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Pancreas Transplantation

The prevalence of diabetes is increasing and is estimated to affect more than 6.5% of the US population, up from 4.9% in 1990 -- a 33% increase.[59] By the year 2020, 250 million people will be afflicted worldwide.[60] The economic burden is equally impressive. In 1999, Medicare expenditures for ESRD were $12.7 billion and non-Medicare expenditures were $5.2 billion, bringing the total cost of the ESRD program to $17.9 billion, an increase of 7.2% from 1998.[61]
Outcomes of pancreas transplantation have continued to improve in recent years, and pancreas transplantation has become an accepted treatment of selected patients with type 1 diabetes. Pancreas conservation techniques have improved, surgical techniques continue to be perfected, current immunosuppressive protocols are yielding excellent survival rates, and quality of life is better after SKP transplantation in diabetic patients.

Introduction

Whole-organ pancreas transplantation was pioneered more than 30 years ago in an effort to improve the outcomes of patients with concomitant diabetes mellitus (DM) and uremia.[1] Preceded by refinement of surgical techniques and organ preservation in large animals, clinical pancreas transplantation began at the University of Minnesota in 1966. Early pancreas transplant recipients were typically patients who, because of severe secondary complications of DM, no longer benefited from conventional medical therapy.[2] High patient acuity, technical problems, and a high incidence of acute rejection accounted for poor patient outcomes in the early years of pancreas transplantation.

Until recently, despite substantial improvements in quality of life reported by many pancreas transplant recipients, the perception persisted that pancreas transplantation was an experimental procedure.[3] However, significant advances have been made and pancreas transplantation is the only treatment for type 1 DM that can induce insulin-independent normoglycemia. Currently, pancreas transplantation is considered a therapeutic option for patients with all stages of DM, even those with advanced extrapancreatic complications.

Current Status of Pancreas Transplantation

The incidence of pancreas transplantation in the United States has increased annually since 1990. From 1990 through 1999, the number of pancreas and kidney-pancreas transplants increased from 60 to 358 and from 459 to 933, respectively.

In April 1999, combined or simultaneous pancreas-kidney (SPK) and pancreas after kidney (PAK) transplantation gained acceptance as Medicare-reimbursed treatments for type 1 DM. Solitary pancreas transplantation, or pancreas transplant alone (PTA), was not covered in the original Health Care Financing Agency (HCFA) Medicare ruling, nor was pancreas transplantation that followed non-Medicare reimbursed kidney transplantation. Revision of the HCFA ruling in October 1999 broadened Medicare coverage to include both procedures.[4] Pancreas transplantation and postoperative immunosuppressive therapy are also covered by some private insurance carriers.

More than 15,000 pancreas transplants were reported to the International Pancreas Transplant Registry (IPTR) between 1966 and October 3, 2000[5]; 11,000 of those procedures were performed in the United States. SPK transplantation is by far the most common approach, accounting for 86% of cases performed in the United States between 1994 and 2000[6]. PTA transplantation accounted for 4% of cases, while PAK transplantation accounted for the remaining 10%.[5]

Refined surgical techniques and better immunosuppressive drug regimens have significantly improved patient and graft survival rates for all pancreas transplant procedures. United Network for Organ Sharing (UNOS) data reveal that SPK is associated with better graft survival compared with PTA transplantation.[7] Data from the 2000 IPTR Annual Report documented a 1-year patient survival rate of 95% in SPK recipients; kidney and pancreas graft survival rates were 92% and 82%, respectively, between 1998 and 2000.[5] One-year patient and graft survival rates of 100% and 76%, respectively, for the PTA transplantation were recorded during this same time period, while 1-year patient and graft survival rates were 94% and 74%, respectively, following PAK transplantation.[5] Improved graft survival in SPK transplant recipients is thought to be the result of multiple factors, including improved methods for diagnosing acute kidney rejection. Detection of acute pancreatic rejection is more difficult because of the lack of specific and sensitive indicators.[1] The objectives of this chapter are to:

  • Describe the current status of pancreas transplantation
  • List underlying diseases and conditions that may result in the need for pancreas transplantation
  • Identify patient populations who may benefit from pancreas transplantation
  • Outline key steps in the evaluation of patients for pancreas transplantation
  • Summarize current recommendations for immunosuppression
  • List the most common postoperative complications of pancreas transplantation
  • Discuss recent advances in treatment and management of pancreas transplant recipients.

