Pancreatic islet transplantation: present and future (2003)

In 1993, the Diabetes Control and Complications Trial (DCCT) showed that the microangiopathic complications of type 1 diabetes were the direct result of hyperglycaemia.1 However, DCCT also showed that even the most obsessional care, be it with multiple injections or insulin pumps, failed to normalise HbA1c or completely prevent progression of these complications. The only way to achieve normal (or even near-normal) levels of HbA1c without encountering a substantially increased risk of hypoglycaemia is with a ‘closed loop’ system whereby the amount of insulin entering the circulation is adjusted semicontinuously to match requirements. Insulin pumps driven by glucose sensors may provide the answer in due course, but for the time being only transplantation achieves this goal. Whole pancreas transplants took off 20 years ago when cyclosporin was introduced, and some 20 000 have now been performed worldwide.2 Most have been done in patients in end-stage renal failure in conjunction with a simultaneous renal transplant. They result in normal levels of HbA1c without hypoglycaemia and hence dramatically improve quality of life.3 They not only arrest but also reverse progression of both nephropathy and retinopathy.4, 5 The simultaneous transplantation of a pancreas with a kidney reduces cardiovascular risk6-8 and several recent studies have demonstrated a very significant improvement in life expectancy.9-11 Despite major advances in the technique of whole pancreas transplantation in the past decade, so that the one-year graft survival rate is now approximately 80%,2 problems caused by the digestive enzymes secreted by the exocrine pancreas result in substantial postoperative morbidity. Since a patient with type 1 diabetes has only lost the pancreatic beta-cells, which comprise less than 2% of the pancreas, the concept of isolating and transplanting just the islets (thereby obviating the need for surgery) has been an attractive one for many years. However, it was not until three years ago that the major breakthrough by Shapiro and Lakey in Edmonton, summarised in their accompanying article (see page 145), resulted in an increase in the one-year insulin independence rate following islet transplantation from 8% to more than 80% to match the results of whole pancreas transplantation. This has suddenly made islet transplantation a viable clinical procedure comparable to the transplantation of other organs, and it is now recognised as such by health insurance companies in Canada. These dramatically improved results are due to a combination of factors. In the first place, the Edmonton group uses their own team of surgeons to procure the pancreas whenever possible, cooling the pancreas as fast as possible and handling it very gently. Secondly, they have refined the technique of pancreas digestion and islet purification to achieve the maximum islet yield. And thirdly, they have used a completely new immunosuppressive regimen. Prior to Shapiro, islet transplants had been carried out, like whole pancreas transplants, in patients in end-stage renal failure and had used the same immunosuppressive regimens. That is to say, induction therapy with an antilymphocyte antibody and triple maintenance therapy with a combination of steroids, a calcineurin inhibitor (cyclosporin or tacrolimus) and azathioprine (or more recently mycophenolate). Normally, one would expect changes to such a regimen to take place piecemeal, one drug being substituted at a time. But Shapiro tore up the book, changed the induction therapy to an IL-2 receptor antibody, left out the steroids, reduced the dose of tacrolimus (recognising that since the islets were injected into the portal vein it was portal rather than systemic levels of the drug that mattered) and added sirolimus, which was then a brand new immunosuppressive agent. Furthermore, he did it in patients who were not in renal failure, a group that had not previously been offered islet transplants (partly because whole pancreas graft survival is better when a kidney is transplanted simultaneously, and partly because if you transplant islets on their own you have no rejection marker). And it worked. Generous funding of major centres in North America to replicate this work has resulted in impressive progress since then. The Edmonton group has just transplanted their 50th patient,12 and more than 200 patients have been transplanted in 15 centres with the new protocol (compared with a total of less than 500 worldwide previously). In Europe, only three centres (Giessen, Milan and Geneva) have been included in the ‘first wave’, while in the UK many centres are still struggling to get the procedure off the ground. Many practical issues arise. In the UK, there is currently no organ sharing system in place, even for whole pancreas transplantation, as there is for livers or kidneys. Surgeons are not routinely trained in pancreas retrieval, and priority tends to be given to the liver for which good retrieval protocols and organ sharing networks are in place. Yet the successful transplantation of islets depends critically on their viability after pancreatic digestion, and this in turn depends on meticulous retrieval. If we in the UK are going to be serious players in this game, and not be left behind as we were with whole pancreas transplantation, a national pancreas procurement system urgently needs to be introduced to maximise the use of available pancreases. Each year in the UK, there are over 700 multiorgan donors. But in 2001, the last year for which statistics are