Islet transplantation

Beta-cell replacement therapy may be achieved either with whole pancreas or islet transplantation. Whole pancreas transplantation has been performed since 1966, mainly in the setting of a simultaneous pancreas-kidney transplantation in patients with type 1 diabetes and end-stage renal disease due to diabetic nephropathy. Pancreas transplantation is a major surgical procedure, associated with a considerable risk for complications. Since only the endocrine tissue is required to treat patients with diabetes mellitus who are considered eligible for beta cell therapy, it was a logical next step to pursue investigations into the possibility of transplanting only the pancreatic islets.

Islet isolation

In order to transplant islets, they first need to be isolated from a pancreas. In the sixties and seventies of the twentieth century Lacy et al. played an important role in establishing a procedure to digest the pancreas and separate the pancreatic islets from the exocrine tissue after which the islets can be studied and transplanted.[1]

The islet isolation method was further optimized for human pancreas, and the first islet transplants were performed in man by 1980.[2] To comply with safety regulations, specialized laboratories (nowadays often Good Manufacturing Practice (GMP) certified) were established to generate high quality islet cell products for patient use.

The number and quality of the islets are important outcome variables of the islet isolation procedure. Islet number is most often expressed as islet equivalents, or IEQ (one IEQ is considered equivalent to a pancreatic islet with a diameter of 150 μm). The definition of islet quality has not been standardized between different centers. Islet preparation, islet viability, and in vitro islet function tests are used to evaluate the islet cell product before human use.

Islet transplantation

Once an islet preparation has been released for transplantation by the islet isolation laboratory, the islets are infused into the portal vein of the liver, currently the transplantation site of choice. The usual technique is transhepatic catheterization of the portal vein under ultrasound guidance, following which the islets are infused and embolize the smaller branches of the portal vein. Alternatively, access to the hepatic portal vein can be achieved by a laparoscopic procedure.

The liver is the favored “adoptive” site for pancreatic islets, but individual cases of islet transplantation at alternative sites such as the forearm have been reported.

The procedure-related complications of islet transplantation are relatively minor. Bleeding from the liver and portal vein thrombosis can occur but these complications usually occur in a frequency of < 5%. The risk of portal vein hypertension can be minimized by limiting the cumulative volume of infused tissue and carefully monitoring the portal vein pressure during and after the islet infusion.

Long-term outcome of islet transplantation

Although the long-term results of islet transplantation were initially disappointing, the Edmonton group led by James Shapiro transformed the field by showing that all members of a cohort of 7 patients with type 1 diabetes could achieve insulin independence.[3] Enthusiasm for this procedure increased greatly and human islet isolation and transplantation centers were set up around the world to implement the Edmonton protocol. However, the long-term outcome in an extended Edmonton cohort was disappointing, with insulin independence in around 10% of patients at 5 years follow-up.[4]

Factors that adversely affect islet graft outcome are allorejection, recurrent autoreactivity, immediate blood-mediated inflammatory reaction (IBMIR), adverse effects of immunosuppressive agents and impaired vascularization.

Further optimisation of the entire islet isolation and transplantation process was needed. Strategies ranged from a critical selection of organ donors, pancreas procurement and pancreas preservation to improvement of islet isolation, careful recipient selection, adaptations of the immunosuppressive regimen and supporting therapeutic measures peri-transplantation. These efforts have led to a gradual improvement in outcome reported by several groups.[5], and recent studies showed that insulin independence is present in about 50% of patients after 5 years.[6]

Islet transplantation for whom?

Islet transplantation can be performed in an autologous or allogeneic setting.

Autologous islet transplantation (islet autotransplantation)

Patients who suffer from a benign pancreatic disease that requires pancreatectomy are eligible for islet autotransplantation. The rationale for this procedure is that glycemic control can be very difficult in patients who have undergone total pancreatectomy because they have also lost the balancing effect of pancreatic glucagon.

In patients who undergo partial pancreatectomy, islet autotransplantation can prevent and/or delay the development of diabetes mellitus. The pancreas is digested following pancreatectomy, although isolation of the islets can be very difficult due to fibrosis when chronic pancreatitis is present. As much islet-containing tissue as is safely possible is then infused into the portal vein.

Up to 30 % of patients remain insulin-free when total pancreatectomy is combined with islet autotransplantation. Ongoing endogenous insulin secretion can be estimated by measurement of C-peptide, and the procedure reduces both the risk of vascular complications associated with diabetes and of hypoglycemia-related problems associated with insulin therapy. The degree of islet function is directly related to by the islet mass that is infused.

Allogeneic islet transplantation

Allogeneic islet transplantation is mainly performed in patients with severe beta cell failure, usually due to type 1 diabetes, associated with recurrent (severe) hypoglycemia and hypoglycemia unawareness. Other co-morbidities may also be present, such as gastrointestinal autonomic neuropathy, which results in variable food absorption and makes glycemic control even more difficult to achieve .