End-Stage Pancreatic Disease

DM is a global health problem affecting an estimated 100 million people worldwide.[8] Approximately 16 million Americans are affected, of which half are undiagnosed.[3] DM is a syndrome characterized by chronic hyperglycemia and other metabolic disturbances. The metabolic abnormalities of DM are due to cellular destruction of the insulin-secreting beta cells in the islets of Langerhans. Beta cell destruction is marked by the appearance of IgG islet cell antibodies. Attack of the beta cells leads to infiltration by macrophages, natural killer cells, and activated cytotoxic T cells. These cells release cytokines that trigger nitric oxide or superoxide production. Beta cells are extremely susceptible to oxygen toxicity and are unable to destroy free radicals. The end result of this cascade of events is failure of the beta cells to release insulin and the loss of glucose homeostasis. This is a gradual process of autoimmune destruction, presumably triggered by a virus, in genetically predisposed individuals. Genetic predisposition is believed to involve as many as 16 genes, and the risk for developing the disorder is 5 times greater when the father has the disease than when the mother has it.[9] When approximately 80% to 90% of the beta cells are destroyed, insulin production is diminished, resulting in hyperglycemia and other signs and symptoms of DM. Shortly thereafter, all beta cells are destroyed and insulin production ceases.

DM affects every organ and system in the body. Chronic effects of DM include neuropathy, microvascular changes, and macrovascular changes, and result in significant morbidity and mortality from complications of the eyes, kidneys, nerves, and blood vessels. Patients with type 1 DM are 25 times more prone to blindness, 17 times more prone to kidney disease, have 5 times the incidence of gangrene, and twice the incidence of heart disease compared with nondiabetic patients.[10] Retinopathy is the second leading cause of blindness in all persons and the leading cause of blindness in persons between the ages of 20 and 60 years.[11,12] Approximately 34% of individuals with type 1 diabetes develop end-stage renal disease (ESRD) as a secondary complication within 15 years of disease onset.[3] Ten percent of individuals with diabetes will require a major amputation during their lifetime as a result of microvascular abnormalities. Diabetes accelerates atherosclerosis, resulting in cardiovascular disease, which is the leading cause of death in diabetic persons. The life expectancy of individuals with diabetes is approximately one third lower than that of nondiabetic individuals.

Although diligently managed insulin therapy can control hyperglycemia, successful treatment requires restrictive life-style modifications such as careful dietary management, structured physical activity, smoking cessation, limiting alcohol consumption, and stress management. In addition, insulin therapy is associated with the risk of frequent and severe hypoglycemia and frequent episodes of hypoglycemic unawareness.[1] Currently, successful pancreas transplantation is the only treatment that consistently provides minute-to-minute glycemic control.[1] Thus, the relative short-term and long-term risks and benefits must be considered when deciding between transplantation and medical treatment.

Indications for Pancreas Transplantation

Pancreas transplantation restores euglycemia, slows the progression of end-organ complications, and improves quality of life in patients with insulin-dependent diabetes. Because pancreas transplantation is not without risks, it is generally indicated in patients with complications of type 1 DM more serious than the risk of transplant surgery and chronic immunosuppression. There is also a subgroup of patients with type 2 DM (typically 30-40 years of age) who become insulin-dependent several months after the introduction of oral antihyperglycemic agents and develop secondary complications of DM 10-20 years later.[1] This group of patients may in fact have type 1 DM and, therefore, benefit from pancreas transplantation, particularly if they develop below-normal C-peptide levels.[1]

Contraindications

The major absolute contraindication to pancreas transplantation is uncorrectable cardiovascular disease. Other absolute contraindications include active infection, positive HIV or hepatitis B virus surface antigen serology, malignancy within the past 3 years, active substance abuse or dependence, recent history of noncompliance, psychiatric illness, active untreated peptic ulcer disease, irreversible hepatic or pulmonary dysfunction, or other systemic illness that would compromise recovery or significantly limit life expectancy.[13] Relative contraindications include advanced vascular disease, advanced autonomic neuropathy, extreme obesity (> 150% ideal body weight), recent retinal hemorrhage, active smoking, and age < 18 years or > 60 years. Although some centers regard a history of blindness, major amputation, stroke, and corrected coronary artery disease (CAD) as contraindications to transplantation, some patients with these problems can be successfully transplanted.

Impaired glucose tolerance may also occur as a secondary disorder in patients with chronic pancreatitis. Ketoacidosis and diabetic coma are infrequent and the secondary end-organ complications typically observed in persons with type 1 and type 2 DM seldom occur.[14] Thus, patients with chronic pancreatitis are not candidates for pancreatic transplantation.

