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The general perception of islet transplantation among the diabetes community is somewhat negative, as insulin independence was maintained in only a small minority and there are fears about the safety of lifelong immunosuppression. There has been substantial progress in refining the islet transplant procedure to enhance its safety, reduce the toxicity of immunosuppression and improve long-term graft function. Longer-term follow-up studies have clarified the indications for islet transplantation; frequent, severe hypoglycemia, hypoglycemia unawareness and glycemic lability; facilitated informed consent and provided a framework for more realistic expectations, and suggest beneficial effects on microvascular complications. One hundred thirty-eight individuals have undergone islet transplantation at the University of Alberta over the last 12 years. Of these, 109 (79%) have full or partial graft function. Patient survival is 96% with no deaths due to transplantation. Three subjects have been hospitalized because of severe opportunistic infection and 3 have progressed to require renal replacement therapy. Current protocols are able to achieve insulin independence rates of 60% beyond 4 years. Safer and more effective islet transplantation, along with refinements in immunosuppressive therapy, make islet transplantation a more attractive option for a subset of persons with type 1 diabetes who suffer from frequent, severe hypoglycemia, lability and/or hypoglycemia unawareness, and resulting in excellent glycemic control and freedom from hypoglycemia.
Résumé
L’opinion générale de la communauté diabétique sur la transplantation d’îlots est quelque peu négative, comme l’insulino-indépendance est maintenue par un petit nombre seulement et qu’il y a des craintes concernant l’innocuité de l’immunosuppression permanente. Des progrès considérables quant au raffinement de la technique de transplantation d’îlots ont eu pour effet d’améliorer son innocuité, de réduire la toxicité de l’immunosuppression et d’améliorer le fonctionnement du greffon à long terme. Les études de suivi à plus long terme ont précisé les indications de la transplantation d’îlots (hypoglycémie grave et fréquente, ignorance de l’hypoglycémie et instabilité glycémique), facilité le consentement informé et fourni un cadre pour des attentes plus réalistes, et elles laissent entrevoir des effets bénéfiques concernant les complications microvasculaires. Cent trente-huit individus (138) ont subi une transplantation d’îlots à l’Université de l’Alberta au cours des douze dernières années. Parmi eux, 109 (79 %) ont un fonctionnement du greffon complet ou partiel. La survie des patients est de 96 % sans décès attribués à la transplantation. Trois (3) sujets ont été hospitalisés en raison d’infection opportuniste grave et 3 ont évolué vers la thérapie de remplacement rénal. Les protocoles actuels peuvent atteindre des taux d’insulino-indépendance de 60 % au-delà de 4 ans. Une transplantation d’îlots sécuritaire et plus efficace de même qu’un raffinement dans le traitement immunosuppresseur font de la transplantation d’îlots une option plus attrayante pour un sous-ensemble de personnes ayant un diabète de type 1 qui souffrent d’hypoglycémie grave fréquente, d’instabilité glycémique ou d’ignorance de l’hypoglycémie, et entraînent une excellente maîtrise glycémique et l’absence d’hypoglycémie.
A cure for type 1 diabetes remains elusive. Almost 90 years since the discovery of insulin, therapy for type 1 diabetes has remained essentially unchanged, relying on the subcutaneous delivery of exogenous insulin. Many thought the publication describing insulin independence in a series of 7 consecutive individuals undergoing islet transplantation (
) heralded the imminent arrival of freedom from exogenous insulin and a cure for diabetes. However, many diabetes professionals were skeptical, recognizing that given the limited organ supply and the inefficiency of the islet isolation procedure, this was not a therapy that would be available for more than a tiny proportion of patients, and that for many, the risks of long-term immunosuppression would outweigh the risks of diabetes (
). These views were reinforced by case reports describing a range of adverse events and follow-up studies indicating most subjects resumed exogenous insulin therapy with less than 10% insulin independent at 5 years (
This article seeks to describe recent progress in islet transplantation. We provide an update on the status of islet transplantation at the University of Alberta, a description of refinements in terms of patient selection, the transplant procedure itself, maintenance immunosuppression, and an assessment of the current risk-benefit ratio and indications for islet transplantation.
Historical Perspective
Prior to the discovery of insulin, transplantation of fragments of ovine pancreas into a patient with type 1 diabetes was attempted (
). It was not until the 1970s that islet transplantation was able to reverse diabetes in mice. A report from 1991 described some of the first successes of islet transplantation in people with type 1 diabetes (
At that stage, “success” was defined by the ability to detect c-peptide. In the first 3 cases of islet transplant alone, the islets were rejected within 2 weeks. Later, multiple transplants were performed in type 1 subjects who were already established on effective immunosuppression (for a previous kidney transplant). Between 14 and 154 days, 2 subjects became insulin independent (
In the following decade, it was difficult to replicate these data. Registry data showed insulin independence in only 12.4% of recipients for more than 1 week, and in only 8.2% at 1 year (
). Thus the achievement of insulin independence in 7 consecutive subjects followed for a mean of 1 year was indeed a major step forward in the field of clinical islet transplantation (
Previous Assessments of Risks of Islet Transplantation
As might be expected for a new procedure, many reports following this publication focused on safety or descriptions of unexpected observations or complications. This was important to define the risks of islet transplantation, which could then be compared with any benefits.
