Pancreas Transplantation

 Authored by Dixon Kaufman, MD, Director of Pancreas Transplantation, Associate Professor, Department of Surgery, Division of Transplantation, Northwestern University Medical School

Coauthored by Alan Koffron, MD, Director, Living-Donor Transplantation, Assistant Professor of Surgery, Department of Surgery, Division of Transplantation, Northwestern University Medical School

Dixon Kaufman, MD, is a member of the following medical societies: American Association for the Study of Liver Diseases, American Association of Immunologists, American College of Surgeons, American Diabetes Association, American Medical Association, American Society of Transplant Surgeons, Association for Academic Surgery, Central Surgical Association, Illinois State Medical Society, National Kidney Foundation, Phi Beta Kappa, Society for Surgery of the Alimentary Tract, and Society of University Surgeons

Edited by Ron Shapiro, MD, Professor, Department of Surgery, University of Pittsburgh; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Douglas M Heuman, MD, FACP, Director of Hepatology, McGuire Veterans Affairs Medical Center, Professor, Department of Internal Medicine, Division of Gastroenterology, Medical College of Virginia; Michael E Zevitz, MD, Consulting Faculty, Clinical Assistant Professor, Department of Medicine, Finch University of Health Science, Chicago Medical School; and Mary C Mancini, MD, PhD, Chief, Division of Cardiothoracic and Vascular Surgery, Professor, Department of Surgery, Louisiana State University Health Sciences Center

eMedicine Journal, December 13 2001, Volume 2, Number 12

INTRODUCTION

 

Background: The purpose of pancreas transplantation is to ameliorate type I diabetes and produce complete insulin independence. The first successful pancreas transplant in conjunction with a simultaneous kidney transplant was performed by 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 cadaveric organ donor. However, select cases of living donor pancreas transplants have been performed. About 100 transplant centers in the United States perform pancreas transplants. About 1400 cases are performed annually in the United States.

About 85% of pancreas transplants are performed with a kidney transplant (both organs from the same donor) in diabetic patients with renal failure. This is referred to as a simultaneous pancreas-kidney (SPK) transplant. About 10% of cases are performed after a previously successful kidney transplant. This is referred to as a pancreas-after-kidney transplant. Five percent are performed as pancreas transplant alone in nonuremic patients with very labile and problematic diabetes. An alternative new therapy that also may ameliorate diabetes is islet transplantation. That procedure is experimental and is not yet as efficient as pancreas transplantation. That procedure generally is limited to individuals without renal failure who have with very labile diabetes.

Pathophysiology: 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 transplant produces a normoglycemic and insulin-independent state. It will reverse the diabetic changes in the native kidneys of patients with very early diabetic nephropathy, prevent recurrent diabetic nephropathy in patients undergoing an SPK transplantation, reverse peripheral sensory neuropathy, stabilize advanced diabetic retinopathy, and significantly improve 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 cc 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:

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 transplant results are reported to the Scientific Registry 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%, 89%, and 85%, respectively. Compared to diabetic recipients of a kidney alone, the addition of a pancreas improves long-term patient and kidney graft survival. Recipients of a pancreas-after-kidney or a pancreas transplant alone have an average 1-year pancreas graft survival rate of about 70-75%.

CLINICAL

 

History: Evaluation of candidates for pancreas transplantation involves the following:

Causes: Type I diabetes is an autoimmune disease that results in selective loss of the insulin-producing beta cells of the islets of Langerhans. No reliable way to predict who will develop diabetes is available, nor does a cure exist. Transplantation of the pancreas is a treatment option designed to replace the islets. Immunosuppression to prevent organ rejection is sufficient also to prevent recurrent autoimmune diabetes.

WORKUP

 

Lab Studies:

Imaging Studies:

Other Tests:

TREATMENT

 

Surgical Care: The timing of allocation of the pancreas to a specific patient relative to the procurement of the organ has important implications. Determining donor human leukocyte antigen (HLA) typing, serologies, and crossmatch results with patients on the pancreas transplantation waiting list will permit the ideal situation of allocating the cadaveric pancreas (plus kidney, with SPK transplantation) prior to procurement of the organs. This sequence of events has several advantages, as follows:

Diet: Following successful pancreas transplantation, no dietary restrictions are required. In fact, the diet can be liberalized to include virtually anything because blood sugar control is restored to normal.

Activity: Following successful pancreas transplantation, few activity restrictions are needed. Extreme contact sports probably should be avoided to prevent accidental trauma to the newly placed intra-abdominal organs.

MEDICATION

 

All pancreas transplant recipients require life-long immunosuppression to prevent a T-cell alloimmune rejection response. The Food and Drug Administration (FDA) has approved several new immunosuppressive agents, and several others currently are in clinical trials.

Two broad classifications of immunosuppressive agents exist—intravenous induction/antirejection agents and maintenance immunotherapy agents. No consensus exists as to the single best immunosuppressive protocol, and each transplant program utilizes various combinations of agents slightly differently.

