Current sources of transplantable organs

 

At present, all transplantable tissues and organs are obtained from human donors, who are able to provide body parts for further use regardless of whether they are dead or alive. Given the potential medical risks involved, all aspirant donors must meet certain strictly enforced qualifying criteria before surgeons will even consider removing their organs for use in others. First, donors must be within a set age group, usually 2 to 60 years of age, although the limit that is enforced varies depending on the type of organ under consideration. Second, donors must be free of various diseases that could compromise the health of patients who receive their organs. Here, they should have no easily transmissible and fatal diseases such as HIV and hepatitis, plus they should not have cancer, diabetes, or any other internal disorder that could spread from the donated organ into the rest of the recipient’s body. Finally, the donor should be broadly compatible in size, height and weight to a potential organ recipient. While the physiology and structure of specific organs is the same amongst all humans, there is a reasonably good correlation between similarity of organ size and operating efficiency, with organs that are accustomed to functioning within a particular environment risking failure if they operate outside of their normal parameters. For example, a heart provided by a 60 kg female donor is, ceteris paribus, more likely to have difficulty working in a 120 kg male recipient than it is in a 60 kg female recipient due to the greater stress that may be placed upon it in order to meet the needs of the bigger body of the new host.

 

In addition to these general requirements, there are also a range of specific requirements that depend on whether an organ is being provided by a living or dead donor. In the discussion that follows, we examine various pertinent issues relating to the advantages and disadvantages of employing each of these two classes of organ donor.

 

i) Living donors

In the formative stage of transplantation, the pool of organ and tissue donors was made up primarily of living people, most of whom were identical twins or genetically close relatives of the recipients. The main reason for this policy was that due to various clinical factors, the use of cadaveric organs was deemed to be a largely worthless procedure providing poor prospects of survival, with only living donor organs that had close antigen matches being deemed to offer recipients any viable prospects of long-term survival. Nowadays, while the use of cadaver organs offers much better survival prospects than was possible in the past, live donors continue to be used, with developments in extraction techniques enabling them to provide an ever greater range of organs and tissues without hampering their own health or prospects of survival.

 

Two factors make organs obtained from living donors superior to cadaver organs. Initially, the rationale behind related live donation was its clinical superiority to cadaveric donation, as it has been clear for a long time that “organs from all living donors demonstrate consistently superior results to those from cadaver sources over both the short and long term” [1]. Until the cyclosporine era, kidneys from living related donors had a greater than 90% one-year graft survival rate against a comparable figure of under 50% with cadaver sourced organs, with about 50% of living transplant recipients surviving for longer than 20 years, while fewer than 25% of cadaver organs managed to function 7 years after transplantation [2]. At present, the successful use of anti-rejection drugs has reduced the difference in annual survival rates between live and cadaveric kidneys to a margin of around 10%, although greater amounts of immunosuppression are still required by recipients of cadaver organs, which negatively affects both their general health and overall recovery prospects.

 

More recently, live donation has been used primarily due to its ability to reduce the waiting time that potential organ recipients have to face before they qualify for a transplant. Clinically, living donation has certain undeniable merits. It enables doctors to conduct extensive tests on all eligible donors in order to ensure that the recipient receives the organ with the best possible antigen match. As the transplant can be scheduled in advance, pre-operative preparation of both donor and recipient can be undertaken in order to maximise the chances of graft survival – while the donor’s health is boosted so that the organ is in optimal operating condition, the recipient can be readied with an initial course of drug therapy and through other measures that facilitate the accommodation of a new organ. Furthermore, as the donor and recipient can be operated on while together in the same hospital, the amount of time in which an organ can deteriorate while out of the body is likely to be minimal, enabling graft function to be accomplished almost immediately rather than after a couple of days, with less need being expressed for remedial therapy such as dialysis [3]. By ensuring that recipients do not wait too long for a new organ to work, substantial cost savings may also be generated, as these patients are less likely to require full time hospital care in order to recover from any complications and ailments caused by their disease before receiving a transplant [4]. Finally, from a psychological perspective, live donation is useful in that it allows for better monitoring and preparation of a potential recipient’s state of mind [5]. This is since they can be mentally prepared to receive an organ at a certain time, and are thus able to avoid the constant anxiety of waiting for a well-matched cadaver organ and then having their expectations ruined when it is not obtained.

 

In order to be medically acceptable, live donation has had to be proven as being a safe procedure posing no significant risks to the donor, for unlike blood and bone marrow, most tissues and organs cannot be replaced. Instead, when donors give part of their organs while alive, the most that they can hope to achieve is to compensate for the loss of organ function that has been denied to them. Due to this risk, doctors must conduct extensive batteries of tests to ensure that potential donors are not only free of transmissible diseases and have functioning, high quality organs to offer, but are also able to personally endure the consequences of losing an organ. Here, donor safety is measured as a combined function of the short term risks of surgery and the long term risks of suffering organ failure. In the short run, donors face small general risks of death through infection and anaesthesia, possible damage to other organs incurred during the removal procedure, as well as the prospect of suffering severe pain, which may require a period of hospitalisation and time off work for several weeks [6]. With partial living liver donation, there are unlikely to be any long term problems stemming from donation due to this organ’s ability to regenerate lost tissue, while with partial lung and pancreas donation, although these organs are unable to restore lost tissue, no major problems appear to be posed to donors with respect to organ diminished function.