Procedural risks
Islet transplants are generally performed under local anesthesia. The portal vein is accessed via a transhepatic puncture, which can usually be quickly achieved by an experienced interventional radiologist; but access can be difficult and require multiple passes through the liver (
). Thus intraperitoneal bleeding from the hepatic puncture is an expected risk of the procedure. Other less common risks include biliary leaks, pneumothorax or hemopneumothorax. On the other hand, islets express high levels of tissue factor and are highly thrombogenic (
). Although only small volumes (≤5 cc) of highly purified islet tissue are transplanted, there is a risk of portal vein thrombosis. Portal vein thromboses were a major problem in early studies of islet autotransplantation, where large volumes of unpurified islets were infused into individuals undergoing pancreatectomy (
Previously, bleeding was reported in 5 of 54 procedures, requiring blood transfusion in 4 subjects, while portal vein thrombosis was detected in 2 subjects (
Two important risks of lifelong immunosuppression are increased susceptibility to infection and neoplasia. Transplant recipients are at particularly high risk for cancers associated with viral infections (e.g. lymphoma, liver, anogenital), but also have increased risk for other cancers (e.g. lung, kidney, skin) (
). The most frequent cancers with increased risk are lymphoma, lung, liver and kidney. The excess absolute risks for these are 1.68, 0.85, 1.1 and 0.76 per 1000 patient years, respectively. (Though prostate and breast cancer are common after transplant, the risk is lower.) The risks vary significantly for different organ transplants, with lung recipients at high risk for lymphoma and lung cancer, and liver cancer being much more common after liver transplant (
Post-transplant lymphoproliferative disorders (PTLD), including lymphoma, are associated with Epstein-Barr Virus (EBV) infection. EBV may be transmitted from the donor or reactivated in the recipient. The risk of PTLD varies by organ transplanted and seems related to the intensity of immunosuppression (
) is encouraging, it is clear that long-term follow-up will be required to define risks of malignancy in islet recipients. In the meantime, routine screening for malignancy and surveillance for skin cancers (squamous and basal cell carcinomas) are prudent.
Unusual complications
Several reports highlighted novel observations in islet transplant recipients. Irregular patterns of hepatic steatosis were observed on ultrasound and magnetic resonance image (
). The hepatic steatosis may be due to the local secretion of insulin by islets in the liver although the significance of this remains unclear. Ovarian cysts and menstrual abnormalities were also described in female islet recipients, which seemed to be related to the use of sirolimus (
The “Edmonton Protocol” had employed sirolimus and a lower dose of tacrolimus because of a desire to avoid the nephrotoxicity of calcineurin inhibitors. It has become clear that sirolimus can have nephrotoxic effects, causing heavy proteinuria after islet (
). These data were concerning, as it was hoped that islet transplantation would reduce progression of microvascular complications.
Adverse drug effects
It became clear that the combination of sirolimus and tacrolimus was associated with significant adverse effects. Almost all recipients experienced diarrhea or oral ulcers. Increases in blood pressure or cholesterol levels required additional pharmacotherapy (
). Other common side effects included peripheral edema, cytopenias and fatigue. A significant number of subjects had sirolimus withdrawn, either because of adverse effects, loss of graft function or both (Fig. 1).
Figure 1Reasons for sirolimus discontinuation in 47 islet transplant recipients. In some individuals sirolimus was withdrawn for more than 1 reason.
Reappraisal of the Benefits of Islet Transplantation
The inability to achieve sustained insulin independence in more than a handful of patients was clearly disappointing; but graft function, indicated by c-peptide secretion, persisted in 80% of subjects at 5 years (
). If individuals with sustained graft function (i.e. partial graft function) benefit, islet transplantation may be justifiable even if insulin independence cannot be maintained.
Subjects with partial function maintained excellent glycemic control compared with c-peptide negative subjects (glycated hemoglobin [A1C] 6.7 vs. 9.0%, p=0.025) and had significantly lower insulin requirements than pre-transplant (0.34 vs. 0.66 u/kg/day) (
). Registry data show more than 50% achieve the composite of both A1C <6.5% and absence of severe hypoglycemia for more than 1 year; but this is lost if grafts fail (
These data, demonstrating excellent glycemic control as well as protection from hypoglycemia even if insulin independence is not sustained, have reframed the goals of islet transplantation and helped define the population for whom islet transplantation may be considered. The current goals, indications and contraindications are summarized in Table 1.
