by David Sutherland, MD, PhD
An estimated 1 million people in the United States have been diagnosed with Type 1 diabetes. Approximately 30 percent to 50 percent of them will experience secondary complications of the disease, such as heart disease, high blood pressure, stroke, diabetic retinopathy, blindness, kidney disease, nervous system disease, and amputation. A patient's risk of experiencing these complications increases as his or her total lifetime exposure to elevated blood glucose levels increases.
The Diabetes Control and Complications Trial, a clinical study conducted from 1983 to 1993 by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), illustrated that if a patient has a qualified diabetes care team and intensive insulin treatment, the patient's blood glucose levels could be normalized for several years. However, this intensive treatment may be difficult to achieve and sustain because it would increase the patient's burden of diabetes management, require increased medical services and patient monitoring, and be accompanied by more frequent episodes of severe hypoglycemia.
Currently, the only way to restore normal blood glucose levels without the risk of hypoglycemia is to replace the patient's islets, either by transplantation of a whole pancreas or by infusion of isolated pancreatic islets. Beta-cell replacement therapy (pancreas and islet transplantation) should be considered as an option for patients with type 1 diabetes and renal insufficiency who are or will be obligated to immunosuppression for a kidney transplant, or for non-uremic patients who experience hypoglycemia-associated autonomic failure or progressive microvascular complications.
Pancreas transplantation
The first pancreas transplant was performed in 1966, simultaneous with kidney transplant, at the University of Minnesota. To date, more than 20,000 patients worldwide have received pancreas transplants. Nearly 2,000 of these have been performed at the University of Minnesota.
Three types of patients that are candidates for a pancreas transplant:
* Diabetic patients with uremia: they would receive a simultaneous pancreas and kidney (SPK) transplant;
* Nephropathic patients who have already had renal insufficiency corrected, usually by a living donor kidney transplant: they would receive a pancreas transplant after they have had their kidney transplant (PAK); and
* Diabetic patients who are nonuremic: they would receive a pancreas transplant alone (PTA).
SPK transplants represent the majority of pancreas transplants, but there is a trend toward performing more PAK transplants as more living-donor kidney transplants are performed to preempt the need for dialysis in diabetics with nephropathy. In addition, more PTA transplants are being performed for patients with diabetes who do not have advanced nephropathy but who have such difficulty managing their diabetes that immunosuppression is justified.
In addition to insulin independence, pancreas transplant patients have experienced prevention and reversal of secondary complications, improved quality of life, lengthened life span, and reduction of health care costs per quality-adjusted life year. A pancreas transplant can save the life of patients with labile diabetes or hypoglycemia unawareness.
The United Network for Organ Sharing (UNOS) captures data on transplants performed throughout the U.S. From January 1999 to May 2003, more than 5,700 patients received cadaver-donor pancreas transplants for the first time. Outcomes measures reported during this period are shown in Table 1.
Islet transplantation
The first islet transplant was performed in 1974, when the islets from a cadaver-donor
pancreas were infused into a diabetic patient who had previously had a kidney
transplant. Since then, more than 700 islet allotransplants have been performed.
Islet transplant is far less invasive than a pancreas transplant; it requires
only a local anesthetic and takes about 60 minutes. The islets are injected
into the liver, where they secrete insulin directly into the circulatory system
to control blood sugars.
Between 1974 and the early 1990s, insulin-independence was difficult to achieve
in patients who had type 1 diabetes. Since that time, islet transplants have
become markedly more successful by increasing the number of islets transplanted
into the patient and by reducing the diabetogenic side effects of immunosuppression.
New generations of immunosuppressive medications have eliminated the use of
prednisone in most recipients and have allowed calcineurin inhibitors to be
used in low, nondiabetogenic doses.
Recent islet transplant trials have achieved improved results, including the Universities of Alberta, Miami and Minnesota. Most patients at the first two centers required islets isolated from two or more donor pancreases to achieve insulin independence, but at the University of Minnesota we have been able to do so with a single donor by careful selection of large donors for low insulin-requiring recipients and by an isolation process that preserves islet viability to the utmost.
Two islet transplant trials were recently performed at the University of Minnesota,
with patients who had type 1 diabetes and who experienced hypoglycemia unawareness.
Twelve of 14 patients achieved insulin independence after receiving islets from
one cadaver donor pancreas each. After transplant, patients had excellent glycemia
control, as shown by elimination of severe hypoglycemia post transplant, normal
HbA1c levels, and normal oral glucose-tolerance test results.
