Organ transplantation

 

Numerous archaeological records indicate that the transfer of body parts was a topic of much interest in several early civilisations. For example, manuscripts dating to before 1000 BC suggest that the ancient Egyptians had an interest in skin grafts, while records from 700 BC demonstrate that a group of ancient Hindu surgeons had, in Sanskrit, explained how to graft skin when performing nasal reconstruction. According to Chinese medical lore, a couple of doctors, Hua T’o and Pien Ch’isi, pioneered the transplantation of a variety of organs in the third century BC [1]. Finally, during the era of Roman rule and in the subsequent Dark Ages, various transplant related “miracles” were said to have occurred, with the most notable of these being performed in the fourth century AD by the patron saints of medicine, Cosmos and Damien, when they replaced the diseased leg of a parishioner with the leg of a dead Moor (leaving the patient with one white and one black leg).

 

The validity of these early accounts is questionable, for not only are they difficult to verify, but no follow up work was undertaken to capitalise on the successes alleged to have been made. Consequently, transplantation was, for a long time, to be ranked alongside astronomy and alchemy as one of the “dark” sciences, with serious interest in this field as a legitimate medical science only developing during the Renaissance. One of the first studies to be conducted here was published in 1547, when Gaspare Tagliacozzo demonstrated how nasal reconstruction could be performed using skin grafted from the forearm, with the skin slowly being severed from its original site as it took hold on its new site. In 1728, the surgical innovator John Hunter, who had Edward Jenner as a student, is believed to have implanted the claw of a rooster into its own comb, with the implant adapting well to its new location [2]. In the early 1800s, Baronio succeeded in grafting large amounts of skin between different sites on test animals, while the first interspecies transplant is believed to have also occurred during this period, when the tail of a rat was grafted onto the comb of a rooster [3]. In 1823, the first modern incident involving a proper skin graft on a human was attributed to Carl Bunger, who managed to reconstruct a patient’s nose using skin obtained directly from her thigh. During the late 1800s and early 1900s, various surgical techniques that are still used in transplantation were developed, with Alex Carrel and Charles Guthrie playing a particularly important role in perfecting blood vessel suture techniques that allowed for a graft to be connected to the blood system of the new host [4]. 

 

It was, however, only in the twentieth century that transplantation was to develop in earnest, where, despite many failures, scientists persevered in their research and eventually succeeded in developing appropriate methods of transferring, with minimum immune response, an expanded range of internal organs into recipients. In the remainder of this section, we look at details relating to the transplantation of each of the main solid organs in the body. In addition to considering the features, functions and failings of each organ, we also examine some of the key historical milestones relating to the manner in which obstacles to the grafting of different organs were overcome.

 

i) The kidneys

Located in the middle of the abdomen are two bean shaped kidneys, each of which is about the size of a fist. In each kidney, there are approximately one million filtering units known as nephrons, which remove waste products from the blood. Almost 200 litres of blood are processed in total each day during a continuous cleaning cycle, with this waste being expelled, together with any excess water, from the body in the form of urine. In addition, the kidneys are involved in the conversion of vitamin D to its active form as well as in the creation of renin (a hormone that regulates blood pressure) and erthiopoitin (a hormone that stimulate the production of red blood cells in the bone marrow) [5]. 

 

Important causes of kidney failure include physical injuries, bacterial infections, exposure to poisonous elements in drugs and metal compounds, hereditary defects, or the development of diabetes or high blood pressure [6]. In these cases, destruction of the nephrons takes place, resulting in a loss of filtering capacity that causes a decrease in urine production accompanied by an increase in the quantity of water and waste stored in the body. This build-up of water can lead to organ damage and failure, such as breathing difficulties in the lungs or inflammation of heart and stomach tissue. In addition, there may be an imbalance in the bodily composition of various mineral elements, affecting the organs if they have too much or too little of a particular element.

