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:

• In the US: Currently, the prevalence of type I diabetes in the United States is estimated to be 800,000 individuals, and 30,000 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 1400 pancreas transplants are performed each year. The number is limited by the number of cadaveric 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 transplants 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 pretransplant work-up 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 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:

• Renal disease: Preexisting advanced renal disease is observed in significant numbers of pancreas transplantation candidates. It therefore should be assumed that coincident extrarenal disease is present.

• Diabetic retinopathy: Diabetic retinopathy is a ubiquitous finding in patients with diabetes and end-stage renal disease (ESRD). Significant vision loss may be observed. Also, patients may be overtly blind. Blindness is not an absolute contraindication to transplantation because many blind patients lead very independent lives. Although rarely a problem, confirm that a patient with significant vision loss has an adequate support system to ensure help with travel and immunosuppressive medications.

• Gastroparesis: Impaired gastric emptying (gastroparesis) is an important consideration because of its significant implications in the posttransplantation course. Patients with severe gastroparesis may have difficulty tolerating oral immunosuppressive medications that are essential to prevent rejection of the transplantations. Episodes of volume depletion with associated azotemia frequently occur in patients with SPK transplantations. Patients typically require careful treatment, including motility agents such as metoclopramide, cisapride, or erythromycin.

• Coronary artery disease: The most important comorbidity to consider in patients with type I diabetes with diabetic nephropathy is coronary artery disease (CAD). Diabetic patients with ESRD are estimated to carry a nearly 50-fold greater risk of cardiovascular events than the general population. This type of patient may have several risk factors in addition to diabetes for development of CAD, including hypertension, hyperlipidemia, and smoking. Because of neuropathy associated with diabetes, patients may have asymptomatic myocardial ischemia-induced angina. The prevalence of significant (>50% stenosis) CAD in patients with diabetes who are starting treatment for ESRD is estimated to be 45-55%.

• Stroke: Patients with ESRD and diabetes also experience an increased rate of strokes and transient ischemic attacks. Deaths related to cerebral vascular disease are approximately twice as common in patients with diabetes compared to patients without diabetes once ESRD has occurred. Patients with diabetes experience strokes more frequently and at a younger age than do age- and gender-matched nondiabetic patients with stroke.

• Peripheral vascular disease: Lower extremity peripheral vascular disease is significant in patients with diabetes. Patients with ESRD are at risk for amputation of a lower extremity. These problems typically begin with a foot ulcer associated with advanced somatosensory neuropathy.

• Autonomic neuropathy

• Autonomic neuropathy is prevalent and may manifest as gastropathy, cystopathy, and orthostatic hypotension. The extent of diabetic autonomic neuropathy commonly is underestimated.

• Neurogenic bladder dysfunction is an important consideration in patients receiving bladder-drained pancreas-alone transplantation or SPK transplantation. Inability to sense bladder fullness and empty the bladder predisposes to high postvoid residuals and the possibility of vesicoureteral reflux. This may affect renal allograft function adversely, increase the incidence of bladder infections and pyelonephritis, and predispose to graft pancreatitis.

• The combination of orthostatic hypotension and recumbent hypertension results from dysregulation of vascular tone. This has implications for blood pressure control following transplantation, especially in patients with bladder-drained pancreas transplantations who are predisposed to volume depletion. Therefore, careful reassessment of the posttransplantation antihypertensive medication requirement is important.

• Sensory and motor neuropathies are common in patients with longstanding diabetes. This may have implications for rehabilitation after transplantation. It also is an indicator for potential risk of injury to the feet and subsequent diabetic foot ulcers.

• Mental or emotional illnesses: Mental illnesses, including neuroses and depression, are common. Diagnosis and appropriate treatment of these illnesses is an important pretransplantation consideration, with important implications for ensuring a high degree of medical compliance.

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:

• Pretransplantation recipient laboratory evaluation: The pertinent components of a complete pretransplantation recipient medical evaluation are outlined below. The emphasis of the evaluation should be to identify and treat all coexisting medical problems that may increase the rate of morbidity and mortality of the surgical procedure and adversely impact the posttransplantation course. In addition to a thorough medical evaluation, the social issues of the patient should be evaluated to determine conditions that may jeopardize the outcome of transplantation, such as financial and travel restraints and a pattern of noncompliance.