The goals are to prevent acute or chronic rejection, minimize drug toxicity, minimize rates of infection and malignancy, and achieve the highest possible rates of patient and graft survival.

Drug Category: Antirejection/induction agents -- Induction immunotherapy consists of a short course of intensive treatment with intravenous agents. Antilymphocyte antibody induction therapeutic agents are varied and include polyclonal antisera, mouse monoclonals, and so-called humanized monoclonals. Polyclonal antisera, such as antilymphocyte globulin (ALG), antilymphocyte serum (ALS), and antithymocyte globulin (ATG) are equine, goat, or rabbit antisera directed against human lymphoid cells. The effects significantly lower and almost abolish circulating lymphoid cells critical to rejection response.

The agents are very effective at prophylaxis against early acute rejection, which is especially beneficial in managing the recipient with delayed graft function. The agents provide an effective immunologic cover during a period where the calcineurin inhibitors either are delayed or administered in subtherapeutic doses until graft function improves. Induction agents are used less often if immediate graft function occurs, such as recipients of living kidney donors, especially HLA-ID grafts.

Drug Name

Antithymocyte globulin (equine), lymphocyte immune globulin (Atgam) -- Only polyclonal preparation approved by FDA for prophylaxis of rejection as induction agent. Primarily IgG from hyperimmune serum from horses.

Adult Dose

10-20 mg/kg/d IV for 7-14 d

Pediatric Dose

Administer as in adults

Contraindications

Documented hypersensitivity; severe unremitting leukopenia or thrombocytopenia

Interactions

None reported

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Infection, leukopenia, or thrombocytopenia may occur; adverse reactions include fever, chills, and malaise; IV route reduces risk of phlebitis; emergency resources should be available to manage rash, dyspnea, hypotension, or anaphylaxis immediately

 

Drug Name

Muromonab-CD3 (Orthoclone OKT3) -- A mouse antihuman monospecific antibody directed against CD3 antigen on T lymphocytes. Binding of OKT3 to CD3 molecule causes T-cell modulation or results in elimination of circulating T cells. The agent is extremely effective at reversing acute rejection episodes.

Adult Dose

5 mg/d IV for 7-14 d

Pediatric Dose

2.5-5 mg/d IV for 7-14 d

Contraindications

Documented hypersensitivity

Interactions

None reported

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

CHF, pulmonary edema, or infections may occur; adverse reactions include fever, chills, malaise, headache, and cytokine release syndrome

 

Drug Name

Dacliximab (Zenapax) -- Humanized monoclonal antibody that specifically binds to and blocks interleukin-2 (IL-2) receptor on surface of activated T cells.

Adult Dose

1 mg/kg IV for 5 doses beginning at time of transplant and then q14d

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity

Interactions

Immunocompromised patients have a decreased response to vaccines

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Only administer if adequate supportive medical resources are available

 

Drug Name

Basiliximab (Simulect) -- Chimeric monoclonal antibody that specifically binds to and blocks the IL-2 receptor on the surface of activated T cells.

Adult Dose

20 mg IV at time of transplant, then repeat 4 d posttransplant

Pediatric Dose

2-15 years: 12 mg/m2 IV; not to exceed 20 mg

Contraindications

Documented hypersensitivity

Interactions

Immunocompromised patients have decreased response to vaccines

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

Long-term effect on ability of immune system to respond to antigens unknown

 

Drug Name

Antithymocyte globulin, rabbit (Thymoglobulin) -- A purified immunoglobulin solution produced by the immunization of rabbits with human thymocytes is used to treat acute rejection.

Adult Dose

1.25-1.5 mg/kg/d IV for 7-14 d

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity

Interactions

None reported

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Infection, leukopenia, and thrombocytopenia may occur; adverse reactions include fever, chills, malaise, and headache

 

Drug Name

Methylprednisolone (Solu-Medrol, Adlone, Medrol) -- Steroids ameliorate delayed effects of immune reactions.

Adult Dose

0.25-1 g IV at time of transplant, then tapered for next 2-3 doses

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity; viral, fungal, or tubercular skin infections

Interactions

Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels of methylprednisolone; phenobarbital, phenytoin, and rifampin may decrease levels of methylprednisolone (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Hyperglycemia, edema, osteonecrosis, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use

Drug Category: Maintenance immunosuppression agents -- Several immunosuppressive agents currently are in use for maintenance immunotherapy in kidney transplant recipients. Optimal maintenance immunosuppressive protocol has not been developed. Maintenance immunosuppressive agents are required for life.

Drug Name

Prednisone (Deltasone, Orasone, Meticorten) -- Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Adult Dose

20-60 mg/d PO during first mo posttransplant, then taper to approximately 5 mg/d PO over next y

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease

Interactions

Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

 

Drug Name

Azathioprine (Imuran) -- Active component of azathioprine is 6-mercaptopurine. Acts as purine analog that interacts with DNA and inhibits lymphocyte cell division.