Table 1Current goals, indications and contraindications for clinical islet-alone transplantation
Inability to achieve acceptable glycemic control without provoking primary indications, particularly in the context of progressive microvascular complications
Recent Progress and Refinements in Islet Transplantation
There have been substantial revisions and refinements to all aspects of the transplant procedure, including organ procurement, islet isolation, cross matching and the drugs used for induction and maintenance immunosuppression (Fig. 2), with the goals of improving outcomes (long-term insulin independence, single donor insulin independence), safety and tolerability.
Figure 2Schematic of current “standard” islet transplant protocol used at the University of Alberta.
Some of the major changes involve the use of lymphodepleting antibodies for induction, which are associated with improved single donor insulin independence rates (
), and a move away from sirolimus to a combination of tacrolimus and mycophenolate mofetil. This combination has been used for some time at other centres (including Vancouver) and is just as effective but much better tolerated than sirolimus (Fig. 3) (
). There has been a striking reduction in the incidence of adverse effect (Fig. 3) which is qualitatively less severe currently (personal observation). The major side effects of tacrolimus and mycophenolate include headache, tremor and diarrhea. These are, generally, dose dependent and resolve with dose adjustment.
Figure 3Frequency of most common adverse effects of maintenance immunosuppression in 34 subjects who were transitioned, because of intolerance, from sirolimus (trough 10-12 ng/ml) plus tacrolimus (3-6 ng/ml) to a combination of tacrolimus (trough targets 8-10 ng/ml) and mycophenolate mofetil (MMF, 2 g per day as tolerated).
The risks of bleeding at our centre have been reduced, from 13.7% to close to 0%, by the introduction of effective ablation of the catheter tract using microfibrillary collagen “flour” (
). This has permitted much more aggressive anticoagulation, including intravenous heparin for 48 hours post-transplant which has reduced the risk of portal vein thrombosis towards 0% (
Supplemental islet infusions have also been shown to be a safe and effective means to restore insulin independence in subjects who have had to resume insulin therapy after a period of insulin independence (
Promising data suggesting a beneficial effect of islet transplantation for microvascular complications have emerged. A crossover study from Vancouver has shown superior outcomes for retinopathy after islet transplant compared with intensive medical therapy, with no subjects in the transplant group experiencing progression of retinopathy (
Data from the Vancouver group have also provided reassurance regarding renal outcomes. By including only subjects with preserved renal function (glomerular filtration rate [GFR] > 70ml/min) and, in general, avoiding the use of sirolimus, they found that the decline in GFR was slower after islet transplant than in the medical therapy arm (1.27 vs. 2.98 ml/min/year, p<0.0001) (
). These longer-term data are particularly reassuring, as earlier reports showed changes in GFR after islet transplant that were similar to those reported in Edmonton (-0.31 vs. -0.39 ml/min/month) (
Data from the Collaborative Islet Transplant Registry (www.citregistry.org) indicate that insulin independence rates are improving in more recent eras and have identified a number of factors associated with improved outcomes. Recent era and the use of lymphodepleting antibodies predict greater and more durable insulin independence (
Rickels M, Barton FB, Alejandro R, et al. Factors of islet transplant success: Results from the Collaborative Islet Transplant Registry 1999-2010. In: 13th World Congress of International Pancreas and Islet Transplant Association. Prague: 2011.
Shapiro AJ, Toso C, Imes S, et al. Five-year results of islet-alone transplantation match pancreas-alone transplantation with alemtuzumab, Tac/MMF, with strong suppression of auto and alloreactivity. In: 13th World Congress of International Pancreas and Islet Transplant Association. Prague: 2011.
As of June 2011, more than 300 transplant procedures had been performed in 138 subjects from across Canada (Fig. 4). The baseline characteristics of these subjects are described in Table 2. Sixteen subjects had received only 1 transplant; the others had received 2 (n= 88), 3 (n= 27) or 4 (n= 7) infusions.
Figure 4Place of current residence of islet transplant recipients treated at the University of Alberta. Inset panel shows the number of islet infusions performed at the University of Alberta along with key dates.
Table 2Baseline characteristics of 138 islet transplant recipients from the University of Alberta. Data are mean (range) or mean ± standard deviation or n
As of June 2011, or at time of last contact, a cross-sectional analysis of transplant status showed that 109 subjects (79%) had full or partial graft function, while 29 subjects (21%) had no islet function (Table 3). Of the 109 subjects who had full or partial graft function, 48 were insulin independent and had excellent glycemic control (A1C 6.1%), while 61 with partial function (c-peptide positive but requiring exogenous insulin) had good glycemic control (A1C of 7.0%). Current data for subjects with graft loss were incomplete, but glycemic control was suboptimal (A1C 8.3%). The median durations of insulin independence and c-peptide positivity, number of donors and islets transplanted are presented in Table 3.