Pretransplant Evaluation

Candidates for pancreas transplantation demonstrate varying degrees of end-organ and tissue disease manifested in neuropathies, macrovascular disease, and microvascular disease. A thorough pretransplant evaluation is conducted by the multidisciplinary transplant team comprised of surgeons, nurse coordinators, social worker, and financial coordinator. Referrals are made to nutritionists, pharmacists, and other specialists as indicated. Diagnostic studies aid in determining eligibility for transplantation and the extent of secondary complications of DM ,

Neuropathy

Neuropathy is the most common complication of DM,[15] but is poorly understood. Distal portions of neurons are affected. Axonal degeneration preferentially involves unmyelinated nerve fibers, and Schwann cell abnormalities result. Motor, sensory, and autonomic nerve conduction is affected throughout the body and is manifested as bilateral peripheral neuropathy (sensory and motor) and various forms of dysautonomia: cardiac autonomic dysfunction, orthostatic hypotension, gastropathy, neurogenic bladder, and sexual dysfunction.[9,16]

Peripheral Neuropathy

Peripheral neuropathy is a major contributing factor to loss of limbs from foot and leg amputation. Ulceration is the most common complication in the diabetic forefoot and underlies more than 90% of cases of pedal osteomyelitis.

Diabetic neuropathy may be painless or painful. Painless neuropathy manifests as impaired light-touch sensation, position sense, vibratory perception, and diminished or absent ankle deep tendon reflexes. Painful sensory diabetic neuropathy primarily affects small nerve fibers, resulting in decreased temperature perception and paresthesias. Symmetrical distal sensory neuropathy is more frequent than symmetrical motor neuropathy or asymmetrical neuropathy. Proximal diabetic amyotrophy evolves subacutely or acutely and causes motor weakness of the proximal thigh and buttock muscles, and is painful. Cranial nerve III-neuropathy is also painful and has an acute onset. Truncal radiculopathy follows the distribution of truncal roots and frequently causes intense pain.

Evaluation for somatic polyneuropathy may include assessment of neuropathic symptoms (numbness, paresthesias, hyperesthesias, and pain) and deficits (bilateral loss of stretch reflexes and vibratory sensation, gait abnormalities, Charcot's neuro-osteoarthropathy [limited joint mobility at the first metatarsophalangeal joint and dysfunction of the plantar fascia],[9] foot and/or wrist drop), pathologic nerve conduction studies, pathologic quantitative sensory testing, and/or pathologic quantitative autonomic testing.

Cardiac Dysautonomia

Cardiac autonomic dysfunction (impairment in parasympathetic and sympathetic cardiac function) leads to diminished heart rate variability, resting tachycardia (which results from a progressive, generalized decline in parasympathetic modulation of heart rate), changes in circadian rhythmicity with sympathetic activity predominating at night, and ventricular ectopy,[17] which increases the risk of sudden cardiac death.[18-21]

Measures of cardiac autonomic function include lab-evoked and 24-hour measures of heart rate variability. Lab-evoked measures evaluate the baroreceptor reflex -- heart rate response (R-R interval variability) to respiratory maneuvers (deep breathing and Valsalva maneuver) -- and reflect a beat-to-beat balance of adrenergic and cholinergic outflow. In the normal heart, sinus arrhythmia is a vagal-mediated response that can be induced during 1 minute of slow, deep breathing (6 breaths/minute). This response is often absent in the presence of cardiac autonomic dysfunction.[22] The Valsalva ratio (VR) is calculated by dividing the patient's heart rate during forceful exhalation (40 mm Hg for 15 seconds) by the lowest heart rate occurring within 15 seconds after the maneuver. The VR reflects cardiac parasympathetic function with a cardiac sympathetic and vascular adrenergic component.[22] Evoked measures of cardiac autonomic function are only useful for detecting severe cardiac autonomic dysfunction.

The 24-hour measures are more sensitive and can be used to detect early and subtle changes in cardiac autonomic function, and have been used to assess cardiac autonomic function and identify transplant candidates at-risk for sudden cardiac death.[23] Measurement of 24-hour heart rate variability (R-R interval variability) with power spectral analysis assesses: (1) time domain measures of interbeat variability, associated with vagal function, circadian function, and sudden cardiac death; and (2) frequency domain measures that quantify total neural sympathetic and parasympathetic activation of the heart. Patients wear a Holter monitor for continuous EKG recording. Power spectral analysis transforms variations in R-R intervals into frequency waveforms that quantify parasympathetic, sympathetic, and total neural modulation of heart rate.

Gastric Dysautonomia

Gastric neuropathy, estimated to occur in 20% of individuals with type 1 DM, causes diabetic gastroparesis leading to reduced gastric motility and delayed gastric emptying. As a result, blood glucose levels can be erratic and difficult to control. Dehydration from persistent vomiting may lead to diabetic ketoacidosis. Diarrhea occurs in approximately 5% of individuals with DM and is likely related to neuropathy. Diarrhea is also more common in diabetic individuals with concomitant damage to other organs. Impaired fluid absorption from the intestines, damage to the anal sphincter muscles, and impaired sensation in the rectum contribute to fecal incontinence. Fear of vomiting or incontinence may lead to social isolation as individuals become homebound, which can lead to depression.