Adult Dose

1-3 mg/kg/d PO qd; maximum 150 mg/d

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity; low levels of serum thiopurine methyl transferase (TPMT); significant leukopenia

Interactions

Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine

Pregnancy

D - Unsafe in pregnancy

Precautions

Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur; check TPMT level prior to therapy and follow liver, renal, and hematologic function; pancreatitis rarely associated

 

Drug Name

Mycophenolate (CellCept) -- Inhibitor of enzyme inosine monophosphate dehydrogenase (IMPDH). Results in inhibition of lymphocyte proliferation. Used for prophylaxis of organ rejection in patients receiving allogeneic renal allografts.

Adult Dose

1-1.5 g/d PO usually divided bid

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity

Interactions

May elevate levels of acyclovir and ganciclovir; antacids and cholestyramine decreases absorption, reducing levels (do not administer together); probenecid may increase levels of mycophenolate; salicylates may increase toxicity of mycophenolate

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Do not use with azathioprine; discontinue if significant leukopenia develops; increases risk for infection; increases toxicity in patients with renal impairment; caution in active peptic ulcer disease

 

Drug Name

Cyclosporine (Sandimmune, Neoral, Gengraf) -- Calcineurin inhibitors that diminish IL-2
production in activated T cells. These agents bind to the intracellular immunophilin cyclophilin, interfering with the action of calcineurin, which inhibits nuclear translocation of the nuclear factor of activated T cells (NFAT).

Adult Dose

Dosed according to blood concentrations
12-hour trough concentration range: typically is 150 ± 50 ng/mL by TDx immunoassay
Initial dose: 9 ± 3 mg/kg/d PO divided q12h

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity; uncontrolled hypertension or malignancies

Interactions

Carbamazepine, phenytoin, isoniazid, rifampin, phenobarbital, and other drugs that induce CYP3A4 may decrease cyclosporine concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, clarithromycin, and other drugs that inhibit CYP3A4 may increase cyclosporine levels/toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzymes; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO

 

Drug Name

Tacrolimus (Prograf) -- Calcineurin inhibitor that diminishes IL-2 production in activated T cells. Binds to intracellular immunophilin, FKBP, interfering with the action of calcineurin, which inhibits nuclear translocation of the NFAT. FDA approved for prophylaxis of organ rejection in patients receiving allogeneic renal allografts.

Adult Dose

Dosed according to blood concentrations
12-hour trough concentration range: typically is 9 ± 3 ng/mL by IMx immunoassay
Initial dose: 0.125 ± 0.05 mg/kg/d PO divided q12h; IV dosing approximately one third that of PO administered as continuous infusion over 24 h

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity

Interactions

Levels/toxicity may increase with diltiazem, nicardipine, clotrimazole, verapamil, erythromycin, ketoconazole, itraconazole, fluconazole, bromocriptine, grapefruit juice, metoclopramide, methylprednisolone, danazol, cyclosporine, cimetidine, and clarithromycin; tacrolimus levels may decrease with rifabutin, rifampin, phenobarbital, phenytoin, and carbamazepine

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Has nephrotoxic effects; do not administer simultaneously with cyclosporine; tonic clonic seizures may occur

 

Drug Name

Sirolimus (Rapamune) -- Inhibits lymphocyte proliferation by interfering with signal transduction pathways. Binds to immunophilin FKBP to block action of mTOR. FDA approved for prophylaxis of organ rejection in patients receiving allogeneic renal allografts.

Adult Dose

6 mg PO loading dose, then 2-5 mg PO qd; trough blood concentrations >8 ng/mL correlated with immunosuppressive activity

Pediatric Dose

Not established

Contraindications

Documented hypersensitivity

Interactions

Levels/toxicity may increase with diltiazem, nicardipine, clotrimazole, verapamil, erythromycin, ketoconazole, itraconazole, fluconazole, bromocriptine, grapefruit juice, metoclopramide, methylprednisolone, danazol, cyclosporine, cimetidine, and clarithromycin; levels may decrease with rifabutin, rifampin, phenobarbital, phenytoin, and carbamazepine

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

May exacerbate hyperlipidemia and thrombocytopenia

 

FOLLOW-UP

 

Further Outpatient Care:

In/Out Patient Meds:

Complications:

Percutaneous access of intra-abdominal fluid collection for Gram stain and culture is essential. The flora typically is mixed with bacteria and often fungus, particularly Candida. Broad-spectrum antibiosis is essential. Surgical exploration and repair of the enteric leak is necessary. A decision must be made on whether the infection can be eradicated without removing the pancreas allograft. Incomplete eradication of the infection will result in progression to sepsis and multiple organ system failure. Peripancreatic infections can result in development of a mycotic aneurysm at the arterial anastomosis that could cause arterial rupture. Transplantation pancreatectomy is indicated if mycotic aneurysm is diagnosed.

Prognosis:

Patient Education:

MISCELLANEOUS

 

Medical/Legal Pitfalls:

BIBLIOGRAPHY

 

eMedicine Journal, December 13 2001, Volume 2, Number 12