Table 3Current status of islet transplant recipients. Data are mean ± standard deviation, n (%), or median (range)
Full function is insulin independence with good control. Partial function is c-peptide positive but using exogenous insulin. Graft loss is no detectable c-peptide and/or with no detectable c-peptide. Insulin independence good control without exogenous insulin for at least 4 weeks.
∗ Current A1C data only available for 10 subjects.
Graft loss was more common in transplants performed early on in the program. Graft loss was seen in 24/71 (34%) of subjects transplanted before 2005, compared with 5/67 (7.5%) since 2005. Duration of follow-up was longer in the earlier group (96 ± 31 vs. 36.3 ± 25 months).
Patient survival by Kaplan Meier is 96% after 12 years. Six individuals have died. Three of the deceased had discontinued immunosuppression prior to their death. No deaths appear related to complications of the transplant or immunosuppression. Three subjects have progressed to end-stage renal disease, of whom 2 have received renal transplants. Three subjects had severe opportunistic infections causing hospitalization. All have recovered. Immunosuppression was withdrawn in 2 subjects who then lost graft function, while the other subject remains insulin independent. There have been no cases of post-transplant lymphoproliferative disorder. Six subjects have had skin cancers (1 melanoma, 5 squamous or basal cell carcinomas) and 2 have had other malignancies treated successfully. Valganciclovir is used routinely for 3 months post-transplant as prophylaxis against Cytomegalovirus infection. An active Cytomegalovirus surveillance program begins then. Cytomegalovirus transmission has been detected in 8 subjects; but only 1 developed Cytomegalovirus disease (1 other had Cytomegalovirus viremia and the other 6 had seroconversion only) (
Over the last decade, there has been substantial progress in islet transplantation, with much higher rates of insulin independence that are longer sustained. The procedure has been refined and is significantly safer, while, at the same time, the current immunosuppressant therapies are significantly better tolerated with fewer adverse effects. The long-term safety of islet transplantation appears more favourable than first feared, and some of the anticipated benefits for microvascular complications are beginning to be recognized. There is clear evidence that outcomes vary significantly between centres, with the best outcomes being achieved in experienced centres (
There are, however, many unanswered questions, and current data have important limitations that must be acknowledged. To date, no randomized trials in islet transplantation have been reported. Many reports are observational and, most comparisons are with historical controls. Consequently, observed effects (both positive and negative) may be overestimated. Similarly, important confounders may be overlooked and inferences of causality made. As an example, while it may seem reasonable to assume that improved A1C and reduced hypoglycemia in c-peptide positive subjects are attributed to the transplant, other factors such as close monitoring and follow-up could play a role. Likewise, it could be that poor adherence, psychosocial and other factors could be causes for both decline in graft function and poor control, rather than deterioration of glycemic control solely being the consequence of graft loss.
The benefits of strict glycemic control for microvascular complications are not in doubt. Improved outcomes for retinopathy after islet transplant appear to be confirmed by data from Vancouver and Edmonton. However, the Vancouver study employs a cross-over design where transplantation always follows medical therapy. The benefits would likely be less dramatic with a randomized study.
Although islet transplantation is often perceived as a cure for diabetes, it is not an alternative to conventional insulin therapy for the vast majority of people with type 1 diabetes. Nevertheless, for a subset of patients with frequent, severe hypoglycemia and/or glycemic lability, islet transplantation can provide the ability to achieve both excellent glycemic control and freedom from hypoglycemia even if insulin independence is not maintained. With a better understanding of the effectiveness of islet transplantation, we can help our patients appreciate better the risks and benefits and have more realistic expectations of this procedure. As a community, we will continue to strive to further refine and enhance islet transplantation until the elusive goal of a cure for diabetes is reached.
Author Disclosures
No conflicts of interest were declared.
References
Shapiro A.M.
Lakey J.R.
Ryan E.A.
et al.
Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen.
Rickels M, Barton FB, Alejandro R, et al. Factors of islet transplant success: Results from the Collaborative Islet Transplant Registry 1999-2010. In: 13th World Congress of International Pancreas and Islet Transplant Association. Prague: 2011.
Shapiro AJ, Toso C, Imes S, et al. Five-year results of islet-alone transplantation match pancreas-alone transplantation with alemtuzumab, Tac/MMF, with strong suppression of auto and alloreactivity. In: 13th World Congress of International Pancreas and Islet Transplant Association. Prague: 2011.
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