Symptoms of gastroparesis include nausea, vomiting, abdominal bloating, early satiety, loss of appetite, and heartburn as a result of esophageal regurgitation. It is important to elicit information regarding the severity and frequency of symptoms and their impact on the patient. Some patients experience severe, refractory pain requiring hospitalization for aggressive pain management. Pancreas transplantation alleviates symptoms of gastroparesis in some patients.[24,25]

Several diagnostic tests are used to document gastroparesis. Diabetic gastroparesis may not affect liquid digestion, so barium x-rays are not useful. Instead, a radioisotopic gastric emptying scan or a barium beefsteak meal is used. The former involves feeding the patient food containing a radioisotope followed by sequential imaging scans that detect the amount of food with the isotope remaining in the stomach at different points in time. If more than half of the food remains in the stomach after 2 hours, the diagnosis of gastroparesis is made.[26] Similarly, the stomach contents are visualized at specific points in time after the patient consumes a meal containing barium.

Less commonly used tests include gastric manometry, which measures electrical and muscular activity in the stomach during digestion through a catheter inserted orally into the stomach, and noninvasive cutaneous electrogastrography.

Urinary Dysautonomia

During the pretransplant evaluation, candidates are questioned about history of urinary tract infections, kidney stones, and reflux. Candidates are also asked about their ability to sense bladder fullness, difficulty starting or maintaining a urine stream, urinary frequency, and emptying of the bladder. A urine sample for urine analysis and culture is obtained. Postvoid catheterization may be done to detect residual urine. In patients with recurrent urinary tract infections, a voiding cystourethrogram, a cystoscopy, and/or urodynamic pressure-flow studies may be done.

Macrovascular Disease

Diabetic macrovascular disease manifests in the form of atherosclerotic heart disease, peripheral vascular disease, and infection. Atherosclerosis occurs as a response to cardiac vessel injury. There is proliferation of the subendothelial smooth muscle in the arterial wall and deposition of lipids in these lesions. Peripheral vascular disease develops as a result of occlusion of small arteries and arterioles. The predisposition to infection is multifactorial: impaired vision and touch; tissue hypoxia; increased glycosylated hemoglobin (HbA1c) on the red blood cells, which impedes the release of oxygen to tissues; and rapid proliferation of pathogens in glucose-rich body fluids.

Cardiovascular Disease

Cardiovascular disease is the major cause of morbidity and mortality following pancreas transplantation. The high incidence of CAD and the increased risk for cardiovascular events in diabetic transplant candidates make a thorough cardiac evaluation essential. Goals of the cardiac evaluation include determination of risk for perioperative myocardial infarction (MI), estimation of the effect of cardiac risk on long-term prognosis, and identification of patients who can benefit from modification of cardiovascular risk factors.[27] Cardiac risk stratification includes history and clinical assessment for atherosclerotic risk factors and diagnostic testing. Cardiac angiography is considered the gold standard for the diagnosis of CAD; stenosis > 70% is considered significant. There is debate, however, over the best way to evaluate diabetic transplant candidates and recipients because of anecdotal evidence that cardiovascular events occur in the absence of significant stenosis in persons with diabetes.

Although cardiac disease is a significant cause of morbidity and mortality in persons with diabetes, routine cardiac catheterization of diabetic transplant candidates is expensive and may precipitate acute renal failure. A clinical algorithm to predict the presence of CAD in diabetic transplant candidates has been developed. Use of this screening algorithm may help to identify individuals at low risk for CAD and avoid unnecessary angiography prior to transplantation. In a sample of 70 patients, this screening algorithm had a sensitivity of 97% (accurately predicted 97% of patients with significant CAD) and a negative predictive value of 96% (accurately predicted 96% of patients who did not have disease). Diabetic transplant candidates under 45 years of age and lacking the following risk factors are unlikely to have CAD (negative predictive accuracy of 96%): 5 or more pack/years smoking history, nonspecific ST waves on electrocardiogram (ECG), and DM duration > 25 years.[28]

By contrast, Manske[29] found that 88% of patients with insulin-dependent diabetes over the age of 45 years had 1 or more significant (> 70%) coronary stenoses. Other predictors of significant coronary stenosis were the number of years patients had suffered from diabetes and abnormal ST-T segment on ECG (inverted T-waves in leads where the QRS complex had a net positive deflection and ST-T segment elevation or depression >/= 1 mm). Recommendations include assessment of risk factors such as hypertension, dyslipidemia (hypercholersterolemia, hypertriglyceridemia, and decreased high-density lipoprotein cholesterol), left ventricular hypertrophy with diastolic dysfunction, hyperhomocysteinemia, and endothelial dysfunction. The endothelium regulates vascular tone through the release of vasodilators, such as nitric oxide, and vasoconstrictors, such as endothelin. Endothelial dysfunction, an alternation in the balance between endothelium-derived relaxing factors and endothelium-derived contracting factors,[30] can be determined by assessing brachial artery diameter changes in response to arterial occlusion (flow-mediated) and vasomotor response to cold stress or pharmacologic stimuli such as acetylcholine.

