Pancreas Transplantation 

The purpose of pancreas transplantation is to ameliorate type I diabetes and produce complete insulin independence. The first successful pancreas transplantation in conjunction with a simultaneous kidney transplantation was performed by W.D. Kelly, MD, and Richard Lillehei, MD, from the University of Minnesota in 1966. Until about 1990, the procedure was considered experimental. Now it is a widely accepted therapeutic modality, with virtually all insurance carriers covering the procedure, including Medicare. The pancreas comes from a deceased organ donor. However, select cases of living-donor pancreas transplantations have been performed. About 100 transplant centers in the United States perform pancreas transplantations. About 1200 cases are performed annually in the United States.

About 75% of pancreas transplantations are performed with kidney transplantation (both organs from the same donor) in patients with renal failure who are diabetic. This is referred to as a simultaneous pancreas-kidney (SPK) transplantation. About 15% of pancreas transplantations are performed after a previously successful kidney transplantation. This is referred to as a pancreas-after-kidney transplantation. The remaining 10% of cases are performed as pancreas transplantation alone in nonuremic patients with very labile and problematic diabetes. An alternative new therapy that may also ameliorate diabetes is islet transplantation, which is experimental and is not yet as efficient as pancreas transplantation. See the image below.

History

Experiments in pancreas transplantation began long before the discovery of insulin. In 1891, pieces of dog pancreas autotransplanted beneath the skin prevented diabetes after removal of the intra-abdominal pancreas. Subsequent experimentation with intrasplenic transplantation did not succeed because of graft necrosis. In 1916, sliced human pancreas was transplanted into 2 patients, but the grafts were completely absorbed. The first pancreatic xenotransplantation was performed in 1893 in London; a 15-year-old boy underwent subcutaneous implantation of a pancreas.

Despite extensive animal experimentation, pancreatic transplantation did not become a reality until 1966, when W.D. Kelly performed the first human, whole-organ pancreatic transplantation for treatment of type 1 diabetes mellitus. Because of poor outcomes, few procedures were performed until 1978. Much of the early work was performed by Sutherland and colleagues at the University of Minnesota. With improved immunosuppressive regimens and newer surgical techniques, the 1980s ushered in a new era in pancreas transplantation.^[1] According to the International Pancreas Transplant Registry, nearly 10,000 pancreatic transplantations were recorded by 1998.

Most of the pancreatic transplantations have been performed in patients with type 1 diabetes mellitus and a lack of insulin production. The most common indication is renal failure; therefore, the pancreas transplantation is typically performed simultaneously with a kidney transplantation.^{[2, 3]} In some patients with hypoglycemic unawareness or other diabetic complications, isolated pancreas transplantation has been performed. However, the results have been somewhat inferior to those of the combined procedure.

Various technical concerns must be considered in patients undergoing pancreas transplantation, including whether or not the venous drainage should be into the systemic circulation or into the portal vein.^[1] Another controversial topic is whether the exocrine secretions should be drained enterically or into the bladder as initially described. The complications of graft pancreatitis and bladder leakage that plagued early experiences with pancreas transplantation have largely been resolved as a result of both better technical expertise and fewer rejection- and immunosuppression-related complications.

Type I diabetes mellitus is an autoimmune disease wherein the insulin-producing pancreatic beta cells are destroyed selectively. Presently, no practical mechanical insulin-delivery method exists that, coupled with an effective glucose-sensory device, replaces pancreatic insulin secretion well enough to produce a near constant euglycemic state without risk of hypoglycemia. Therefore, individuals with type I diabetes must resign themselves to manual regulation of blood glucose levels by subcutaneous insulin injection and, as a consequence, typically exhibit wide deviations of plasma glucose levels from hour to hour and from day to day.

Hyperglycemia is the most important factor in the development and progression of the secondary complications of diabetes. These observations, and the fact that conventional exogenous insulin therapy cannot prevent the development of secondary complications of type I diabetes, have led to a search for alternative methods of treatment.

