Transplantation of a normal pancreas is a treatment method for patients with insulin-dependent diabetes mellitus (IDDM). Pancreas transplantation can restore glucose control and is intended to prevent, halt, or reverse the secondary complications from diabetes mellitus.
Achievement of insulin independence with resultant decreased morbidity and increased quality of life is the primary health outcome of pancreas transplantation. While pancreas transplantation is generally not considered a life-saving treatment, in a small subset of patients who experience life-threatening complications from diabetes mellitus, pancreas transplantation could be considered life-saving. Pancreas transplant alone (PTA) has also been investigated in patients following total pancreatectomy for chronic pancreatitis. In addition to the immune rejection issues common to all allograft transplants, autoimmune destruction of beta cells has been observed in the transplanted pancreas, presumably from the same mechanism responsible for type 1 diabetes mellitus. (1)
Pancreas transplantation occurs in several different scenarios such as a:
- Diabetic patient with renal failure who may receive a cadaveric combined (frequently known as simultaneous) pancreas-kidney transplant (CPK or SPK);
- Diabetic patient who may receive a cadaveric or living-related pancreas transplant after a kidney transplantation (pancreas after kidney, i.e., PAK);
- Non-uremic diabetic patient with specific severely disabling and potentially life-threatening diabetic problems who may receive a PTA; or
- Segmental pancreas transplantation from a living related donor (LRD) has also been performed. The early rationale for LRD pancreas transplant was to reduce the rejection rate. LRD represents a very small proportion of all pancreas transplants.
The total number of adult pancreas transplants (pancreas and pancreas-kidney) in the U.S. peaked at 1,484 in 2004; the number has since declined. (2) In 2011, there were 287 pancreas transplants and 795 pancreas-kidney transplants in the U.S.
According to International Registry data, the proportion of pancreas transplant recipients worldwide who have type 2 diabetes mellitus has increased over time, from 2% in 1995 to 7% in 2010. (3) In 2010, approximately 8% of SPK, 5% of PAK, and 1% of PTA were performed in patients with type 2 diabetes mellitus.
The approach to retransplantation varies according to the cause of failure. Surgical/technical complications such as venous thrombosis are the leading cause of pancreatic graft loss among diabetic patients. Graft loss from chronic rejection may result in sensitization, increasing both the difficulty of finding a cross-matched donor and the risk of rejection of a subsequent transplant. Each center has its own guidelines based on experience; some transplant centers may wait to allow reconstitution of the immune system before initiating retransplant with an augmented immunosuppression protocol.
Potential contraindications subject to the judgment of the transplant center:
- Known current malignancy, including metastatic cancer,
- Recent malignancy with high risk of recurrence,
- Untreated systemic infection making immunosuppression unsafe, including chronic infection,
- Other irreversible end-stage disease not attributed to kidney disease,
- History of cancer with a moderate risk of recurrence,
- Systemic disease that could be exacerbated by immunosuppression,
- Psychosocial conditions or chemical dependency affecting ability to adhere to therapy.
In addition, the vast majority of pancreas transplant patients will have type 1 diabetes mellitus. Those transplant candidates with type 2 diabetes mellitus, in addition to being insulin-dependent, should also not be obese (body mass index [BMI] should be 32 or less). According to International Registry data, in 2010, 7% of pancreas transplant recipients had type 2 diabetes mellitus. (3)
Islet Cell Transplantation
Transplantation of pancreatic islet cells is defined as removing isolated islet cells from a donor pancreas to the recipient. In autologous transplantation, the donor and recipient is the same individual. For allogeneic transplantation, the donor and the recipient are not the same individual, but matched as closely as possible to promote islet cell engraftment. Autologous islet transplantation, performed in conjunction with pancreatectomy, is proposed to reduce the likelihood of IDDM. Moreover, allogeneic islet cell transplantation is being investigated as a treatment or cure for patients with type 1 diabetes mellitus.
In autologous islet transplantation, during the pancreatectomy procedure, islet cells are isolated from the resected pancreas using enzymes, and a suspension of the cells is injected into the portal vein of the patient’s liver. Once implanted, the beta cells in these islets begin to make and release insulin.
In the case of allogeneic islet cell transplantation, cells are harvested from the deceased donor’s pancreas, processed, and injected into the recipient’s portal vein. Up to 3 donor pancreas transplants may be required to achieve insulin independence. Allogeneic transplantation may be performed in the radiology department.
Chronic pancreatitis: Primary risk factors for chronic pancreatitis include toxic-metabolic, idiopathic, genetic, autoimmune, recurrent and severe acute pancreatitis, or obstructive (the TIGAR-O classification system). Patients with chronic pancreatitis may experience intractable pain that can only be relieved with a total or near total pancreatectomy. However, the pain relief must be balanced against the certainty that the patient will be rendered an insulin-dependent diabetic. Autologous islet transplantation has been investigated as a technique to prevent this serious morbidity.
Type 1 diabetes mellitus: Allogeneic islet transplantation has been used for type 1 diabetes mellitus to restore normoglycemia and, ultimately, reduce or eliminate the long-term complications of diabetes mellitus such as retinopathy, neuropathy, nephropathy, and cardiovascular disease. Islet transplantation potentially offers an alternative to whole-organ pancreas transplantation. However, a limitation of islet transplantation is that 2 or more donor organs are usually required for successful transplantation, although experimentation with single-donor transplantation is occurring. A pancreas that is rejected for whole-organ transplant is typically used for islet transplantation. Therefore, islet transplantation has generally been reserved for patients with frequent and severe metabolic complications who have consistently failed to achieve control with insulin-based management.
Islet cells are subject to regulation by the U.S. Food and Drug Administration (FDA), which classifies allogeneic islet cell transplantation as somatic cell therapy, requiring premarket approval. Islet cells also meet the definition of a drug under the federal Food, Drug, and Cosmetic Act. Clinical studies to determine safety and effectiveness outcomes of allogeneic islet transplantation must be conducted under FDA investigational new drug (IND) regulation. While at least 35 IND applications have been submitted to the FDA, no center has submitted a biologics license application.