• Blood chemistries

• Liver function tests

• Complete blood count

• Coagulation profile

• Infectious profile

• Hepatitis B and C serologies

• Cytomegalovirus (CMV) serologies (immunoglobulin M/immunoglobulin G [IgM/IgG])

• Epstein-Barr virus serologies (IgM/IgG)

• Varicella-zoster serologies (IgM/IgG)

• Rapid plasma reagin (syphilis)

• HIV serology

• Purified protein derivative (tuberculosis skin test with anergy panel, when indicated)

• Urinalysis, urine culture, and cytospin (when indicated)

Imaging Studies:

• Chest x-ray (posteroanterior and lateral)

• Exercise/dipyridamole thallium scintigraphy

• Coronary arteriogram (if indicated)

Other Tests:

• C-peptide level confirms that transplantation candidate has type I diabetes.

• A complete cardiac workup, including angiography, is unnecessary in all patients. However, individuals with a significant cardiac history, positive review of systems, type I diabetes, or hypertensive renal disease should undergo a very complete evaluation to rule out significant coronary artery disease. A 12-lead ECG may be needed prior to transplantation.

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:

• Prior allocation allows the transplantation center performing the pancreas transplantation the choice to procure the pancreas as well. It allows patients to be admitted to the hospital and the reevaluation process to begin simultaneously with the procurement of organs, rather than sequentially.

• The cold-ischemia time of the pancreas prior to implantation is minimized. Pancreas allografts do not tolerate cold-ischemia as well as kidney allografts. Ideally, the pancreas should be revascularized within 24 hours from the time of cross-clamping at procurement.

• Finally, prior allocation also allows identification of 0-antigen mismatched donor-recipient pairs before procurement, which minimizes cold-ischemia time if the organs need to be transported across country.

• Pancreas transplantation surgery: The surgical techniques for pancreas transplantation are diverse, and no standard methodology is used by all programs. The principles are consistent, however, and include providing adequate arterial blood flow to the pancreas and duodenal segment, adequate venous outflow of the pancreas via the portal vein, and management of the pancreatic exocrine secretions. The native pancreas is not removed. Pancreas graft arterial revascularization typically is accomplished using the recipient right common or external iliac artery. The Y-graft of the pancreas is anastomosed end-to-side. Positioning of the head of the pancreas graft cephalad or caudad is not relevant with respect to successful arterial revascularization.

• When the pancreas transplantation is performed simultaneously with kidney transplantation, it is not uncommon for the kidney transplantation to be implanted first. The kidney is based on the recipient left iliac vessels. Both organs may be transplanted through a midline incision and placed intraperitoneal.

• Occasionally, considering placement of pancreas transplantation based on the left iliac vessels is necessary because of previously placed kidney transplantation on the right side. In this sequential pancreas-after-kidney transplantation procedure, the intra-abdominal approach is used. Mobilization of the left iliac vessels medial to the sigmoid colon is somewhat more challenging.

• The pancreas typically is drained into the bladder if a pancreas transplantation alone or pancreas-after-kidney transplantation is performed in order to utilize measurement of urinary amylase as a method of detecting rejection. However, some programs have had good experience with enteric drainage of the pancreas transplantation alone, using other markers for rejections, such as clinical signs and symptoms of pancreas graft pancreatitis and serum amylase or lipase levels coupled with biopsy.