Islet transplantation is often considered a last resort option when optimization of glycemic control has failed to provide an acceptable outcome for the patient. In this context optimized glucose control might for example include continuous glucose monitoring, insulin pump therapy and intensive coaching by a diabetes team which includes a medical psychologist.

Unfortunately, no randomized clinical trials have compared the clinical outcome of optimized exogenous insulin therapy versus islet transplantation. In a study comparing patients on the waiting list for islet transplantation that receive insulin therapy, and patients who have undergone islet transplantation, the latter group had a lower rate of complications associated with improved glycemic control. Patients with type 1 diabetes and previous kidney transplantation are also considered eligible for islet transplantation, with the added advantage that these patients already use immunosuppressive agents.

What do potential recipients of an allogeneic islet transplantation need to know?

Several issues should be discussed so that patients can make an informed decision and to avoid unrealistic expectations about the medical and psychosocial impact of islet transplantation.

Glycemic control

With any beta-cell replacement therapy clinicians and their patients hope to achieve normalization of glucose homeostasis without a need for anti-hyperglycemic agents. In most studies at least 2 islet transplantation procedures, preferably performed in a limited time period, are necessary to obtain insulin independence.

Although currently only a minority of patients will be insulin independent beyond 5-10 years, partial restoration of endogenous insulin secretion may greatly improve quality of life by abolishing unpredictable swings in glucose control, eliminating or reducing hypoglycemic episodes, and alleviating the fear of hypoglycemia[7]. These outcomes and the goals of treatment should be carefully explained and discussed with patients.

Long-term diabetes-related complications

Established diabetes-related complications due to the presence of long-term hyperglycemia will generally not improve following islet transplantation, and existing of structural damage in the retina, kidney, nerves and both larger and smaller vessels that are involved in cardiac, cerebral and peripheral vascular disease will remain.

However, the progression of retinopathy, neuropathy, nephropathy and vascular disease will be positively influenced by islet transplantation. Additional reports have appeared on improvement in cardiovascular function, endothelial function, nerve conduction and symptoms of diabetic neuropathy. In patients with type 1 diabetes who have previously undergone kidney transplantation, there are data to indicate that kidney graft outcome also improves after islet transplantation.[8]

Immunosuppressive agents

For patients who have not undergone a previous organ transplantation the most important “price to pay” for islet transplantation, considering the low rate of procedure-related complications, is the side effects of current immunosuppressive therapy to prevent allorejection of the islet graft.

Immunosuppressive agents are associated with an increased risk of infections and malignancies (in particular virus-related cancer such as skin cancer). Calcineurin inhibitors that are often prescribed as a cornerstone of immunosuppressive therapy can cause a decline in kidney function. Especially in patients with diabetic nephropathy and proteinuria the risk of worsening nephropathy is considerable. Other side effects that are specific to certain immunosuppressive agents also need to be discussed in order to manage expectations. Thus the beneficial effects of an islet transplantation should be carefully weighed against the potentially harmful side effects of the long-term use of immunosuppressive agents.

HLA sensitization

Exposure to non-self HLA antigens will increase the risk for the generation of anti-HLA antibodies. This risk is increased further in islet transplantation when islet grafts from several donors are used in single or consecutive islet transplantation procedures.

Potential strategies that could reduce this risk such as HLA matching and living pancreas donation by a family member are generally not performed in islet transplantation. The relatively small number of patients on islet transplantation waiting lists in conjunction with the shortage of donor pancreas precludes this option for most centers.

Living pancreas donation by partial pancreatectomy for subsequent islet isolation and transplantation has given rise to occasional case reports in the scientific literature, but carries increased risks for the donor, and is unlikely to be widely used. In the interim, it should be noted that HLA sensitization could create a problem if further organ transplants become necessary.

References

  1. ^ Ballinger WF, Lacy PE. Transplantation of intact pancreatic islets in rats. Surgery 1972;72(2):175-186.

  2. ^ Robertson RP. Islet transplantation as a treatment for diabetes - a work in progress. N Engl J Med 2004;350(7):694-705.

  3. ^ Shapiro AM, Lakey JR, Ryan EA et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343(4):230-238.

  4. ^ Ryan EA, Paty BW, Senior PA et al. Five-year follow-up after clinical islet transplantation. Diabetes 2005;54(7):2060-2069.

  5. ^ Barton FB, Rickels MR, Alejandro R et al. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care 2012;35(7):1436-1445.

  6. ^ Bellin MD, Barton FB, Heitman A et al. Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes. Am J Transplant 2012;12(6):1576-1583.

  7. ^ Ryan EA, Shandro T, Green K et al. Assessment of the severity of hypoglycemia and glycemic lability in type 1 diabetic subjects undergoing islet transplantation. Diabetes 2004;53(4):955-962.

  8. ^ Fiorina P, Shapiro AM, Ricordi C, Secchi A. The clinical impact of islet transplantation. Am J Transplant 2008;8(10):1990-1997.

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