A cardiovascular history is taken to determine previous or current palpitations, sensation of "racing heart," angina, hypertension, hyperlipidemia, MI, cardiac surgery, stroke, orthopnea, nocturnal dyspnea, foot ulcers, and amputation. Silent ischemia may occur with increased physical activity and manifest as fatigue and/or shortness of breath.

A thorough physical assessment of the cardiovascular system is performed and includes the following:

  • Thorax inspected for heaves and jugular venous distention, palpated for thrills and enlarged or shifted PMI
  • Heart sounds auscultated
  • Supine and standing blood pressure levels monitored to assess for orthostatic hypotension
  • Carotid arteries auscultated for bruits
  • Extremities assessed for peripheral edema and impaired peripheral circulation characterized by diminished or absent peripheral pulses; shiny, taut skin with hair loss; and claudication with exercise[31,32]
  • Extremities assessed for coolness to touch, cyanosis, and skin breakdown with ulcerations.

Although not routine, 24-hour blood pressure monitoring may be done to detect nocturnal hypertension.

Lipid profiles, a resting 12-lead ECG, and cardiac imaging tests are generally performed. Altered cardiac geometry (increased left ventricular mass, posterior wall thickness, interventricular septal wall thickness) and function (both diastolic and systolic) have been reported in transplant candidates and recipients with type 1 and type 2 DM[33-36]; however, the relevance of these findings is unclear. Echocardiography (2D-guided M-mode with Doppler) allows noninvasive examination of the patient's heart size and position, movement of the chambers and valves, and blood flow and velocity, including left ventricular ejection fraction at rest and/or during stress (exercise or pharmacologic induction). The myocardial perfusion scan utilizes radioactive imaging agents (thallium 201, technetium Tc99m [Cardiolite], or technetium Tc 99m tetrofosmin) to diagnose ischemic heart disease and detect myocardial wall and pump defects during increased oxygen demand.[37]

Exercise stress tests with radioactive imaging at peak exercise level have been used before and after transplantation to assess cardiac risk. As a result of peripheral neuropathy and muscle weakness, however, many diabetic transplant candidates and recipients are unable to exercise (walk on a treadmill) intensely or long enough to achieve a maximal heart rate and the cardiac stress level necessary to test for CAD. Therefore, in lieu of physical stress, cardiac stress may be pharmacologically induced with agents such as dipyridamole, adenosine, or dobutamine.

The accuracy of dipyridamole thallium testing for prediction of the absence of significant coronary artery stenosis in diabetic transplant candidates has been reported as 81% to 100%.[38] In diabetic transplant candidates with concomitant ESRD, the ability of dipyridamole thallium testing to predict the absence of CAD ranged from 70% to 89%. The presence of diffuse coronary atherosclerosis and left ventricular hypertrophy in diabetic uremic patients is thought to diminish the accuracy of the test. However we have found pharmacologic stress cardiac imaging to be an acceptable screening methodology. Transplant candidates with a reversible defect on thallium testing selectively undergo coronary angiography and are referred for revascularization (angioplasty or cardiac artery bypass surgery) if significant stenosis is found.

Doppler ultrasonographic evaluation of the carotid and peripheral arteries allows noninvasive anatomic imaging of vessel patency and also provides information about hemodynamics.[37] Individuals with significant carotid artery stenosis or occlusion require surgical correction before they can be listed for pancreas transplantation. Abdominal ultrasound with visualization of the iliac arteries and veins and abdominal aorta is performed preoperatively, as are studies to detect deep venous thrombosis (DVT). Individuals with a history of DVT, pulmonary embolus, cerebral vascular event, autoimmune disease (ie, lupus or Hashimoto's thyroiditis), vasculitis, or previous graft loss due to thrombosis are evaluated for hypercoagulability.

Microvascular Disease

DM causes thickening of the capillary basement membranes, which results in tissue hypoxia and ischemia, most commonly in the retina and kidney. The retina is a highly metabolic organ and is therefore very sensitive to ischemia. Renal glomerular changes result in diffuse intercapillary glomerulosclerosis.

