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History of transplantation at Addenbrooke's

Renal transplantation

Renal transplantation in Cambridge was established by Professor Sir Roy Calne in 1966.

Following his experimental work on chemical immunosuppression which had resulted in the demonstration of the effectiveness of azathioprine as a chemical immunosuppressant agent he returned to the UK and had already established a unit at Westminster Hospital before being appointed to the chair in Cambridge. At that time, Addenbrooke’s was still relatively small, and had no postgraduate clinical medical school. The prospect of kidney transplantation had been greeted with great suspicion by colleagues in Cambridge, but with the assistance of David Evans, consultant nephrologist and Valerie Joysey, who set up the tissue typing laboratory, both dialysis and renal transplantation were soon established and grew rapidly.

Currently renal transplantation in Cambridge includes an expanding living related and unrelated renal transplantation program with routine laparoscopic donor nephrectomy, and expanding use of kidneys from donors after circulatory death.

Complementing all of this activity, the transplant unit provides extensive support to renal dialysis, performing approximately 400 vascular access procedures per year.

Liver transplantation

Thomas Starzl in Denver performed the world’s first liver transplant in 1963, and despite difficulties and a brief moratorium on further transplants by 1968 had published a small case series. Most of these patients had died soon after surgery, but undeterred by the initial poor results, Roy Calne remained enthusiastic about developing a Cambridge liver transplant programme.

In 1967 he had developed the technique of liver transplantation in pigs at the Agricultural Research Station at Babraham, a small research facility close to Cambridge, and had shown that the grafts were rejected less severely than other tissue, a “liver effect” which provided an ongoing research interest. Even though there was great pessimism and opposition from medical and surgical colleagues in Cambridge, Roy Calne was ready to conduct human liver transplantation, and went on to perform Europe’s first successful adult liver transplant in May 1968, in a 46 year old woman with hepatocellular carcinoma. The donor was a child with viral meningitis, whose parents had consented for the kidneys and liver to be retrieved when mechanical ventilatory support was to be discontinued. When the details of the donor and recipient were discussed amongst other consultants in the surgical department, there was uniform opposition to the transplant going ahead. By chance Professor Francis Moore, chief of Surgery at The Peter Brent Brigham Hospital, Boston happened to be in Cambridge visiting his son. Francis Moore was a pioneer in liver transplantation, having developed his technique in dogs, and was a mentor to Roy Calne during his time as a young research fellow in Joseph Murray’s laboratory. Moore was absolutely convinced that the liver transplant should proceed, and in fact assisted Calne with the surgery. The recipient recovered from a long and technically demanding operation, but unfortunately died two months later due to bronchopneumonia. Of the initial series of patients, one survived for five and a half years, and for a time was the longest living liver transplant recipient.  

After the first few liver transplants in Addenbrooke’s, a joint program with Professor Roger Williams at King’s College Hospital, London was established; King’s providing the hepatolgical expertise and Cambridge the surgical skills and technical vision. The program allowed suitable patients to be identified for transplantation, with the surgery being carried out by Roy Calne predominantly in Cambridge, and post-operative care directed by Roger Williams. This was to remain the basic structure of the Cambridge/King’s program, with the number of surgeons at Cambridge and of hepatologists at Kings increasing over time for the next 20 years. 

In these early years of transplantation, all donor organs were procured from non-heart beating donors, as the diagnostic criteria for brain stem death had not yet been established in the UK. The transplant surgical team and recipient patient would often travel to the same hospital as the donor in order to minimise the period of cold ischaemia. The logistics of organising this was immensely complex if the donor happened to be in a peripheral unit. In one case, this arrangement resulted in a liver transplant being performed in a small district general hospital in Newmarket. Initial post-operative recovery would usually be in a unit that the recipient would probably never even have visited, and it could take as long as 2-3 weeks before the patient could be transferred back to Addenbrooke’s or King’s. During this interim period, a medical registrar would be sent up from King’s to help with the post-operative management, a practice which continued in later years with registrars from the King’s liver unit being involved in the Cambridge ICU care.