• Two choices are available for venous revascularization—systemic and portal. No clinically relevant difference in glycemic control has been documented. Currently, approximately 15% of pancreas transplantations are performed with portal venous drainage and the remainder with systemic venous drainage.
• Systemic venous revascularization commonly involves the right common iliac vein or the right external iliac vein following suture-ligation and division of the hypogastric veins.
• If portal venous drainage is used, dissecting out the superior mesenteric vein (SMV) at the root of the mesentery is necessary. The pancreas portal vein is anastomosed end-to-side to a branch of the SMV. This may influence the methodology of arterial revascularization using a long Y-graft placed through a window in the mesentery to reach the right common iliac artery. Portal venous drainage of the pancreas is more physiologic with respect to immediate delivery of insulin to the recipient liver. This results in diminished circulating insulin levels relative to that in systemic venous-drained pancreas grafts.
• Handling the exocrine drainage of the pancreas is the most challenging aspect of the transplantation procedure. Several methods exist. Very few programs use duct injection. Pancreatic exocrine drainage is handled by means of anastomosis of the duodenal segment to the bladder or anastomosis to the small intestine. Currently, approximately 75% of pancreas transplantations are performed with enteric drainage, and the remainder are performed with bladder drainage.
• The bladder-drained pancreas transplantation was a very important modification introduced in about 1985. This technique significantly improved the safety of the procedure by minimizing occurrence of intra-abdominal abscess from leakage of enteric-drained pancreas grafts.
• With the successful application of the new immunosuppressant agents and the reduction of the incidences of rejection, enteric drainage of the pancreas transplantations has enjoyed a successful rebirth. Enteric drainage of pancreas grafts is physiologic with respect to the delivery of pancreatic enzymes and bicarbonate into the intestines for reabsorption. Enterically drained pancreases can be constructed with or without a Roux-en-Y. The enteric anastomosis can be made side-to-side or end-to-side with the duodenal segment of the pancreas. The risk of intra-abdominal abscesses is extremely low, and avoidance of the bladder-drained pancreas has significant implications with respect to the potential complications that include the following: bladder infection, cystitis, urethritis, urethral injury, balanitis, hematuria, metabolic acidosis, and the frequent requirement for enteric conversion.

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/m^2 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:

• Transplantation outpatient follow-up care
• Typical visit schedule following discharge from the hospital is as follows:

• Two or 3 visits in week 1
• Two visits in week 2
• One visit in week 3
• Monthly thereafter, until 6 months posttransplantation
• Every 3 months through the first year
• Every 6 months through the second year
• Annually thereafter

• Laboratory follow-up studies occur in the transplantation clinic and at a local laboratory near the patient’s home. A typical schedule is as follows:

• Every Monday, Wednesday, and Friday in month 1

• Every Monday and Thursday in month 2

• Every Monday in months 3-6

• Every other week in months 7-24

• Every month after 24 months

• Typical laboratory evaluation includes complete blood count, electrolytes, BUN, creatine, glucose, serum amylase, and immunosuppression blood levels (if transplantation recipient is receiving cyclosporine, tacrolimus, or sirolimus).

In/Out Patient Meds:

• Immunosuppression medications

• Immunosuppression must be taken for as long as the patient's transplanted organs are functioning. Immunosuppression cannot be stopped, or rejection of the organs will ensue.

Complications:

• Surgical and nonimmunological complications of pancreas transplantation: Surgical complications are more common after pancreas transplantation as compared to kidney transplantation. Nonimmunological complications of pancreas transplantation account for graft losses in 5-10% of cases. These occur commonly within 6 months of transplantation and are as important an etiology of pancreas graft loss in SPK transplantation as acute rejection is.

• Thrombosis: Vascular thrombosis is a very early complication, typically occurring within 48 hours and usually within 24 hours of the transplantation. This generally is due to venous thrombosis of the pancreas portal vein. The etiology is not defined entirely but is believed to be associated with reperfusion pancreatitis and the relatively low-flow state of the pancreas graft. Prudent selection of donor pancreas grafts, short cold-ischemia times, and meticulous surgical technique are all necessary to minimize graft thrombosis.

• Transplantation pancreatitis: Pancreatitis of the allograft occurs to some degree in all patients postoperatively. Temporary elevation in serum amylase levels for 48-96 hours after transplantation is common. These episodes are transient and mild, without significant clinical consequence. Interestingly, patients receiving simultaneous kidney-pancreas transplantation commonly have a greater degree of fluid retention for several days after transplantation, as compared to a recipient of kidney transplantation alone. Though not proven, this may be related to the graft pancreatitis that ensues in the perioperative period. The retained fluid is mobilized early postoperatively. It is important to minimize the risk of delayed kidney graft function by shortening cold-ischemia time so that the retained third-spaced fluid may be eliminated rapidly to avoid an episode of heart failure or pulmonary edema.