Diabetic Retinopathy

Pancreas transplant candidates generally demonstrate some degree of retinopathy and may also have cataracts or glaucoma. During the ophthalmic examination, candidates are asked about blurry or double vision; seeing rings, flashing lights, blank spots, dark spots, or floating spots; pressure or pain in the eyes, and loss of peripheral vision. Diabetic retinopathy may occur without these signs, so a yearly ophthalmic assessment is recommended. The severity of retinopathy is determined from 7-field fundus photographs. Based on these photographs, retinopathy is graded according to the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, which was also used, in a modified form, in the Diabetic Control and Complications Trial. A grade is assigned for each eye based on the severity of diabetic retinopathy for each lesion. Characteristics that are graded include: new vessel development, presence of hard and soft exudates, arteriovenous nicking, retinal elevation, vitreous hemorrhage, macular edema, retinal thickening, microaneurysms, drusen, papillary swelling, hard exudate rings, macular hole, subretinal hemorrhage, and presence of a deep pale spot at the center of the macula.[39] The retinopathy "step" or "level" for each individual is derived by calculating the scores for each eye, giving the eye with the highest level greater weight.

Diabetic Nephropathy

The decision to perform PTA vs SPK or PAK transplantation depends on the presence and severity of diabetic nephropathy because the nephrotoxic side effects of calcineurin inhibitors given as part of the immunosuppressive regimen after transplantation further compromise native kidney function. PTA is recommended if the creatinine clearance is above 60 mL/min. PAK transplantation is recommended for patients with a creatinine clearance above 40 mL/min, and preemptive SPK transplantation is recommended in patients with a creatinine clearance below 30 mL/min.[13]

Blood chemistries used to assess for nephropathy include serum creatinine and blood urea nitrogen (BUN).[37] Proteinuria is the earliest manifestation of renal dysfunction, usually occurring after 10-15 years of insulin therapy. Patients are screened for microalbuminuria (trace albumin in urine), a marker of renal vascular damage, by measuring the albumin excretion rate. Kidney filtration is quantitated from tests of renal clearance: (1) 24-hour urine for creatinine and insulin clearance, and (2) renal plasma flow estimated by para-aminohippurate clearance.

Procedures for Pancreas Transplantation

Pancreas transplantation can be performed via a number of surgical techniques and approaches. The whole pancreas or a segment of the pancreas can be transplanted. Segmental pancreas transplantation is done on a limited basis when there is a living pancreas donor. Management of exocrine secretions of the pancreas, a critical factor in the success of pancreas transplantation, can be accomplished via pancreatic duct occlusion, enteric drainage, or bladder drainage.[1] Pancreatic duct occlusion with a polymer prevents exocrine secretion, but with this method it is not possible to monitor amylase in the exocrine secretions as a marker for rejection. Bladder drainage is the most frequent technique used in the United States. However, enteric drainage is gaining favor.[5] As previously described, there are 3 approaches to pancreas transplantation, depending on the extent of renal involvement: (1) PTA, (2) SPK, and (3) PAK transplantation.

The Systemic-Bladder Technique

The systemic-bladder (bladder-diversion) technique (Figure 1) directs venous outflow and insulin drainage into the iliac vein; exocrine drainage is via anastomosis of a donor duodenal segment to the recipient's urinary bladder. The primary advantages of the systemic-bladder approach are fewer technical complications and allowance for assessment of pancreatic function via direct measurement of urinary amylase levels. Hyperinsulinemia, the primary disadvantage of the systemic-bladder approach, results from nonphysiologic delivery of insulin into systemic circulation.[1,2] Bladder drainage of a PTA or SPK transplant is avoided in patients with neurogenic bladder dysfunction, as there is an increased risk of bladder infection, pyelonephritis, and graft pancreatitis.
 
The Portal-Enteric Technique
The portal-enteric technique (Figure 2) results in delivery of insulin into the portal vein and enteric drainage of the pancreatic exocrine secretions. The donor portal vein is anastomosed to the side of the recipient's superior mesenteric vein. The transplanted duodenal segment is attached to a Roux-en-Y limb of the recipient jejunum in a side-to-side manner to establish enteric exocrine drainage. [1,2] This approach is more physiologic than the systemic-bladder approach, resulting in normal carbohydrate and lipid metabolism. In addition, fasting hyperinsulinemia and metabolic acidosis are avoided,[1,2,40] as are urinary tract infection, hematuria, and reflux pancreatitis.[41]
Diagnosis of acute rejection with the portal-enteric technique requires a percutaneous pancreas biopsy. A novel technique, the Roux-en-Y venting jejunostomy, has been used to monitor for rejection via an endoscopic biopsy. Pancreatic function can also be monitored by amylase levels in the ostomy drainage. With this approach the anastomosis is decompressed, thus preventing leakage, and gastrograffin can be inserted via the jejunostomy tube to assess the integrity of the anastomosis and early identification of leaks.