The complex arrangement of moving the patient to the donor hospital came to an end in 1976 when the Royal Colleges established a Code of Practice for diagnosing brain-stem death, where death was defined as ‘irreversible loss of the capacity for consciousness, with irreversible loss for the capacity to breathe.’ As a result, organs could be retrieved from “heart-beating” donors in peripheral hospitals and then be brought back to Cambridge for implantation. Of note, the use of organs from “heart-beating” donors had been standard practice in Starzl’s unit in Denver for many years.

In many cases long-distance travel, sometimes in terrifying weather conditions, would be necessary to acquire donor organs. A donor surgeon, together with an assistant, scrub nurse and technician would leave Cambridge in a helicopter taking off from a playing field next to the hospital or a privately hired small plane from the local airport, fly to the donor hospital, retrieve the liver and then fly back to Cambridge for the implantation. The whole trip from start to finish could take as long as 36 hours. In one case a trip to the Netherlands was necessary to retrieve a liver from a young girl who had recently undergone cardiac bypass surgery. The logistics were challenging and Celia Wight (previously a theatre sister) became the first transplant coordinator and rapidly established herself as a key figure who would contact the various people who were crucial to the whole venture proceeding successfully, adapt to delays and was the model for our current coordinators.

The results for liver transplantation were poor during the 1970s, with only 10% of patients surviving beyond one year, and only one patient in a series of 60 alive at 5 years post-transplant. These figures constitute the initial set of data that are seen in the European Liver Transplant Registry. During the latter half of the 1970s and into the following decade, results for liver transplantation greatly improved. This was due to a combination of factors: organs sustained less warm ischaemic damage as livers were retrieved from “heart-beating” donors, more suitable recipients were selected for transplantation, improved immunosuppression and greater anaesthetic and surgical experience. For instance, the technique of flushing the reperfused liver with plasma protein fraction after unclamping of the inferior vena cava, to prevent hyperkalaemic cardiac arrest, was instituted in the mid 1970s.

Of the 2168 liver transplants between 1968 and 2008 (see figure 2), there were 26 intra-operative deaths, but only one occurrence after 1998. This has come about due to better evaluation and management of peri-operative cardiovascular disease, improved circulatory volume management, selective usage of veno-venous bypass (12), and judicious correction of coagulopathy.

One of the main complications in the early history of liver transplantation, contributing to a major part of post-operative morbidity and mortality, had been biliary leaks and biliary obstruction with sludge. Bile leaks would often be mistaken for rejection, and patients inadvertently treated with increasing doses of steroids with adverse consequences. Various types of biliary drainage were first used, including the use of a gall-bladder conduit (13, 14). This involved anastomosing the Hartmann's pouch of the donor gallbladder to the donor common bile duct, and then connecting the gallbladder fundus to the recipient bile duct. The anastomoses would be splinted with a T-tube, and irrigation with one litre of saline per day for the first ten post-operative days would be carried out. The T-tubes would remain in situ for 3 months. Most patients who have had a gallbladder conduit have gone on to develop bile duct strictures and these have subsequently required conversion to Roux-en-Y choledochojejunostomy. Current practice is to perform a direct duct to duct anastomosis without stenting of any sort or a Roux loop for retransplants or cases of primary sclerosing cholangitis where the recipient duct is itself affected by the underlying disease process.

As successful transplantation became more usual liver transplantation developed across Europe and other centres opened in the United Kingdom eventually expanding to include Kings, The Royal Free, Birmingham, Leeds, Edinburgh and Newcastle. The development of a local surgical liver transplant service at King’s in 1990 prompted the appointment of Graeme Alexander as the first Cambridge based hepatologist in 1991 followed soon after by Alex Gimson and further colleagues and marked the division of the original Cambridge/Kings collaboration into two separate units as they are today.  