• Complications of bladder-drained pancreas transplantation

• Bladder-drained pancreas transplantation is a safer procedure than enteric-drained pancreas transplantation with respect to the possibility of intra-abdominal abscess. However, it is hampered by numerous less morbid complications. The pancreas transplantation will eliminate approximately 500 cc of richly bicarbonate fluid with pancreatic enzymes into the bladder each day. Change in pH of the bladder accounts, in part, for a greater increase in urinary tract infections. In some cases, a foreign body, such as an exposed suture from the duodenocystostomy, acts as a nidus for urinary tract infections or stone formation.

• Acute postoperative hematuria of the bladder-drained pancreas usually is due to ischemia/reperfusion injury to the duodenal mucosa or to a bleeding vessel on the suture line that is aggravated by the antiplatelet or anticoagulation protocols to minimize vascular thrombosis. These cases are self-limited but may require change in bladder irrigations and, if severe, cystoscopy to evacuate the clots. Occasionally, performing a formal open cystotomy and suture ligation of the bleeding vessel is necessary intraoperatively. If relatively late chronic hematuria occurs, transcystoscopic or formal operative techniques may be necessary treatments.

• Sterile cystitis, urethritis, and balanitis may occur after bladder-drained pancreas transplantation. This is due to the effect of the pancreatic enzymes on the urinary tract mucosa and is experienced more commonly in male recipients. Urethritis can progress to urethral perforation and perineal pain. Conservative treatment with Foley catheterization and operative enteric conversion represent the extremes of the continuum of treatment.

• Metabolic acidosis routinely develops as a consequence of bladder excretion of large quantities of alkaline pancreatic secretions. Patients must receive oral bicarbonate supplements to minimize the degree of acidosis. Because of the relatively large volume losses, patients also are at risk of episodes of dehydration exacerbated by significant orthostatic hypotension.
• Reflux pancreatitis can result in acute inflammation of the pancreas graft, mimicking acute rejection. It is associated with pain and hyperamylasemia and is believed to be secondary to reflux of urine through the ampulla and into the pancreatic ducts. Often, the urine is found to be infected with bacteria. This frequently occurs in a patient with neurogenic bladder dysfunction. This complication is managed by Foley catheterization. Reflux pancreatitis will resolve quickly. The patient may require a complete workup of the cause of bladder dysfunction, including a pressure-flow study and voiding cystourethrogram. Interestingly, in older male patients, even mild hypertrophy of the prostate has been described as a cause of reflux pancreatitis. If recurrent graft pancreatitis occurs, enteric conversion may be indicated.
• Urine leak from breakdown of the duodenal segment can occur and usually is encountered within the first 2-3 months following transplantation but can occur years following transplantation. This is the most serious postoperative complication of the bladder-drained pancreas. The onset of abdominal pain with elevated serum amylase, which can mimic reflux pancreatitis or acute rejection, is a typical presentation. A high index of suspicion for urinary leak is necessary to make the diagnosis accurately and swiftly. Supporting imaging studies using a cystogram or CT scan are necessary to confirm the diagnosis. Operative repair usually is required with exploration. The degree of leakage can be determined best intraoperatively, and proper judgment can be made whether direct repair is possible or more aggressive surgery involving enteric diversion or even graft pancreatectomy is indicated.

• Complications of enteric-drained pancreas transplantation

• The most serious complication of the enteric-drained pancreas transplantation is leak and intra-abdominal abscess. This serious problem usually occurs 1-6 months after transplantation. Patients present with fever, abdominal discomfort, and leukocytosis. A high index of suspicion is required to make a swift and accurate diagnosis. Imaging studies involving CT scan are very helpful.

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.

