Additionally, there is substantive research into xenotransplantation, or transgenic organs; although these forms of transplant are not yet being used in humans, clinical trials involving the use of specific cell types have been conducted with promising results, such as using porcine islets of Langerhans to treat type 1 diabetes. However, there are still many problems that would need to be solved before they would be feasible options in people requiring transplants.

Recently, researchers have been looking into means of reducing the general burden of immunosuppression. Common approaches include avoidance of steroids, reduced exposure to calcineurin inhibitors, and other means of weaning drugs based on patient outcome and function. While short-term outcomes appear promising, long-term outcomes are still unknown, and in general, reduced immunosuppression increases the risk of rejection and decreases the risk of infection. The risk of early rejection is increased if corticosteroid immunosuppression are avoided or withdrawn after kidney transplantation.[102]

Many other new drugs are under development for transplantation.[103] The emerging field of regenerative medicine promises to solve the problem of organ transplant rejection by regrowing organs in the lab, using person's own cells (stem cells or healthy cells extracted from the donor site).

Timeline of successful transplants

Society and culture

Comparative costs

One of the driving forces for illegal organ trafficking and for "transplantation tourism" is the price differences for organs and transplant surgeries in different areas of the world. According to the New England Journal of Medicine, a human kidney can be purchased in Manila for $1000–$2000, but in urban Latin America a kidney may cost more than $10,000. Kidneys in South Africa have sold for as high as $20,000. Price disparities based on donor race are a driving force of attractive organ sales in South Africa, as well as in other parts of the world.

In China, a kidney transplant operation runs for around $70,000, liver for $160,000, and heart for $120,000.[64] Although these prices are still unattainable to the poor, compared to the fees of the United States, where a kidney transplant may demand $100,000, a liver $250,000, and a heart $860,000, Chinese prices have made China a major provider of organs and transplantation surgeries to other countries.

In India, a kidney transplant operation runs for around as low as $5000.

Safety

In the United States of America, tissue transplants are regulated by the U.S. Food and Drug Administration (FDA) which sets strict regulations on the safety of the transplants, primarily aimed at the prevention of the spread of communicable disease. Regulations include criteria for donor screening and testing as well as strict regulations on the processing and distribution of tissue grafts. Organ transplants are not regulated by the FDA.

In November 2007, the CDC reported the first-ever case of HIV and Hepatitis C being simultaneously transferred through an organ transplant. The donor was a 38-year-old male, considered "high-risk" by donation organizations, and his organs transmitted HIV and Hepatitis C to four organ recipients. Experts say that the reason the diseases did not show up on screening tests is probably because they were contracted within three weeks before the donor's death, so antibodies would not have existed in high enough numbers to detect. The crisis has caused many to call for more sensitive screening tests, which could pick up antibodies sooner. Currently, the screens cannot pick up on the small number of antibodies produced in HIV infections within the last 90 days or Hepatitis C infections within the last 18–21 days before a donation is made.

NAT (nucleic acid testing) is now being done by many organ procurement organizations and is able to detect HIV and Hepatitis C directly within seven to ten days of exposure to the virus.[112]

Transplant laws

Both developing and developed countries have forged various policies to try to increase the safety and availability of organ transplants to their citizens. Austria, Brazil, France, Italy, Poland and Spain have ruled all adults potential donors with the "opting out" policy, unless they attain cards specifying not to be. However, whilst potential recipients in developing countries may mirror their more developed counterparts in desperation, potential donors in developing countries do not. The Indian government has had difficulty tracking the flourishing organ black market in their country, but in recent times it has amended its organ transplant law to make punishment more stringent for commercial dealings in organs. It has also included new clauses in the law to support deceased organ donation, such as making it mandatory to request for organ donation in case of brain death. Other countries victimized by illegal organ trade have also implemented legislative reactions. Moldova has made international adoption illegal in fear of organ traffickers. China has made selling of organs illegal as of July 2006 and claims that all prisoner organ donors have filed consent. However, doctors in other countries, such as the United Kingdom, have accused China of abusing its high capital punishment rate. Despite these efforts, illegal organ trafficking continues to thrive and can be attributed to corruption in healthcare systems, which has been traced as high up as the doctors themselves in China and Ukraine, and the blind eye economically strained governments and health care programs must sometimes turn to organ trafficking. Some organs are also shipped to Uganda and the Netherlands. This was a main product in the triangular trade in 1934.