 

Mild kidney failure, which involves the partial destruction of processing capacity, can often be tolerated if the remaining portion of the kidney is able to compensate for this loss by increasing its filtering capacity. Even if a whole kidney that is damaged or diseased must be surgically removed, a patient may still maintain suitable filtering function, as the remaining organ might simply increase in size and function to make up for this loss of capacity [7]. However, if there is an irreversible loss in function affecting both kidneys, patients will be diagnosed as having end stage renal disease (ESRD). This condition is often treated through the use of a renal dialysis machine, which operates like an artificial kidney by purifying the blood of a patient of undesired wastes and water. While this machine does mimic the general activities of the kidney, it does have several disadvantages that make it unsuitable for long-term use, with transplantation generally being viewed as a more desirable and cost-effective option for dealing with this disease.

 

While Carrel and Guthrie did experiment on grafting kidneys, the first recorded kidney transplant was performed in 1902, when Emerich Ullman, using magnesium tubes, was able to connect an allografted kidney to the neck vessels of a dog, with full renal function ensuing. Between 1905 and 1910, various physicians attempted to transplant animal kidneys into human patients, although all these efforts failed. In 1933, the first human kidney was transplanted, when a kidney obtained from a cadaver was placed in the thigh of a poisoned patient – once again, the result was failure due to immune system rejection [8].

 

In the period around World War 2, only limited research into kidney transplants was undertaken, although the first renal dialysis machines were invented and refined during this period. While continued efforts were made, with negligible success, to transplant cadaver kidneys into human recipients, the first living donation was only performed in 1952, when a mother donated a kidney to her son, with the graft surviving for 22 days before failing [9]. The first successful transplant of a kidney was finally performed on 22 December 1954, when Joseph Murray transferred a kidney between identical twins [10]. For most of the following decade, the majority of kidney transplants were to involve identical twins, as transplants with non-identical twins yielded poor results, even when early immunosuppression was used. In 1962, Murray was to perform the first successful unrelated renal allograft, with this successful operation being attributable, in large part, to the use of the new drug azathioprine [11]. Henceforth, renal transplantation was to become a more widely practised procedure, as it could now be performed on the majority of patients who had no genetically identical siblings or willing living donors.

 

ii) The heart

The heart, which is about the size of a fist, lies in the centre of the chest. It can, quite simply, be described as a large, hollow muscle made up of two pumps linked to either the lungs or the extremities of the body. As the central component of the cardiovascular system, the heart is responsible for pumping oxygen enriched blood from the lungs to the rest of the body whilst returning depleted blood to the lungs for replenishment, with the entire blood supply of the body passing through it every minute. In addition, the heart has a secondary function of regulating blood pressure, which is done by producing a hormone that can be used by the kidneys to eliminate excess salts from the body.

 

Heart transplants are most often recommended as the final treatment option for people with severe coronary artery disease, cardiomyopathy, or irreparable structural defects [12]. Coronary artery disease, which is a modern disease that is becoming increasingly prevalent, is brought about by factors such as obesity, high blood pressure, excess cholesterol, and smoking. While it may manifest itself as angina (chest pain), the primary symptom involves the build up of blood clots that completely block or constrict the width of the arteries, impeding normal blood circulation [13]. As blood flow through the arteries is retarded, the heart is forced to work harder, which can strain its structure and damage the muscle fibre beyond repair, eventually resulting in the occurrence of heart attacks and other forms of heart failure. While this disease is not curable, it can often be managed through changes in personal lifestyle factors, the prescription of pharmaceutical products, or though surgery, such as heart bypass operations. Sometimes, these treatments may fail to slow down the spread of this disease, leading to chronic heart failure, where the heart fails to pump blood as effectively as it should. A second major problem is cardiomyopathy, which again involves damage to heart muscle that can result in swollen heart tissue, irregular heartbeat rhythms and limited pumping ability [14]. While this condition may be caused by the same factors that lead to chronic artery disease, it is also attributable to genetic disorders, as well as to causes that have yet to be fully determined. Finally, transplantation may be required because of the presence of congenital birth defects and structural weaknesses that cannot be corrected through alternative procedures. These include the presence of holes in heart tissue, irregular heartbeat patterns (which may be resolved through the fitting of pacemakers) and valve disease, where heart flaps may be damaged and thereby inflame adjoining tissue.