One such treatment, pancreas transplantation, has the potential to achieve better glycemic control and alter the progression of long-term complications. A successful pancreas transplantation produces a normoglycemic and insulin-independent state. It reverses the diabetic changes in the native kidneys of patients with very early diabetic nephropathy, prevents recurrent diabetic nephropathy in patients undergoing an SPK transplantation, reverses peripheral sensory neuropathy, stabilizes advanced diabetic retinopathy, and significantly improves patients' quality and quantity of life.

The insulin released by the endocrine pancreas graft is secreted into the blood stream. Because the exocrine pancreas produces about 800-1000 mL per day of fluid, it must be diverted in either the bladder or bowel. If the pancreas graft is attached to the bladder, the losses of pancreatic fluid rich in bicarbonate may produce relative acidosis. This usually is treated by bicarbonate supplementation. Because the pancreas graft comes from another individual, the recipient's immune system can mount a rejection reaction and destroy the graft. To prevent that problem, immunosuppression medications must be taken daily and forever to prevent rejection. Chronic immunosuppression elevates the risk of viral and fungal infections and some types of malignancy.

Frequency

United States

Currently, the prevalence of type I diabetes in the United States is estimated to be 1,100,000 individuals, and 35,000 new cases are diagnosed each year. The total annual cost of diabetes, including hospital and physician care, laboratory tests, pharmaceutical products, and patient workdays lost because of disability and premature death, exceeds $90 billion.

Only about 1,200 pancreas transplantations are performed each year. The number is limited by the number of deceased donor organs available for transplantation. Candidates for the procedure have type I diabetes and generally are aged 55 years or younger. Ninety-five percent of pancreas transplantations are performed in patients with renal disease or a previous functioning kidney transplant. The recipients must be healthy to undergo the surgical procedure. Therefore, the pretransplantation workup emphasizes diagnosis of significant cardiovascular disease, established nontreatable infectious disease, and cancer.

Mortality/Morbidity

At the turn of the century, a patient diagnosed with type I diabetes mellitus had an average life expectancy of only 2 years. The development of insulin as a therapeutic agent revolutionized the treatment of diabetes mellitus by changing it from a rapidly fatal disease to a chronic illness. Unfortunately, this increased longevity allowed the development of secondary complications, including nephropathy, neuropathy, retinopathy, and macrovascular and microvascular complications, occurring 10-20 years after disease onset.

Pancreas transplantation results are reported to the Scientific Registry of Transplant Recipients (SRTR) of the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR). Based on this information, the national 1-year patient, kidney, and pancreas survival rates for recipients of an SPK transplant are 95%, 91%, and 86%, respectively. Compared to patients with diabetes who receive a kidney alone, the addition of a pancreas improves long-term patient and kidney graft survival.^[4] Recipients of a pancreas-after-kidney (PAK)transplant or a pancreas transplant alone have an average 1-year pancreas graft survival rate of 78-83%.

Another study showed that pancreas after living donor kidney transplantation resulted in significantly higher patient survival and kidney graft survival compared with living donor kidney transplant alone at 8 years of follow up. In addition, pancreas transplant during the first year after kidney transplant has shown improved long-term patient survival compared to living donor kidney transplant alone.^[5]

In one published retrospective study, differences in mortality were examined in consecutive patients with diabetes who were older than 50 years compared with well-matched recipients younger than 50 years undergoing pancreas transplantation (the majority were simultaneous kidney-pancreas transplants) at a high-volume European center. Despite US data suggesting an increased risk of mortality in recipients older than 45 years compared with patients younger than 45 years, it is becoming clear that carefully selected patients with diabetes who are older than 50 years can undergo successful pancreas transplantation with similar patient and allograft survival outcomes.^[6] This trend toward considering pancreas transplantation in older recipients appears to have begun earlier in the United States and is now gaining momentum in Europe as well, as evidenced in this study. It must be emphasized that careful cardiac evaluation is essential to this process of patient selection.