Advances in organ preservation and immunosuppression were central to the evolution of transplantation in Cambridge. Whereas donor organs were initially preserved using Hartmann’s solution or saline with plasma protein (15), the development of University of Wisconsin in the mid 1980s (16-18) led to a great reduction in cold ischaemic injury, and improved the situation for procurement and exchange of livers between centres.

Immunosuppression

The initial immunosuppressive approach, as developed by Roy Calne at the Royal College of Surgeons and then later at the Peter Bent Brigham Hospital, had involved the use of the anti-leukaemic drug 6-mercaptourine (19, 20), with the first clinical immunosuppressive regimens consisting of azathioprine, a derivative of 6-mercaptourine, and prednisolone in renal transplants and cyclophosphamide and prednisolone in liver transplants (13).

 The low rejection rates in this initial series were probably due to a (high) dosage effect, as evidenced by the high rates of sepsis.

A major advance in organ transplantation was the introduction of ciclosporin. Ciclosporin had been used by Roy Calne in orthotopic heart transplants in pigs (21) and renal transplants in a dog model (22). Having witnessed prolonged graft acceptance in these studies, the first clinical use in transplantation was in 1978 in Cambridge, in recipients of cadaveric renal allografts, soon followed by liver and pancreas transplant recipients (23). These patients developed nephrotoxicity, an unexpected complication given the lack of renal impairment in any of the dog studies, and a high incidence of lymphoma. Nevertheless, after modifying the ciclosporin dosage, the results of renal transplantation had improved from a 50% 1-year graft survival to over 80%. Following the introduction of ciclosporin, a watershed in transplantation occurred and instead of being viewed as an experimental procedure, it became an established form of treatment and transplantation of other organs such as the heart, lungs and pancreas became more widespread. Before the introduction of ciclosporin, survival of heart and lung allografts had been so poor, that, to quote Norman Shumway “history of heart transplantation can be divided into the time before ciclosporin and the time after ciclosporin (24).” The “triple therapy” of low dose ciclosporin, with prednisolone and azathioprine, subsequently became the most popular immunosuppressive regimen around the world.
A new era of immunosuppressive agents was heralded with the development of monoclonal antibodies by Cesar Milstein at the MRC Laboratory in Cambridge (25). Other investigators such as Waldmann, Hale and Winter pursued this field and humanised monoclonal antibodies, such as CAMPATH-1H are now routinely used as induction therapy (26, 27), and allow lower doses of maintenance immunosuppression.

Paediatric transplantation

Although an adult liver transplant programme had been in place for almost 20 years, the Cambridge/King’s paediatric program did not start until 1984.

The first paediatric liver transplant in the UK took place in Cambridge in December 1983 in a 3 year old child called Ben Hardwick with biliary atresia, who subsequently survived for 14 months. Ben’s case had been highlighted on the That’s Life television program by Esther Rantzen and given the resulting increased public exposure of liver transplantation, suitable donor organs became increasingly available so that between 1984 to 1990, 100 children received liver grafts, of which three received combined liver and renal grafts for primary oxalosis (PH1), a metabolic disorder based on a liver enzyme defect, a condition for which liver transplantation was first shown to be an effective treatment in the Cambridge unit (28, 29). The commonest indication for transplantation in this series was biliary atresia, with the overall 1-year survival of recipients increasing from 43% in the initial phase of the programme to 80% in the final year. The improvement came as a result of enhanced immunosuppressive regimens (e.g. ciclosporin), better timing of transplantation, i.e. before the onset of critical illness and encephalopathy, and refinement of surgical technique such as reduced livers and left lobe grafts allowing adult organs to be adapted for transplantation into children. Paediatric hepatology however remained based at King’s and the development of transplant surgery there and the separation of the two programs marked the end of the Cambridge paediatric liver transplant service.