 

In 1905, the first heart transplant was performed when Carrel and Guthrie removed the heart of a small dog and placed it in the neck of a larger dog. While further heart research was to persist intermittently in the following decades, primarily with the work carried out on canine hearts at Stanford, it was only in the 1960s that the first serious attempts were made to treat human patients through heart transplants. In 1964, a chimpanzee heart was placed into a 68-year old recipient, but due to complications, the patient died within one hour of the operation. Interestingly, while a potential human donor was available, as there were no “brain death” laws in effect at the time, the removal of the donor’s still beating heart could not be legally or morally justified [15]. As it is, the first clinical heart transplant involving both a human donor and recipient was performed on 3 December 1967 by a team led by Chris Barnard at the Groote Schuur hospital in Cape Town. The recipient, Louis Washkansky, who received the heart from a brain dead victim of a motor accident, survived for 18 days before succumbing to pneumonia. By 1970, more than 100 heart transplants had been performed at various transplant centres around the world, but due to the high rate of graft rejection, this procedure was soon abandoned as being unviable by all but the most dedicated of researchers. With some notable exceptions, it was only in the early 1980s, following the general introduction of cyclosporine, that heart transplants were to be seen as procedures that could provide recipients with any suitable prospects of long term survival. Consequently, the number of heart transplants performed annually, and the number of people awaiting these transplants, has gradually increased over time, with the ability to transplant this particular organ being seen in some countries as a sign of their medical status, resulting in heart transplantation gaining prominence over other forms of surgical procedure.

 

iii) The lungs

The organs most intricately linked to the heart are the lungs, which envelop the heart and fill most of the space in the upper chest. There are two lungs, each of which is made up of millions of tiny air chambers which form a bag that continuously expands and contracts as a person inhales and exhales air. As the breathing organ of the body, the lungs are involved mainly in the exchange of gases, with carbon dioxide loaded red blood cells pumped in by the heart being revitalised with inhaled oxygen before being returned to the heart for onward distribution to the rest of the body. In addition, the lungs clear the blood of other impurities that may exist, as well as play an important role in the creation of speech, by exhaling air so that the voice is able to carry.

 

Since they come into contact with inhaled air, the lungs are constantly at risk of being infected by pollutants and diseases, such as tuberculosis, silicon dust, asbestos, and cigarette toxins. While mucous and other protective compounds can reduce the potential hazards of infection, contamination can still occur, with these foreign agents slowly destroying the air sacs, thereby destroying the lung’s operating ability. At other times, the lungs can fail to operate if there is a permanent enlargement of the air sacs, a thickening of lung tissue, infliction of physical damage, or the development of a constant blockage, as may happen with emphysema, kidney failure or with hereditary conditions [16]. While medication may counter some of these ailments, long-term complications can develop, so patients may be forced to resort to the use of ventilators, which perform a breathing function for the body. However, these machines are not satisfactory replacements for human lungs as they are only really suitable in a surgical ward, so a transplant may be recommended as a more suitable means of restoring operation to the respiratory system.

 

Although the first lung transplants were performed in the mid-1960s, operations involving this organ were, for many years, rarely performed due to frequent graft failure arising from both immune rejection and technical complications. As a result, it was only in the 1980s that lung transplantation was deemed suitable for widespread implementation. While lungs have traditionally been obtained from cadavers, in 1990, a portion of one lung was removed from a mother and transferred to her daughter during the first successful living donor lung transplant [17]. While this innovation is useful in that it has expanded the size of the potential donor pool, it suffers from the limitation of being suitable for only certain recipients, such as children, since the amount of lung tissue that a person can afford to donate while alive is limited. Another interesting feature is that as humans have two lungs, it is possible for both single and double lung transplants to be performed. Here, clinicians have expressed conflicting opinions as to which is a better course of action to follow. Although a double lung transplant may be superior to a single lung transplant if it prevents a possible infection from spreading between lungs, single transplants have the advantage of doubling the amount of potential recipients without severely compromising the respiratory ability of the recipient, plus their performance is technically less demanding [18]. 