 

Due to its long history, live kidney donation has been intensively studied and found to pose no major risks to donors, largely because their remaining kidney is able to increase in size and function to make up for the loss in capacity brought about by the removal of the other kidney. Although donors do face a long term risk of losing all renal function brought about by disease or damage to the remaining kidney, this should, however, be viewed in the perspective that “virtually all serious renal disease other than tumor … are bilateral and would lead to renal failure even in patients with two kidneys” [7]. In Norway, a long term study found that out of 1200 kidney donations performed nationally from live donors, none died, with only 2 cases of renal failure being reported, 12 and 15 years after donation [8], while in the USA, a similar assessment concluded that the long term likelihood of death as a result of donating a kidney stood at 0.06% [9]. Due to such good survival prospects, it is perhaps not surprising that a survey of some of the largest health insurers in the USA found that none of these companies would cancel coverage or increase premiums should a policy holder have donated a kidney. Furthermore, they would not penalise an applicant seeking cover who had previously donated a kidney (although some would have slightly larger premiums or apply waiting periods before giving new applicants full cover) [10].

 

One controversial question relating to live donors concerns the issue of determining their consent to donate. Unlike dead donors, it is possible to determine first hand what these people feel with respect to giving their organs away, but despite this, doubts still exist as to their motivations when acting in such a way. While efforts are made to educate potential live donors as to the risks of their activities, it is felt that some of these individuals may not fully understand or heed the warnings that are provided to them, especially if they are driven by apparently non-altruistic reasons, to donate their organs. Due to these concerns, this form of donation has generally been restricted to relatives of the recipient or, in exceptional cases, to unrelated donors with a strong emotional bond to the recipient, such as a spouse or long-term friend [11].. The logic behind this restriction is the assumption that while unknown donors may not consent freely to donate or will donate due to what moralists feel are the “wrong” reasons, with relatives, such a situation is unlikely, as these will give freely, out of sheer altruism, to their loved ones. Nevertheless, the idea of family altruism may itself be faulty, as relatives with organs that match those of potential recipients may be pressured to donate due to the existence of family bonds rather than altruism, which means that their consent may actually be less “free” than that of people who are not closely related to the needy person [12]. Thus, the debate surrounding the ethical value of living organ donation is still not settled, with questions still being asked about what form and under what conditions this type of activity should be performed [13].

 

ii) Cadaver donors

While the first successful transplants were undertaken using organs acquired from living donors, it was always clear that this source would have only limited potential for use if transplantation was to be widely performed in the long run. This is since, given the technology of the time, it would obviously be impossible to acquire most organs, notably hearts, from living donors without adversely affecting their survival prospects, while other organs, such as kidneys, would be available in limited numbers if reliance was placed on getting well matched organs from relatives only, which was not possible to cover when non-related donor transplants were developed. Consequently, measures were implemented to develop procedures of procuring and transplanting organs acquired from dead donors, with the rationale being twofold:

1) we cannot harm the dead by removing their organs, which therefore satisfies the medical and ethical requirement of not harming one person to benefit another;

2) it is widely accepted that the needs of living recipients, and society as a whole, exceeds any disrespect that may be caused to the dead.

 

Questions of how to define the start and end of both life and death pose major ethical and philosophical problems. While scientific criteria for measuring these events are used, no way of defining them as concepts exist. Just because the normal functioning of cells is disrupted does not necessarily mean that death has occurred, as the process of dying takes time and manifests itself in different ways. For example, hair and fingernails continue to grow in “dead” people even after the heart has stopped beating, while people with cancer and other malignant diseases that cannot be rectified have no reason to be considered dead just because no return of "normality" to parts of their bodies is possible [14]. Thus, from a purely philosophical perspective, death should be viewed as the corruption of absolutely all growth where no further physical development is possible. For transplantation purposes though, this is unacceptable, as organs must have living cell matter if they are to be successfully transplanted. Thus, defining and ascertaining the onset of death is of value to the transplant community, even though this issue has not traditionally been a matter of concern for individuals in this field. 