PTA Transplantation

The American Diabetes Association recommends PTA transplantation for patients who have a history of: (1) recurrent, acute, and severe metabolic complications (ie, ketoacidosis) requiring medical intervention; (2) acute complications despite repeated trials with exogenous insulin replacement; and (3) incapacitating clinical and emotional problems associated with self-management with exogenous insulin therapy.[42] Potential PTA recipients who have significant and incapacitating secondary diabetic complications often have histologic evidence of diabetic nephropathy.[1] This situation is challenging because PTA recipients often experience calcineurin inhibitor-induced nephrotoxicity that further compromises native kidney function in the early posttransplant period and may contribute to chronic pancreatic dysfunction.[1]

SPK Transplantation

Patients with type 1 DM in conjunction with impending or established ESRD and who are 20-50 years of age are considered optimal SPK transplant candidates.[2] The benefits of preemptive kidney transplantation include avoidance of the complications associated with dialysis experienced by diabetic patients, improved survival rates, reduced costs, enhanced rehabilitation, and amelioration of the diabetic complications that rapidly progress in the presence of ESRD.[2] Patients are typically listed for SPK transplantation when their creatinine clearance approximates 25-30 mL/m2/min or when significant uremic symptoms occur.

PAK Transplantation

Deciding between PAK and SPK transplantation in patients with established diabetic nephropathy is an important decision for patients with a willing living kidney donor. The number of SPK transplantations has plateaued due to limited kidney allocation, making simultaneous cadaveric-pancreas with living kidney donor graft (SLKP) or living donor kidney transplantation followed by PAK attractive alternatives. Recent improvements in pancreas graft survival rates for PAK transplantation have narrowed the advantages of SPK. However, PAK transplantation requires sequential transplant operations and is less cost-effective. Recent data suggest SPK and SLKP transplantation yield equivalent graft (kidney and pancreas) and patient survival rates, with SLKP recipients experiencing fewer delays in kidney graft function and shorter waiting times for transplantation.[43,44]

Postoperative Management

Postoperative care of the pancreas transplant recipient includes monitoring and management of commonly encountered problems. Early postoperative care focuses on infection and thrombosis prophylaxis, prevention of acute rejection, and monitoring of graft function. Typically, patients are given antibiotics during surgery and for 2-5 days after transplantation. Anticoagulation includes low-dose aspirin or, less commonly, dipyridamole beginning a few weeks before transplantation, if possible, and then low-molecular-weight dextran during the first week after surgery.[45] PTA recipients may be given subcutaneous or IV heparin for 5-7 days postoperatively, while patients with a history of thrombosis require sustained anticoagulation therapy. Immunosuppressive therapy has great clinical significance to the nurse caring for the pancreas transplant recipient because acute rejection can be prevented and treated pharmacologically. Pancreatic graft function is monitored by blood glucose, amylase, HbA1c, and C-peptide levels. If the systemic-bladder technique is used, the urinary amylase levels are monitored. Likewise, if the patient has a pancreatic drain, amylase levels in the drainage are monitored.

Fluid Balance/Metabolic Abnormalities

During the initial postoperative period, pancreas transplant recipients are generally cared for in the intensive care unit for frequent monitoring of fluid and electrolyte balance, cardiac parameters, and metabolic function. Fluid volume depletion can occur rapidly due to fluid shifts, brisk diuresis, gastroparesis, and in patients with the bladder-diversion technique, loss of pancreatic fluid into the bladder. Initially, urine output, nasogastric drainage, and wound drainage are measured hourly and hemodynamic assessment is done every 1-2 hours. While hospitalized, weight, heart rate, and blood pressure (standing and recumbent) are measured daily. Laboratory findings include increased BUN and serum creatinine, decreased serum bicarbonate, and increased hematocrit due to hemoconcentration. Administration of albumin and IV fluids with or without bicarbonate prevents dehydration and corrects the metabolic acidosis associated with bladder drainage of pancreatic exocrine secretions. In patients with a duodenocystotomy, urinary catheter drainage is maintained for 5-10 days postoperatively. A cystogram or postvoid ultrasound is performed following removal of the catheter.[45]

In the immediate postoperative period, metabolic acidosis occurs as a result of the release of vasoactive pancreatic peptides secondary to cold ischemia in the graft and dehydration. Except for patients with a bladder-drained pancreas graft, this usually resolves within days with IV bicarbonate administration. In the case of the bladder-drained pancreas, metabolic acidosis persists, as large amounts of bicarbonate are lost through the urine over the first few weeks following transplantation.[46] Difficulties with maintenance of fluid and electrolyte balance, as well as other problems associated with bladder-drained pancreas transplantation, have led to the trend toward enteric conversion (conversion from bladder-drained to portal-enteric technique) of these transplants.[2]

A long-term IV access device may be placed prior to discharge from the hospital for continued IV fluid replacement[45]; some patients require as much as 1-2 liters of IV fluid daily. Patients are taught to take standing and lying blood pressures and to avoid moving quickly from a lying or sitting to a standing position. Treatment of gastroparesis includes dietary changes, if necessary (smaller, more frequent meals, limiting fatty and high-fiber foods), and symptom management, which includes medications to stimulate gastric emptying and reduce nausea and vomiting (metoclopramide, cisapride, domperidone).[24,47]