Starting on 1 May 2007, doctors involved in commercial trade of organs will face fines and suspensions in China. Only a few certified hospitals will be allowed to perform organ transplants in order to curb illegal transplants. Harvesting organs without donor's consent was also deemed a crime.[113]

On 27 June 2008, Indonesian, Sulaiman Damanik, 26, pleaded guilty in Singapore court for sale of his kidney to CK Tang's executive chair, Tang Wee Sung, 55, for 150 million rupiah (S$22,200). The Transplant Ethics Committee must approve living donor kidney transplants. Organ trading is banned in Singapore and in many other countries to prevent the exploitation of "poor and socially disadvantaged donors who are unable to make informed choices and suffer potential medical risks." Toni, 27, the other accused, donated a kidney to an Indonesian patient in March, alleging he was the patient's adopted son, and was paid 186 million rupiah (20,200USD). Upon sentence, both would suffer each, 12 months in jail or 10,000 Singapore dollars (7,600 USD) fine.[114][115]

In an article appearing in the April 2004 issue of Econ Journal Watch,[51] economist Alex Tabarrok examined the impact of direct consent laws on transplant organ availability. Tabarrok found that social pressures resisting the use of transplant organs decreased over time as the opportunity of individual decisions increased. Tabarrok concluded his study suggesting that gradual elimination of organ donation restrictions and move to a free market in organ sales will increase supply of organs and encourage broader social acceptance of organ donation as a practice.

Ethical concerns

The existence and distribution of organ transplantation procedures in developing countries, while almost always beneficial to those receiving them, raise many ethical concerns. Both the source and method of obtaining the organ to transplant are major ethical issues to consider, as well as the notion of distributive justice. The World Health Organization argues that transplantations promote health, but the notion of "transplantation tourism" has the potential to violate human rights or exploit the poor, to have unintended health consequences, and to provide unequal access to services, all of which ultimately may cause harm. Regardless of the "gift of life", in the context of developing countries, this might be coercive. The practice of coercion could be considered exploitative of the poor population, violating basic human rights according to Articles 3 and 4 of the Universal Declaration of Human Rights. There is also a powerful opposing view, that trade in organs, if properly and effectively regulated to ensure that the seller is fully informed of all the consequences of donation, is a mutually beneficial transaction between two consenting adults, and that prohibiting it would itself be a violation of Articles 3 and 29 of the Universal Declaration of Human Rights.

Even within developed countries there is concern that enthusiasm for increasing the supply of organs may trample on respect for the right to life. The question is made even more complicated by the fact that the "irreversibility" criterion for legal death cannot be adequately defined and can easily change with changing technology.[116]

Artificial organ transplantation

Surgeons, notably Paolo Macchiarini, in Sweden performed the first implantation of a synthetic trachea in July 2011, for a 36-year-old patient who was suffering from cancer. Stem cells taken from the patient's hip were treated with growth factors and incubated on a plastic replica of his natural trachea.[117]

According to information uncovered by the Swedish documentary "Dokument Inifrån: Experimenten" (Swedish: "Documents from the Inside: The Experiments") the patient, Andemariam went on to suffer an increasingly terrible and eventually bloody cough to dying, incubated, in the hospital. At that point, determined by autopsy, 90% of the synthetic windpipe had come loose. He allegedly made several trips to see Macchiarini for his complications, and at one point had surgery again to have his synthetic windpipe replaced, but Macchiarini was notoriously difficult to get an appointment with. According to the autopsy, the old synthetic windpipe did not appear to have been replaced.[118]

Macchiarini's academic credentials have been called into question[119] and he has recently been accused of alleged research misconduct.[120]

Research

An early-stage medical laboratory and research company, called Organovo, designs and develops functional, three dimensional human tissue for medical research and therapeutic applications. The company utilizes its NovoGen MMX Bioprinter for 3D bioprinting. Organovo anticipates that the bioprinting of human tissues will accelerate the preclinical drug testing and discovery process, enabling treatments to be created more quickly and at lower cost. Additionally, Organovo has long-term expectations that this technology could be suitable for surgical therapy and transplantation.[121]

See also

References

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