 

Until the middle of the twentieth century, the usual requirement for death to be declared was the cessation of heartbeat and respiration, where no subsequent return of heart function was possible. However, with the development of respirators and other machines that could restart the heart and enable body function to be maintained even after conscience was lost, questions were raised as to whether the traditional method of defining death was still valid. While this issue was motivated primarily by physicians caring for severely injured and elderly patients, interest in this matter from a transplantation perspective was also expressed, in particular by those studying heart transplants. The result was a redefinition of death that not only considered the loss of heart function, but also neurological factors when ascertaining the onset of death. The lead in developing the use of this new criteria was taken in Europe, where, “using the concept of “coma dépassé” (irreversible coma) evoked by French neurophysiologists in the 1950s, French and Belgium surgeons were the first to use kidneys from brain-dead, heart-beating donors a decade later” [15]. While this measure allowed for organs to be used while in a better state than if they had been provided by donors without heart function, social concerns as to whether death had actually taken place continued, with some surgeons even standing accused of murder following organ removal from these donors. The furore over the definition of death reached a climax following the first heart transplant in 1967, when the donated organ, which was still beating, was placed in a new recipient, suggesting to some people that a person who was alive in the traditional sense had lost the underlying source of life to another person. The result was a move to produce a formal definition of brain death, which was achieved in 1968, when a committee of scholars from diverse fields convened by Harvard Medical School “agreed that “irreversible coma” should replace “cessation of vital functions” as the criterion for death” [16]. This measure, popularly known as the “Harvard criteria of brain death”, has since formed the fundamental medical foundation of what death has been reinterpreted to be in many countries.

 

Brain death can be defined as the loss of all brain activity, combining irreversible loss of both upper and lower brain function. Essentially, higher brain function, which involves brain tissues such as the cortex, involves the retention of consciousness (or personal identity) and the capacity for social interaction, while lower brain function, which is centred around the brain stem, involves the ability to integrate and regulate physical functions in order to ensure that the body works coherently [17]. In order to determine brain death, a series of tests are used to determine whether a patient has any functioning neural matter, and whether these cells are sufficient to restore life. The performance of these screening protocols is vital, as physicians must be certain that a person is brain dead, and thus eligible to donate organs, rather than simply suffering from less serious forms of brain injury, such as being in a coma or vegetative state, where upper brain function only may be missing, thereby exempting the removal of organs due to the presence of continued existence and life in the patient.

 

In order to be considered as having the potential to be cadaveric organ donors, people must have suffered severe cerebral trauma, with individuals who fall into such a category most likely being: 1) victims of fatal assaults (usually inflicted by gun shot wounds to the head); 2) suicide victims (here, a self-inflicted head wound with a gun is most likely to result in such a situation); 3) participants in traffic accidents (as a driver, passenger or pedestrian); 4) accident cases (where people have drowned, fallen, inhaled smoke, etc.); or 5) patients suffering from a general medical condition such as cerebral bleeding. While brain death can be diagnosed at any place where the required testing facilities are available, current medical restrictions require that only those people whose death is declared in a hospital can serve as potential cadaveric organ donors, thereby excluding people who die at home or in some non-medical setting. This situation occurs because although the brain is now dead, the remaining organs and tissues must still be living, with the heart having to continue circulating blood within the body. Here though, once brain death takes place, the other organs will soon start to fail, so in order to ensure that they are kept in operating order until removal is possible, all potential donors must to be connected to life-support machinery, which explains the need for proximity to a medical location [18].

 

Once consent to donation has been granted, surgeons have to work rapidly at removing and preserving all applicable organs and tissues from the body until the moment transplantation takes place. This is since the components of the body undergo a process known as ischemia, where they decompose and are gradually rendered useless as the cellular matter that they are made up of dies without replacement [19]. This deterioration cannot be reversed, but it can be slowed down in order to allow preparations to be made for a transplant, with organs having to undergo a process known as perfusion, where they are stored in a preservation solution that limits their rate of decay substantially.

 

Research teams at the University of California, San Francisco (UCSF), were responsible for most of the pioneering work in the field of organ preservation [20]. The first successful preservation technique, developed by Folkert Belzer, was able to maintain kidneys in a usable condition for 72 hours, although it has not been widely employed due to the equipment and labour costs associated with its use. Consequently, the first preservation process to be widely used, due in part to its relatively low cost, was the Collins solution, developed by another UCSF team led by Geoffrey Collins. This cold perfusion solution, which is still in use, contains elements similar in nature and function to intracellular human fluids, and is used to preserve kidneys at temperatures of about 4°C by slowing down their rate of decay while protecting them from the effects of exposure to this cold environment. The chief flaw with these early preservation solutions is that while they are able to maintain kidneys in working condition for a reasonable period of time, they have not always been suitable for the preservation of other organs. This problem was partly resolved when, in 1988, Belzer introduced a new product known as University of Wisconsin (UW) solution, which was able to stabilise the cell membrane of most organs and thereby preserve tissue integrity until surgery could take place. While UW solution is not cheap, it has dramatically improved the storage times of organs such as livers, from a previous maximum of 6 hours to 24 hours [21], although the improvement in storage time for other organs, such as hearts and lungs, has been less substantial.

 

Currently, a variety of other general preservation solutions have been brought into use, although in many cases these are ad-hoc mixtures derived from the mainstream products such as Collins and UW solution, with their commercial availability being limited as their use is often restricted to just one or two transplant centres. The main focus in this field involves the development of preservation solutions that can store organs and tissues for long periods of time, for it is only once body parts can be preserved for substantial periods of time that storage in organ banks will be possible. Amongst the research efforts that have been conducted are attempts at freezing tissue and organs through the process of cryobiology, although, with the exception of some tissues, the results have generally been poor [22].

 

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