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The Future of Organ Transplantation

A look at current and future organ transplantation

Professor John Friend

Although clinically effective transplantation of organs is a recent phenomenon, the potential benefits of organ replacement have been recognised for centuries. Three major advances in medicine in the twentieth century paved the way for the development of transplantation as an effective therapy.

20th century advances

First, the development of vascular surgery — it is no coincidence that Alexis Carrel, who is widely credited for establishing the techniques of successful vascular anastomoses (and won the Nobel prize for this work), spent a considerable time working on experimental models of transplantation. Second, the understanding of transplant immunology — this developed rapidly following the work of a later Nobel prize-winner, Peter Medawar — led to our current knowledge of the mechanisms by which we recognise non-self and reject foreign tissue. The third important development was that of immunosuppressive drugs. Successful kidney transplantation was carried out (in a few units) during the 1950’s, but only between identical twin donor and recipient. Transplantation between non-identical individuals was impossible because there was no means to prevent rejection. Total body irradiation was known to be highly effective in suppressing the immune system, but was frequently fatal and therefore not clinically useful. The discovery of azathioprine used in combination with steroids allowed kidney transplantation to develop during the 1960’s. Later, the discovery of cyclosporine enabled heart, liver and lung transplantation to expand rapidly during the 1980’s.

Why transplant surgery is different

Transplantation is markedly different from other surgical disciplines not only because the surgery involves organ replacement but also because of the complexity of the postoperative care required. A technically successful operation can still fail because of inadequate control of rejection, or if the patient succumbs to infection or a side-effect of the treatment given. Thus, the practice of transplantation requires not only the surgical skills necessary to anastomose blood vessels, ureters or bile ducts but also the medical skills needed to judge the correct doses of immunosuppressive drugs and to control the diverse medical complications which occur in these patients. A very close working relationship between surgical and medical specialists is necessary to achieve the best results.

Kidney transplantation: the shortage of donors

Numerically the largest group of transplant patients are kidney transplant recipients. Approximately 1700 patients with chronic renal failure receive a kidney transplant each year in the UK. Despite this, the demand for transplants exceeds the supply and the national waiting list is greater than 5000 and continues to rise. 650 patients with liver disease undergo transplantation, with a national waiting list of more than 200. Smaller numbers of patients receive cardiothoracic transplants (less than 300 each year) and the service most recently funded by the NHS, pancreatic transplantation currently treats 50–100 patients annually.

Why grafts fail

In the early years of transplantation, it was a significant achievement to have a patient alive and with a functioning transplant one year after the operation. One-year graft survival rates of 80–90% are now routine in kidney, liver and heart transplantation and the emphasis has moved to longer-term (5 or 10 year survival) and quality of life issues.
Acute rejection — a T lymphocyte mediated attack on the graft — occurs much less commonly with the latest generation of immunosuppressive drugs and is usually treatable when it does occur. This is, therefore, now a relatively rare cause for a transplant to fail. However, long-term attrition of transplants remains a real problem. After the first year, the annual risk of a kidney transplant failing is 3–5%. This is most commonly due to a complex syndrome of arterial intimal thickening and progressive fibrosis of the graft — known as ‘chronic allograft nephropathy’. This was previously referred to as ‘chronic rejection’ but is now believed to be the final pathway of graft damage initiated by a wide variety of different stimuli, several of which are not immunological. Graft damage can be caused by preservation injury sustained before transplantation, acute rejection, viral infection and damage to the kidney from the toxic effects of commonly used immunosuppressive drugs. A similar rate of attrition is seen in heart transplantation, but the long-term loss of liver transplants is considerably less, the reasons for which are not fully understood.
The current repertoire of immunosuppressive drugs allows for several drugs, with different modes of action, to be given at relatively low dose, thereby reducing the toxic effects of any individual drug. However, even the most modern drugs produce a non-specific immunosuppressive effect which causes unwanted complications. Immunosuppressed patients are at increased risk of any infection but, particularly, viral infections that are non-pathogenic in the fully immunocompetent patient (opportunist infections). Cytomegalovirus is widely present in the normal population but can cause severe disease in transplant patients. In recent years, a number of drugs have become available which are effective in reducing the risk of disease in high risk patients and treating the disease in those patients in whom the disease has developed.
Immunosuppressed patients are also at increased risk of malignancy. There is a modest increase in incidence across the broad spectrum of cancers, but a dramatically increased risk in the case of skin cancer and lymphoma. It is believed that the enhanced cancer risk is due to suppression of immunosurveillance and that this is most significant in the case of virally-induced tumours.