 

In addition to simple lung transplants, these organs may also be replaced together with the heart in what is known as a heart-lung transplant. Most commonly, this procedure is prescribed for cases of severe pulmonary hypertension and cystic fibrosis [19], where heart problems cause damage to arteries in the lungs, filling them up with blood and damaging lung tissue. In such a situation, while the damaged lungs are being removed, replacement of the heart may also be advised to prevent a recurrence of this problem. Heart-lung transplantation, which was first performed in 1981, is performed relatively infrequently due to the immense technical difficulties that surgeons face when removing and replacing two major organs simultaneously [20].

 

iv) The liver

Of all the organs, the most underrated is probably the liver, even though, with an average mass of 1.5 kilograms, it is one of the largest components of the body. Consisting primarily of four lobes filling the upper abdomen, this boomerang shaped organ is responsible for performing a diverse range of essential body functions, some of which have yet to be fully understood. In essence, the liver is a highly complex chemical factory, as it filters many toxins and wastes from the body while synthesising elements vital for optimal body function, including cholesterol and albumin. In addition, the liver plays a major role in the handling of food, not only by aiding digestion through the creation of bile, but also by acting as a storage location for glucose, vitamins and minerals.

 

While the liver has a remarkable ability to regenerate itself should part of its tissue be destroyed or damaged, there are times when restoration of lost cells is impossible, in which case a transplant may be required [21]. While transplants may be required due to genetic defects with this organ, in most cases, the underlying cause of replacement is cancer or a non-malignant destructive condition such as cirrhosis. While the liver rarely serves as the original focus point for cancer, it can be affected by tumours that originate in other parts of the body (especially biliary and pancreatic cancer), with cancerous cells often settling in the liver as they travel through the blood stream. Meanwhile, cirrhosis is an irreversible condition where healthy liver tissue is slowly replaced by lumps and bands of scar tissue. While such a condition can occasionally be caused due to heart failure or obstruction of the bile ducts and hepatic vein, the two most common causes are chronic hepatitis infection and constant alcohol abuse (where an excess intake of this fluid exceeds the capacity of the liver to process the poisons contained therein). Cirrhosis causes hepatic cell failure (destroying the liver’s ability to detoxify wastes in the blood) and imposes excessive pressure on the veins and spleen, which may then result in thrombosis, with this general damage eventually leading to overall organ failure.

 

While many researchers have been involved since the 1950s in investigating the problems of liver transplantation, the pre-eminent authority in this field has been Thomas Starzl who, since starting work in 1957, has pioneered many of the techniques that continue to be used in this field. While Starzl did conduct a number of failed human liver transplants from 1964 onwards, he was, in 1967, to finally perform what was considered to be the first really successful transplant, when an 18 month old patient with liver cancer who was given a new liver managed to survive for 13 months before succumbing to a mestatic tumour [22]. Soon thereafter, he was to conduct the first series of successful liver transplants where the recipients survived for longer than 1 year, with his innovative use of steroids as an aid to patient recovery becoming a widely used approach in all forms of transplantation over time. In the late 1980s, he was also involved in the first living donor transplant using a liver segment, as well as in the introduction of new pharmaceutical products such as FK-506 into service.

 

v) Minor solid organs

Along with the main solid organs, various lesser organs can also be transplanted into the body. Foremost of these is the pancreas, which plays a major role in the digestion of food and release of energy into the body. This small, finger shaped gland, which is found just behind the stomach, consists of both exocrine and endocrine tissue. The exocrine tissue contains bicarbonate and various enzymes that break down ingested fats, proteins and carbohydrates before these pass through to the smaller intestine for further processing. Meanwhile, interspersed around the “tail” of the pancreas are clusters of endocrine tissue, known as islets of Langerhans, which secrete two hormones, glucagon and insulin, into the blood stream. Glucagon acts like a control lever that releases glucose into the bloodstream from storage locations around the body, thereby increasing the amount of blood-sugar in the body. This released glucose is then processed by the insulin, which stimulates the cells and tissues in the body to absorb the energy that is made available so that they can continue functioning.

