Islet cell transplantation

https://doi.org/10.1053/j.sempedsurg.2014.03.006Get rights and content

Abstract

Islet transplantation has become a promising treatment for selected patients with type 1 diabetes. Here we provide an overview of the procedure including its history, the process of donor selection, and the techniques and procedures involved in a successful transplant. A brief overview of the current immunosuppressive regimens, the long-term follow-up and the reported outcomes will also be discussed. While islet transplantation is currently generally reserved for adults with type 1 diabetes with severe hypoglycemia or glycemic lability, we herein consider the possibility of its application to the pediatric population.

Introduction

Diabetes is a tremendous medical burden worldwide. It currently affects more than 200 million people worldwide, with projections to 5% of the world population by 2025.1 The most severe form of this disease, type 1 diabetes, representing approximately 10% of all cases of diabetes, results from the autoimmune destruction of β-cells within the islets of Langerhans. Since the discovery of insulin, diabetes has become a treatable condition. However, even with optimal insulin therapy, many patients still suffer from a multitude of complications of diabetes including nephropathy, neuropathy, retinopathy, peripheral vascular disease, and coronary artery disease. Intensive insulin therapy was formally tested in the Diabetes Control and Complications Trials (DCCT).2, 3, 4 While this therapy does partially mitigate cardiovascular disease, retinopathy, and nephropathy, there was a substantial increase in the number of adverse hypoglycemic events.3 Innovative means to tighten glycemic control with insulin pumps, dynamic continuous glucose monitoring, and closed loop systems have recently been developed and offer promise of improved control, reduced hypoglycemic risk, and maybe improved protection from secondary diabetic complications but still fall short of a robust cure for diabetes. In parallel, efforts to preserve and restore endogenous beta cell (and islet) mass have continued, both with whole vascularized pancreas transplantation and with islet transplantation. Whole pancreas transplantation was first attempted in 1966,5 and while early results were dismal, considerable advances in surgical technique, immunosuppression, and management have considerably improved the safety and efficacy of this approach. However, whole pancreas transplantation requires a major intra-abdominal surgical procedure, with significant morbidity and mortality. In addition, conceptually, it is really only the endocrine tissue that people with type 1 diabetes need replacing, and therefore a whole pancreas involves the transplantation of about 98% of pancreatic tissue that is not required. The presence of the exocrine pancreas also contributes to the risk of peri-operative infection, graft thrombosis, and graft pancreatitis. Transplantation of the islets of Langerhans alone therefore, is considered to be more refined and less risky for patients, but has, until the last decade, resulted in poor clinical success. We herein focus on clinical and experimental islet transplantation and discuss its possible applicability to the pediatric population.

Section snippets

History of islet transplantation

While islet transplantation in adults has advanced considerably in the first decade of the 21st century, the first recorded attempt at islet transplantation occurred in 1893 in a 13-year-old child dying from the ravages of diabetes. A physician and surgeon at the Bristol Royal Infirmary in the UK implanted “minced” pieces of a recently slaughtered sheep׳s pancreas beneath the subcutaneous tissues in an attempt to reverse his ketoacidotic state—almost 30 years before the discovery of insulin.6

Donor selection

While the success of the Edmonton Protocol centered around the avoidance of corticosteroids and the transplantation of an adequate islet mass,26 there has been an increased understanding that the selection of an optimal pancreas donor can make a dramatic difference in outcomes. Both the number of islets obtained and the quality of these islets can be affected by a number of donor characteristics, including age, body mass index (BMI), and the cold ischemic time.

A study by Lakey et al.28

Human islet isolation

The success of the islet isolation process clearly remains critical to the potential success of islet transplantation overall and requires considerable skill and expense in maintenance of ultra-clean good manufacturing practice (GMP) facilities that meet national governmental oversight. This led to the development of a number of islet transplant networks, including the GRAGIL Network in Switzerland and France,24 the NORDIC network in Scandinavia, and the UK Islet Transplant Consortium (UKITC)

Indications and patient selection for islet transplantation

Current indications for islet allotransplantation are outlined in Table. They do not currently include the pediatric population. However, we will discuss the potential applicability to children below. Indeed, islet transplants have been carried out in children, although most have been in the setting of total pancreatectomy and islet autotransplantation for hereditary pancreatitis.

There are a number of risks associated with islet transplantation, both secondary to the procedure itself and as a

Pre-transplant preparation

Once a patient has been placed on the waiting list for islet transplantation, they await a suitable donor pancreas for islet isolation and transplantation. Once the islet isolation yields sufficient islet mass to meet a potential recipient׳s needs, the patient travels to the transplant center to begin immunosuppressive induction therapy. While islet culture is presently being used routinely, generally between 10% and 20% of the islet mass is “lost” during the culture period. However, these

Long-term follow-up

After islet transplantation, patients are followed up closely in terms of their graft function. They are usually seen in clinic every 1–6 months and their glucose control, weight, blood pressure, and any adverse events are reviewed. Laboratory blood tests include a lipid profile, fasting glucose, complete blood count, electrolytes, renal function, and HbA1c. Graft function is usually assessed by a fasting oral glucose tolerance test, which may be performed every 6 months. Insulin therapy will

Outcomes

The ultimate goal of islet transplantation is insulin independence, it is defined as normal blood glucose levels without the need for exogenous insulin therapy. However, in “brittle” type 1 diabetics with glycemic lability and/or frequent hypoglycemic events, even a partially functional graft can be life changing. The original Edmonton Protocol26 showed remarkable insulin independence rates at 1 year (7/7 patients were insulin independent), a result that was closely echoed by the follow-up

Pediatric islet allotransplantation—A possibility?

In the history of solid organ transplantation, it did not take long for life-saving transplants and the need for chronic immunosuppression in adults to be translated into the pediatric population. In fact, some of the earliest successful liver transplants were carried out in children, and today end-stage renal failure in children is optimally managed with renal transplantation and chronic immunosuppression. Therefore the risks associated with immunosuppression (increased rates of infection and

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