New developments: increasing long term graft survival

The problems of toxicity, long-term graft loss, opportunist infection and cancer constitute a powerful incentive to develop new and more selective means of immunosuppression. Immunological tolerance is the state in which the immune system is reprogrammed to treat a foreign antigen as self, whilst responding normally to all other foreign antigens. If this could be achieved with a transplanted organ, this would allow long-term graft survival without the need for continued drug treatment. Several different strategies have been shown to induce tolerance in experimental animals but, as yet, no means have been invented to achieve this reliably in humans.
 One strategy that has gained popularity in some centres is to deplete lymphocytes at the time of transplantation and to allow recovery of the lymphocytes over a number of weeks/months in the presence of the transplanted organ. A highly effective means of achieving lymphocyte depletion is the monoclonal antibody, Campath. This recognises an antigen that is present on the surface of all lymphocytes and is highly effective in cell killing. Treatment of patients with Campath at the time of transplantation appears to allow a much lower dose of immunosuppressive drugs to be used subsequently. The mechanism is not fully understood, but the ratio of different subsets of recovering lymphocytes is quite different to that in patients who have not been treated. It is possible that the balance of lymphocytes, particularly the important regulatory cells, is critically altered by the process and that this shifts the balance away from rejection and towards tolerance.

Living donors: the solution?

As results improve and risks decrease, transplantation becomes the treatment of choice for more patients. This exacerbates the already severe shortage of donor organs. A number of strategies are being used to attempt to increase the number of transplants that can be done. Increasing the use of organs from living donors is an attractive option – kidney transplants from living donors provide better and more prolonged function than transplants from cadaver donors.
Living donor kidney transplantation is increasing in most countries and now accounts for more than 50% of transplants carried out in the USA. However, there are important ethical issues – these include the need to avoid any coercion of a potential living donor, or to take any risks with the donor (beyond the minimum associated with surgery in a healthy patient). The development of laparoscopic nephrectomy has had a considerable effect of the recruitment of potential kidney donors, although there is little evidence that this is safer, rather that the recovery time is shorter. Living donation is also increasingly popular in liver transplantation – it is possible to remove one lobe of the liver from a living donor and to transplant this successfully. Initially this was carried out from parent to child, but more recently from adult to adult. The risk of hepatic lobectomy is substantially greater than that of nephrectomy and many transplant surgeons in the UK believe that this cannot be justified. Lung transplantation from living donors has also been carried out successfully – transplanting one lobe of a lung, usually from an adult to a child and sometimes using two donors to enable bilateral transplants to be performed.

Non-heart beating donors

Another strategy to increase donor numbers is to use ‘non-heart-beating’ donors. For many years, organs for transplantation have originated from ‘heart-beating’ donors – in whom the diagnosis of death has been made by neurological criteria – the absence of brain stem reflexes and respiratory drive. The circulation is still intact and the organs remain perfused with oxygenated blood until the time of cooling and removal from the abdomen. However, in other potential donors the diagnosis of death is made on cardiac criteria – cardiac arrest. In such donors the organs necessarily suffer a period of warm ischaemia – from the time the circulation stops until the time the surgeon can introduce an aortic cannula and cool the organs. Such donors may be ‘controlled’ – in which cardiac arrest is predicted as part of a planned withdrawal of treatment in a patient (for example) with a catastrophic neurological injury – or ‘uncontrolled’ – in which the cardiac arrest is not anticipated. In the latter, because of the lack of preparation, warm ischaemia times are longer. There is now good evidence that kidney transplants from non-heart-beating donors can be as effective as transplants from ‘conventional’ heart-beating donors. Liver and lung transplantation has also been performed successfully using non-heart-beating donor organs. As more is known about the mechanism of damage to an organ during the process of transplantation, it is likely that transplants will be performed with increasing frequency and success using less ideal donors.
Transplantation is a story of medical success, but also a victim of its own success – the lengthening waiting lists are evidence of the degree to which demand is exceeding supply. It is a field in which clinical practice is close to the scientific frontier and laboratory advance is often followed closely by clinical innovation. It is likely that developments in the basic science of organ preservation, immunology and pharmacology will continue to feed directly into improvements in patient outcomes.
Professor Peter J Friend is Professor of Transplantation at the Nuffield Dept Surgery, John Radcliffe Hospital and Fellow of Magdalen College, Oxford.
http://www.medsci.ox.ac.uk/gazette/previousissues/55vol1/Part1

 

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