• Occurrence of intra-abdominal abscess has been reduced greatly with greater recognition of the criteria for suitable cadaveric pancreas grafts for transplantation. Improved perioperative antibiosis, including antifungal agents, has contributed to the decreased incidence of intra-abdominal infection, as well. No convincing evidence exists that a Roux-en-Y intestinal reconstruction decreases its incidence. Perhaps the most significant contribution to reducing the incidence of intra-abdominal abscess is the efficacy of the immunosuppressive agents in reducing the incidence of acute rejection and thereby minimizing the need for intensive antirejection immunotherapy.
• GI bleeding occurs in the enteric-drained pancreas from a combination of perioperative anticoagulation and bleeding from the suture line of the duodenoenteric anastomosis. This is self-limited and will manifest as diminished hemoglobin level associated with heme-positive or melanotic stool. Conservative management will suffice; the necessity for reoperative exploration is extremely unusual.

Prognosis:

• Survival rates for kidney and pancreas grafts and for patients from 1994-1998, the most recent era analyzed by the Scientific Registry and International Pancreas Transplant Registry, are the best outcomes reported to date. One-year survival rates were 94% for patients, 90% for kidney grafts, and 83% for pancreas grafts. Single-center reports exist that show better outcomes, with 1-year patient, kidney, and pancreas graft survivals of 97%, 95%, and 90%, respectively. Statistically and clinically, the outcome of kidney transplantation is significantly superior in patients receiving SPK transplantation versus patients with type I diabetes receiving kidney transplantation alone.

• For pancreas after kidney transplantation, patient survival has shown steady improvement over the 10-year interval from 1987-1997, with a 1-year patient survival rate from 90-95%. Similarly, pancreas graft functional survival has shown great improvement over this interval from a nadir of 51% to a high of 72% at 1 year after transplantation. The immunologic risk for graft loss for the technically successful cases has been reduced from a high of 28% to only 9% at 1 year. The relative risks for pancreas graft loss in the pancreas after kidney recipient include increasing donor and recipient age, increasing HLA mismatches, and retransplantation. Positive effects are shown with the use of tacrolimus maintenance immunosuppression.

• For patients receiving pancreas transplantation alone, patient survival rates have been very consistent over the period from1987-1997, 93% at 1 year. Pancreas graft functional survival rates have shown significant improvement, from 46-62%. The immunological risk for graft loss for the technically successful cases has been reduced from 38-16% at 1 year. The relative risks for pancreas graft loss for pancreas transplantation alone recipients are increasing donor age and HLA mismatches, and a positive affect can be observed with the use of anti–T-cell induction immunotherapy and use of tacrolimus maintenance immunotherapy.

• Effect of pancreas transplantation on secondary complications of diabetes

• Recipients of successful pancreas transplantation maintain normal plasma glucose levels without the need of exogenous insulin therapy. This results in normalization of glycosylated hemoglobin levels and a beneficial effect on many secondary complications of diabetes. The durability of the transplanted endocrine pancreas has been established with the demonstration that normalization of glycosylated hemoglobin is maintained as long as the allograft functions. The potential lifespan of the transplanted pancreas is not known precisely because, at present, survivors with functioning pancreas transplantations still are doing well more than 16 years after transplantation. The implications of prolonged normalization of glycemia and glycosylated hemoglobin levels are significant with respect to patients’ quality of life, kidney structure, and motor-sensory and nerve function.

• The quality of life of pancreas transplantation recipients has been well studied. Patients with a functioning pancreas graft describe their quality of life and rate their health significantly more favorably than those with nonfunctioning pancreas grafts. Satisfaction encompasses not only the physical capacities but also relates to psychosocial and vocational aspects. The functioning pancreas graft leads to even better quality of life when compared to recipients of kidney transplantation alone. Virtually all patients with a successful pancreas transplantation report that managing their life, including immunosuppression, is much easier since the transplantation. Successful pancreas transplantation will not elevate all patients with diabetes to the level of health and functioning of the general population, but transplantation recipients consistently report a significantly better quality of life than do patients who remain diabetic.