available, there were only 47 (whole) pancreas transplants. In their article, Paget and Downing list the nine current members of the UK Islet Transplant Consortium (see page 150). Yet since both pancreases and isolated islets can readily be transported, it does not make sense for the UK to have more than a small number of islet separation laboratories. A process of attrition is likely, with the very stringent regulations imposed by the MCA on laboratories processing tissues for transplantation (meaning that a qualifying laboratory is going to cost close to half a million pounds) effectively deciding which centres will do the islet separation. Not unreasonably, Diabetes UK has decided that it cannot fund all nine centres. It has contributed substantially to the cost of a new islet separation facility in Leicester, where human islet isolation has been going on for many years, and has agreed to meet the clinical costs of the first 10 transplants from whichever centres do them first. Unfortunately, funding is necessary now and not once we can do it. Even those of us who are lucky enough to have some financial help from our hospital or medical school are currently having to use funds intended for other research to set up the laboratory techniques that Shapiro and Lakey make look so easy. Fewer than 50% of pancreases digested yield sufficient healthy islets for transplantation, and even then two transplants per patient are usually required for insulin independence. Thus, each successful islet transplant currently requires some five donor pancreases. This is changing. The Minneapolis group has been successful with a single donor in 18 out of 21 patients as a result of obsessional attention to detail, modifications to the immunosuppressive protocol, and transplantation of the most insulin sensitive patients. Our own interest is in techniques that allow more islets to survive transplantation so that more of the pancreases can be used and single donor transplantation becomes routine. Experimentally we are now able to ‘cure’ diabetes with about 30% fewer islets using hyperoxia13 and other techniques. The logical ultimate goal of such approaches would be to get sufficient islets to survive to make it possible to think in terms of needing less than a whole pancreas per recipient, so that live donor transplantation from partial pancreatectomies might become possible. For the time being, one needs to think carefully whether it is ethical to use two transplants per recipient to achieve insulin independence. A single transplant will usually abolish hypoglycaemia and achieve near-normal diabetic control (albeit at the expense of the need for a continuing small dose of insulin),14 and would enable twice as many patients to be transplanted. Even then, as Paget and Downing highlight, the small number of donors compared to the very large number of patients with diabetes means that it will only be possible to transplant a small proportion of patients. Who should they be? Those patients with the most unstable diabetes, and particularly those who have lost their hypoglycaemic warning symptoms, appear at first sight to be the obvious choice. But one has to be very careful. In many such patients, diabetic instability results from psychological instability, and we have seen patients lose their transplants through not taking their immunosuppressive drugs. Patients with relentlessly progressive complications despite the best possible (conventional) control form the second potential group. Such patients are typically highly motivated and compliant with protocols, although even then you may be selecting patients who have failed to look after their diabetes adequately in the past. It is not too soon to be referring potentially suitable patients in either group to the nearest centre for detailed evaluation, and this must include a detailed psychological assessment. Since there are risks associated with immunosuppression the obvious third group to target is going to comprise patients who need immunosuppression anyway, usually because they also need (or have already had) a renal transplant. More information is still required, though, on the use of sirolimus-based steroid-free immunosuppressive regimens in renal transplant recipients. The application of beta-cell transplantation on a large scale is going to have to wait for the development of alternative sources of new beta-cells (and of course, the whole issue of islet transplantation in type 2 diabetes would come into the frame if an unlimited supply of beta-cells were available). Paget and Downing suggest that islet encapsulation may make xenotransplantation a viable possibility. The alternative is likely to come from stem cell biology, an area of research in which the UK is heavily involved. The problem is that even if it were possible to provide a patient with a population of beta-cells identical to those with which they were born, the islets would be destroyed for the same reason that their original beta-cells were destroyed – type 1 diabetes is an autoimmune disease. The successful transplantation of isolated islets to effectively cure type 1 diabetes represents a very exciting major advance in the management of difficult diabetes. However, pancreatic transplantation has not so far had a major impact on the management of diabetes in the UK. Exploitation of the potential benefit of the Edmonton breakthrough to the full will require substantial changes in the organisation of both diabetes care and the transplantation services, and will necessitate the establishment of designated quaternary referral centres.