Islet transplantation - an overview
The only treatments for type 1 diabetes that can restore normoglycaemia without significant risk of hypoglycaemia are pancreatic or beta-cell transplantation. These cells may be transplanted within the whole pancreas, as isolated islets of Langerhans or, in rare cases, as purified beta-cells. Islet transplant activity since 2000 has provided data that allow us to look objectively at indications for this procedure and define challenges still to be overcome.
Development of Islet Transplantation
Between 1893 and 1968 attempts to reverse diabetes by transplanting pancreatic tissue provided proof of principle, but cannot be considered precursors of modern islet transplants as techniques differed significantly to those currently used.
Lacy laid the foundations for modern protocols by developing techniques for transplantation of islets isolated by enzymatic (collagenase) digestion. Transplantation of isolated islets by infusion into the hepatic portal circulation using a percutaneous approach became established as the preferred technique, with 113 of the 156 transplants performed up to December 1991 using this site. As well as providing relative ease of access, islets in this site deliver insulin first to the liver, reproducing normal physiology. Islets were transplanted as islet after kidney (IAK), simultaneous islet kidney (SIK), solitary islet (ITA), simultaneous islet liver (SIL) and simultaneous islet, kidney and liver (SIKL) transplants. However, of these early transplants only 17 patients achieved insulin independence, most for less than 12 months.
Through the next decade one year patient and graft survival improved to 96% and 41% respectively, but still only 11% of recipients were insulin independent at 1 year . In 2000, Shapiro et al described a novel protocol that achieved insulin independence sustained to one year in seven consecutive patients receiving ITA for severe hypoglycaemia . Crucially, the low morbidity associated with islet transplantation allowed this protocol to maximise islet mass transplanted by performing multiple transplants in a given recipient from different donors, separated in time. The ITN trial followed, asking whether these successes could be replicated outside Edmonton . Thirty six patients received islet transplants using the Edmonton protocol in nine established centres worldwide. 44% of subjects met the primary endpoint of insulin independence 1 year after the transplant with 5 of these 16 subjects remaining insulin independent at 2 years. A further 28% of subjects achieved partial function. These results predicted more widespread outcomes and, although falling short of what was initially hoped for ‘post Edmonton’, were still good enough to secure a place for islet transplantation in the therapeutic repertoire to be considered for patients with severe hypoglycaemia and in particular hypoglycaemia unawareness.
Up until 2000, IAK and ITA transplants were performed in approximately equal numbers. However, the Edmonton results presaged a shift in this balance with 85% of the solitary islet transplants known to the CITR as of 2010 being ITA .
One recent modification of the original Edmonton protocol is a move away from immediate post-isolation transplantation back to culture of islets prior to transplantation, with 87.2% of the 208 transplants in the 2007-10 CITR cohort being cultured for ≥6h . As well as optimising viability and reducing tissue factor expression, this is essential for transplantation at a site distant from the isolation centre. The success of the Miami Houston collaboration and the GRAGIL and Nordic networks confirmed that islets can be transported for transplantation, allowing the essential isolation expertise to be concentrated in ‘central’ facilities, serving ‘peripheral’ transplanting centres. The UK programme, founded in 2008, is based on such a hub and spoke model.
Indications for islet transplantation
The indication for transplantation was severe hypoglycaemia in 85% of those transplanted between 2007 and 2010 . In the UK this is defined as two episodes of hypoglycaemia, requiring help from other people, within 2 years, most often with impaired awareness. This focus on severe hypoglycaemia is due in part to the mortality associated with severe hypoglycaemia justifying the risks of the transplant procedure, but also due to confidence in a successful transplant improving this debilitating complication of diabetes.
As for all transplanted organs, outcomes following islet transplantation are measured first in terms of patient and transplant survival. Transplant survival is most often defined by fasting C-peptide post transplant ≥3ng/ml. As partial graft function is often seen, this allows graft survival to be confirmed even if the patient is receiving insulin.
The CITR documents 677 patients receiving islet transplants for severe hypoglycaemia between 1999 and 2010 . For patients transplanted between 2007-10 patient survival is >95% at 4 years. 92% of this cohort were C-peptide positive at 1 year post transplant with 83% at 3 years. 66% were insulin independent at 1 year, 55% at 2 years and 44% at 3 years.
Given that the indication for transplantation in 85% of patients is severe hypoglycaemia, the most important outcome is whether these graft survival figures translate into freedom from hypoglycaemia. More than 90% of patients remain free of hypoglycaemia through to five years from last islet infusion. Even grafts achieving only partial function achieve significant reduction in hypoglycaemia . Thus, the UK programme was established with resolution of hypoglycaemia, not insulin independence, as the primary outcome measure.
Considering microvascular complications, islet transplantation has been suggested to slow progression of retinopathy . However, these data are not sufficient to consider this an indication for islet transplantation.
Complications of Islet Transplantation
The CITR documents complications seen post-islet transplantation using modern techniques. The incidence of any clinically reportable adverse event in the first year after transplantation for patients transplanted between 2007 and 2010 was 38% . Immunosuppressive complications are worthy of specific comment as they cause much concern. Overall the 2010 CITR report documents 29 neoplasms in 27 of 571 islet transplant recipients equating to 0.02 neoplasms per person/year . Importantly, the immunosuppressive risks of islet transplantation are no greater than those associated with whole pancreas transplantation and overall morbidity and mortality are significantly less for islet than for whole pancreas transplantation.
For the more risk averse patient, or patient for whom whole organ transplantation is contra-indicated due to medical fitness, islet transplantation is an attractive option for treatment of severe hypoglycaemia. Hypoglycaemia is often abolished with partial graft function, readily achievable with islets from a single pancreas, even if reduced doses of insulin are still required. For many patients, for whom the primary indication is resolution of hypoglycaemia, this is a success and further transplants in pursuit of insulin independence may not be necessary. However, the aim for islet transplantation must be conversion of donated organs to insulin independence at one year, at least as frequently as is seen with whole pancreas transplantation.
How may this be achieved? A shift from use of daclizumab to T cell depleting induction therapies, in particular with concomitant use of TNF-α inhibition and substitution of mycophenolic acid for mTOR inhibitor maintenance immunosuppression, has been associated with improved outcomes. However, an important advance has been recognition of the importance of islet loss immediately post-transplantation due to the immediate blood mediated inflammatory response (IBMIR). Furthermore, metabolic rest of newly transplanted islets has long been felt to be of benefit. In keeping with this recent analysis of transplants performed in Edmonton has defined peri-operative heparin and insulin use as associated with better outcomes . The other variables remaining significant on multivariate analysis were pre-transplant insulin requirement and transplanted islet mass, testifying to the importance of the graft being able to meet the metabolic demands of the recipient. Perhaps, in a departure from traditional thinking in transplantation, the major aim should now be prevention of very early islet loss due to hypoxic, inflammatory and metabolic insults and it is suggested that protocols able to achieve this are more likely to impact on transplant outcomes than further improvements in protocols targeting classical T cell dependent acute rejection.
^ Shapiro AM et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000 Jul 27;343(4):230-8.
^ Shapiro AM et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006 355(13):1318-30.
^ Barton FB et al. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care. 2012 35(7):1436-45.
^ Thompson M et al. Reduced Progression of Diabetic Retinopathy After Islet Cell Transplantation Compared With Intensive Medical Therapy. 2008 Transplantation 85: 1400-05
^ Al-Adra DP et al. Single-Donor Islet Transplantation and Long-term Insulin Independence in Select Patients With Type 1 Diabetes Mellitus. Transplantation. 2014 Jun 6 ePub.