The University of Minnesota's high success rate using a single donor pancreas
is due to a number of factors. First, by using the two-layer pancreas preservation
method, we were able to increase the number of islets isolated from the pancreas
and preserve the ability of these islets to reverse diabetes. The two-layer
pancreas preservation method involves sandwiching the pancreas between a top
layer (which contains a cold preservation solution) and a bottom layer (which
contains fluorocarbons that have been saturated with oxygen). This method delivers
more nourishing oxygen to the pancreas than the cold preservation layer alone
can. Second, during the peritransplant period, we targeted autoreactive T cells
with anti-CD3 antibodies or polyclonal T-cell antibodies, which inhibit activated
autoreactive T cells. Last, we cultured the islets pretransplant so that T-cell-directed
immunosuppression was achieved in the patient well before islet infusion. This
step is critical because it likely reduces islet-directed immune responses mediated
by autoreactive, primed T cells to which the intravascularly transplanted islets
are immediately exposed. Pretransplant culture allows for quality control studies
to be performed before infusion and improves the metabolic efficacy of cultured
islets. Delaying transplantation until two days after the patient starts therapy
with T-cell-depleting antibodies prevents the transplanted islets from being
exposed to the cytokine release associated with the first two antibody infusions.
By revising islet transplant protocols to include these advances, we have been able to achieve outcomes in islet transplant patients that are consistent with the outcomes experienced by pancreas transplant patients. Additional improvements in islet transplant outcomes are expected, as unique glucocorticoid and calcineurin inhibitor-free, nondiabetogenic immunosuppressive regimens have proved safe and effective in relevant preclinical models.
We can expect to see licensure of isolated human islets as biologic products in the foreseeable future as human islet processing techniques are demonstrated to be controlled and consistent, as islet product potency assays illustrate the predictability of post-transplant islet function, and as substantial evidence is provided of the clinical safety and efficacy of islet transplantation. This licensure will help secure third-party reimbursement, which will provide strong incentive to maximize donor pancreas use. In addition, islet transplants will become more available as pancreas preservation techniques are further improved; as regional islet processing centers are created; and as donor pancreas allocation methods, logistics, and technical impediments are overcome.
Treatment considerations
Currently, patients who have either a pancreas transplant or an islet transplant must take immunosuppressive drugs to prevent rejection. Protocols designed to induce immunologic tolerance specific to the donor are underway with islet transplant patients. In the future, immunotherapy will be tailored to the specific needs of the individual transplant patient.
Although a transition from pancreas to islet transplantation may occur over the next few years, pancreas transplantation will always be the better option for certain types of patients. For example, patients with high insulin requirements before transplant would be best served by a pancreas transplant. Diabetic patients with exocrine deficiency would continue to benefit most from an enteric drainage pancreas transplant. And patients who are insulin resistant (type 2 diabetics) or who have very high insulin requirements may need a pancreas transplant in order to obtain enough islets to restore insulin independence from a single donor.
Beta-cell replacement therapy will have a great impact on tissue availability. Of the 6,000 cadaver donors available each year, only half have pancreases suitable for transplantation. Assuming each cadaver pancreas could be split for use in two recipients and that living donors would be used for segmental pancreas transplantation to the extent they have been used for kidney transplants, up to 12,000 pancreas transplants could be performed annually in the U.S. The potential exists to transplant at a rate approaching half the annual incidence of new-onset cases of Type 1 diabetes (30,000 a year) in the U.S.
Although the procedural and immunosuppressive risks now associated with islet transplants will continue to diminish and the efficacy of islet transplant protocols will continue to improve, islet transplants will not be the ultimate approach to diabetes care. However, islet transplants will create and build momentum for the development of xenogeneic and stem/precursor cell-derived islet Beta-cell therapy, which will make cell replacement therapy routine in diabetes care.
Every transplant center should perform pancreas transplantation, and eventually islet transplantation, for treating patients who have diabetes. Every endocrinologist should consider Beta-cell replacement in treating patients with type 1 diabetes who have hypoglycemia-associated autonomic failure or progressive microvascular complications.
Continued clinical research on pancreas and islet transplants is needed to identify the most appropriate patients for transplant, the best time to perform a transplant, and the most suitable donor tissue and transplant protocol for a given patient. Health care providers and third-party payers will support Beta-cell replacement therapy more enthusiastically as prospective, adequately powered clinical trials comparing intensive insulin therapy and Beta-cell transplants earlier in the course of diabetes document superior outcomes in cost-adjusted quality of life. The results of these clinical trials could provide a strong rationale for evidence-based stratification to islet-cell replacement in at-risk patients with incapacitating hypoglycemia or incipient secondary complications.
David Sutherland, MD, PhD, is head of the Transplant Division, director of the Diabetes Institute for Immunology and Transplantation and a professor of surgery at the University of Minnesota.