• The development of diabetic nephropathy in transplanted kidneys residing in patients with type I diabetes has been well established. Marked variability is observed in the rate of renal pathology, including mesangial expansion and a widening of the glomerular basement membrane, in patients with type I diabetes and kidney transplantation alone. The onset of pathological lesions can be detected within a few years of kidney transplantation. Clinical deterioration of renal allograft function can lead to loss 10-15 years after transplantation. A successful pancreas transplantation prevents glomerular structure changes of kidney allografts in patients with type I diabetes. This has been observed in transplanted kidneys of patients undergoing SPK transplantation, as well as in kidneys of recipients undergoing pancreas after kidney transplantation. These studies provide evidence of the efficacy of normalizing blood glucose and glycosylated hemoglobin levels to prevent the progression of diabetic glomerulopathy in
  renal allografts.

• Furthermore, successful pancreas transplantation will halt or reverse the pathology in the native kidneys of patients with type I diabetes and very early proteinuria. Pancreas transplantation recipients all had persistently normal glycosylated hemoglobin values after transplantation for 5-10 years. The thickness of the glomerular and tubular basement membranes and mesangial volume steadily decrease over a 10-year interval. These early studies have important implications for the role of pancreas transplantation alone in patients with type I diabetes and very early changes in native renal function.

• Successful pancreas transplantation has been shown to halt, and in many cases, reverse motor-sensory and autonomic neuropathy 12-24 months after transplantation. This has been studied most extensively in recipients of SPK transplantations. This raises the possibility that improvement of diabetic neuropathy occurs, in part, due to improvement of uremic neuropathy. However, pancreas transplantation alone in preuremic patients also has been shown to result in improvement in diabetic neuropathy. Many patients express subjective improvements of peripheral sensation 6-12 months after pancreas transplantation. Very interestingly, the effect of reversal of autonomic neuropathy in patients with type I diabetes with pancreas transplantation has been associated with better patient survival rates than patients with failed or no transplantation.

• Pancreas transplantation does not have an immediate dramatic beneficial effect on preestablished diabetic retinopathy. Retinopathy appears to progress for at least 2 years following transplantation of the pancreas, but it begins to stabilize in 3-4 years compared to diabetic recipients of kidney transplantation only. Longer-term studies of 5-10 years, similar to those described above, have not been reported.

Patient Education:

• During hospitalization, transplant recipients are prepared for discharge with respect to expectations of medical compliance, education about the pharmacology of their new immunosuppression medications, and lifestyle issues. Patients usually are provided a booklet that delves into the above-mentioned topics.

• Compliance with medical therapy may be one of the most important variables affecting transplant outcome. Transplant recipients must take immunosuppressive medications daily for the rest of their lives.

MISCELLANEOUS

Medical/Legal Pitfalls:

• Many of the medical/legal pitfalls (or risks) in general surgery are applicable to transplantation surgery. Specifically, obtaining informed consent for the surgical procedure is paramount. One difference in transplant surgery is the popularity of enrolling patients into clinical studies. If this is arranged, specific consent forms need to be obtained and filled out by the patient. Also, Institutional Review Board (IRB) approval may be required.

BIBLIOGRAPHY

• Bartlett ST, Schweitzer EJ, Johnson LB, et al: Equivalent success of simultaneous pancreas kidney and solitary pancreas transplantation. A prospective trial of tacrolimus immunosuppression with percutaneous biopsy. Ann Surg 1996 Oct; 224(4): 440-9; discussion 449-52[Medline].
• Gruessner AC, Sutherland DE: Analyses of pancreas transplant outcomes for United States cases reported to the United Network for Organ Sharing (UNOS) and non-US cases reported to the International Pancreas Transplant Registry (IPTR). Clin Transpl 1999; 51-69[Medline].
• Ojo AO, Meier-Kriesche HU, Hanson JA, et al: The impact of simultaneous pancreas-kidney transplantation on long-term patient survival. Transplantation 2001 Jan 15; 71(1): 82-90[Medline].
• Sollinger HW, Odorico JS, Knechtle SJ, et al: Experience with 500 simultaneous pancreas-kidney transplants. Ann Surg 1998 Sep; 228(3): 284-96[Medline].
• Stratta RJ, Larsen JL, Cushing K: Pancreas transplantation for diabetes mellitus. Annu Rev Med 1995; 46: 281-98[Medline].
• United Network for Organ Sharing (UNOS): United Network for Organ Sharing (UNOS). [Full Text].

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