 

While pancreas transplants may be performed it this organ is physically damaged, it is most often required due to severe cases of diabetes mellitus [23]. Here, insufficient insulin is produced, leading to a build-up of unused glucose within the bloodstream. While this deficiency can usually be managed through regular injections of concentrated insulin, not only is this option inconvenient due to the lifestyle restrictions it imposes on a person, but it may also fail to prevent symptoms of insulin deficiency, which can be as severe as blindness and kidney failure, from being exhibited. While solitary pancreas transplants can be performed, a more commonly adopted approach has been to transplant a pancreas together with other organs that may be adversely affected by diabetes, with dual pancreas-kidney transplants being relatively common procedures. Although utilisation of pancreases provided by cadaver donors has been the normal policy, in recent years, pancreas transplants have been undertaken using small pieces of this organ obtained from living donors [24].

 

Another small organ to be transplanted is the small intestine, which is sometimes placed in people who have suffered from a severe attack of gastrointestinal inflammation. With this extremely uncomfortable condition, a patient is unable to receive nourishment orally, but is forced to consume nutrients through intravenous means. While transplantation of this organ, and of the pancreas, was first examined in the late 1950s and early 1960s, it was largely overlooked due to frequent graft failures, even when early forms of immunosuppression were used [25]. Following the introduction of cyclosporine, interest in transplanting this organ was revived, with the number of transplants performed annually slowly rising, with their value being greatest when performed in conjunction with the replacement of other organs that form part of the digestive system.

 

Before concluding our survey of solid organ transplantation, a general overview of the recipient survival rates with respect to these solid organs is provided in Table 8. This data is a comprehensive aggregation of all the organ transplants performed in a large number of medical centres across the USA, each of which may have used different pre- and post-operative procedures in the selection and treatment of both donors and recipients. While individual transplant teams may present studies that provide better results than the ones listed here, these may not prove replicable on a wide scale due to a variety of factors, including the experience and technical skill of the particular doctors concerned as well as the type of immunosuppressive therapy used. Thus, this data gives a good indication of how well a patient can expect to fare following the receipt of a particular organ under most circumstances.

 

Several points need to be clarified about this data. First, kidneys obtained from living donors will, in general, provide better patient graft and survival rates than kidneys obtained from cadavers, for not only are these donors likely to provide a better antigen match to recipients than cadaver donors, but there is also likely to be less cellular damage to their organs, allowing them to function more effectively. Second, there is a very strong correlation between patient and graft survival rates for transplants involving the heart – this is to be expected, for if there is rejection and accompanying failure of the heart, then the recipient will undoubtedly die due to a loss of the heart’s essential function in maintaining blood circulation. Third, the main reason why the maximum survival rates for organs such as the pancreas and lungs are relatively low (compared to kidneys and hearts) is that it was only after cyclosporine was introduced that transplant operations for these types of organ started to be seriously performed. Finally, these figures are about as valid for paediatric recipients as they are for adult recipients, because even though children and infants may be susceptible to greater stress than adults, they have just as great a chance of surviving a transplant operation and living for long periods of time as their elder peers.

 

Table 8: Generalised organ graft and patient survival rates [26]

	1 year survival		3 year survival		5 year survival		Longest recorded
Organ	Graft	Patient	Graft	Patient	Graft	Patient	survival time-1997
Cadaver kidney	88.3	94.4	73.4	88.6	62.7	81.6	32years 11months
Living kidney	94.0	97.8	85.8	94.6	77.4	91.0	34years 11 months
Liver	79.6	87.5	68.9	78.9	63.4	73.9	27years 11months
Heart	85.2	85.7	75.6	76.7	67.9	69.5	22years 8months
Heart-Lung	63.3	63.3	52.5	53.1	42.9	44.3	15years 1months
Pancreas	N/A		N/A		N/A		17years 0months
Lung (double)	N/A		N/A		N/A		9years 4months
Lung (single)	N/A		N/A		N/A		10years 5months

  

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