Pancreas transplantation

The initial pancreas transplant programme began in 1978 at the same time as the introduction of ciclosporin. Initial cases used segmental pancreas grafts in which the pancreatic duct had been injected with latex to occlude exocrine secretion and the pancreas transplanted into the iliac fossa on the opposite side to the transplanted kidney. These grafts failed over time (with one exception – a case which developed a cutaneous pancreatic fistula despite the duct injection), probably due to graft atrophy following the duct occlusion culminating in graft thrombosis. Further technical innovations included segmental grafts with enteric drainage into a Roux loop, bladder drainage and a complex technique known as the paratopic technique where the segmental graft was anastomosed to the splenic vessels, leaving the graft lying in the lesser sac just in front of the native pancreas and with enteric drainage in to the back of the stomach. This technique enjoyed the theoretical advantage of portal venous endocrine drainage but was technically demanding and has been superseded by the current approach of whole organ transplantation, with a duodenal segment drained enterically via a Roux loop. This technique represents the most commonly applied approach worldwide.    

Small bowel transplantation

The Addenbrooke's Hospital Transplant Unit is a designated national adult intestinal transplant unit. The intestinal transplant programme was established in 1998.

The first two patients, aged 22 and 25 years, were referred to the Transplant Unit for assessment for intestinal transplantation, and both were ultimately transplanted after waiting 267 and 346 days respectively for suitable organs to become available.

This reflects the need to minimise warm ischaemic time which was addressed by using only local donors and performing donor and recipient procedures in adjacent theatres. These restrictions became unworkable and listed patients died without grafts ever becoming available. Low availability of appropriate local donor organs led to national changes in priority for intestinal transplant waiting list patients and distant procurement with intensive co-ordination of the donor and recipient procedures was introduced. Following these changes in the last 18 months, 9 patients have undergone 10 small bowel transplantation procedures, two receiving isolated small bowel transplants, five modified multivisceral grafts (all abdominal organs except the liver) and two patients received three full multivisceral grafts (all organs including the liver – one required a retransplant). At the time of writing all are still alive showing a marked improvement on historic outcomes.

Other multi-organ Transplants

The world’s first combined transplantation of the heart, lungs and liver was carried out by a Cambridge/Papw rth team in 1986 in a 35 year-old patient with primary biliary cirrhosis and severe pulmonary hypertension (30).

The heart-lung block and liver were retrieved and implanted separately. Since then a series of 9 patients, most of whom suffered from cystic fibrosis, have had combined heart-lung-liver transplantation, with 1-year and 5-year actuarial survival of 56% and 42% respectively (31). These cases involved a modification of the original procedure, with use of a total en bloc technique (32). Numerous other combined procedures have been performed, including combined liver/kidney, liver/pancreas, heart/kidney and heart/liver transplants, the latter in conjunction with Papworth.

Conclusion

The Cambridge transplant programme has a long history of innovation, both technical and immunological. Like Addenbrooke’s itself the unit has expanded hugely from its early roots and provides a combination of wide ranging basic science research with a busy regional and supra-regional clinical practice.

There are now 9 consultant surgeons working with 12 nephrologists, 4 hepatologists, and 2 gastroenterologists to deliver the service. This is supported by tissue typing and other laboratory services, anaesthesia, intensive care, transplant co-ordinators and a skilled nursing team working closely together in an integrated unit. This combination currently delivers in excess of 150 kidney transplants, 75 liver transplants, 20 pancreas transplants and 5-10 intestinal grafts each year. Over the past 4 decades outcomes have improved beyond recognition and more patients benefit from transplantation than ever before. Many challenges remain and improving long-term results, access to treatment and refinement of our procedures and approaches will continue.   

We would also like to thank the nurses and other staff who have cared for our patients.  Finally we would also like to pay tribute to our patients, and to the donors and their families whose gift allowed transplantation to develop to the present day where successful transplantation has improved and extended so many patients lives.

Acknowledgements

We would like to acknowledge the contribution made by the numerous surgeons, hepatologists and nephrologists, anaesthetists and researchers who have worked in the Cambridge Transplant Unit, many of whom came as visitors or trainees and have gone on to work in or indeed to establish transplantation units throughout the world.