Delayed Graft Function

In the initial postoperative period, blood glucose is monitored frequently (every 2-4 hours) to assess pancreatic endocrine function. Insulin may be administered postoperatively according to a sliding scale, but is generally not required since blood glucose levels approach normal values within 12-24 hours and normalize within several days after transplantation as the corticosteroid dosage is decreased.[45] Donor factors affecting early posttransplantation outcomes following SPK transplantation include donor age, organ import, and cold ischemic preservation time.[48] Prolonged duration of cold ischemic preservation time of the donor organ has been associated with delayed graft function, manifested by the need for insulin after the 5th postoperative day in the absence of technical problems. Although it has been suggested that donor hyperglycemia may have a deleterious effect on initial and long-term graft function, donor hyperglycemia or hyperamylasemia are not contraindications for pancreas donation,[49] but increased donor age is associated with poorer posttransplant outcomes. Maintenance of donor systolic blood pressure above 90 mm Hg, use of insulin to control hyperglycemia, and minimizing donor pancreatic edema by use of intravenous colloid fluids and mannitol have improved early posttransplant outcomes. In addition, administration of calcium channel blockers in the early posttransplant period may decrease the incidence of posttransplant pancreatitis.[50]

Surgical Complications

A number of early postoperative complications such as graft thrombosis, infection, anastomotic leak, pancreatitis, and bleeding can occur. When these problems result in graft loss, they are referred to as technical failures.

Thrombosis

Graft thrombosis is the most common cause of technical failure in pancreas transplant recipients, regardless of procedure type, and inevitably results in graft loss.[6] Thrombosis occurs in 10% to 20% of pancreas transplant recipients,[45] and the incidence is about 3 times higher in PTA transplant recipients compared with SPK transplant recipients. Thrombosis usually occurs within the first postoperative week, but can occur as early as the first 24 hours in patients with good graft function. It may be brought on by conditions that decrease blood flow to the graft, such as acute rejection, hypovolemia, hypotension, or pancreatitis. Donor factors associated with early graft thrombosis include longer cold ischemia time, older age,[51,52] and expiration due to cardiocerebrovascular events.[52] Assessment for thrombosis of the pancreas graft in the immediate postoperative period includes frequent monitoring of serum electrolytes, glucose, and vital signs. In a normal functioning pancreas, the glucose level remains below 200 mg/dL.

Graft thrombosis can be venous or arterial. Venous thrombosis can occur as a result of abnormal blood supply to the pancreas due to conditions contributing to decreased graft blood flow or abnormal anatomy, reperfusion injury, or technical factors. Venous thrombosis generally presents with significant swelling of the graft, an acute onset of pain, a sharp rise in the serum glucose, and increased serum amylase level. Venous graft thrombosis is rarely reversible.[1] Measures to prevent graft thrombosis include bed rest, anticoagulation therapy (systemic heparinization followed by oral anticoagulation), and follow-up Doppler flow studies.[53] Surgical thrombectomy with follow-up anticoagulation is indicated for complete thrombosis.

For example, a 50-year-old man with a 37-year history of type 1 DM received a kidney-pancreas transplant. Twenty-four hours postoperatively he presented with hyperamylasemia, hyperglycemia, and abdominal pain. An ultrasound showed high resistance flow of the main pancreatic artery and no detectable flow within the main pancreatic vein. He was taken to the operating room for an exploratory laparotomy, where the diagnosis of venous thrombosis was confirmed, requiring a pancreatectomy.

Arterial thrombosis may involve the splenic artery, the superior mesenteric artery (SMA) or both. If the SMA is thrombosed, the duodenal segment of the graft is rendered nonviable. There is an acute rise in the serum glucose, and the serum amylase level decreases. The patient with SMA thrombosis presents with gray urine and develops a urine leak from the duodenal segment. There is no abdominal discomfort or pain. Surgery is required for removal of the duodenal segment, and the pancreatic graft is anastomosed to the bladder. If the splenic artery remains patent (thereby preserving perfusion to the body and tail of the pancreas), near normal glucose control is possible. If the body and tail of the pancreas become necrotic, a pancreatic fistula into the peritoneal cavity or a fluid collection usually develops.[1]

There is no treatment for graft thrombosis with the rare exception of partial venous thrombosis. Patients who do not lose their grafts from partial venous thrombosis are treated long-term with Coumadin. The only real intervention for pancreas graft thrombosis is prevention with prophylactic anticoagulation therapy. However, the tradeoff is an increased risk of bleeding.

Infection

Prophylactic perioperative antimicrobial therapy is administered to prevent postoperative infection. Perioperative antibiotics are typically administered for 2-5 days. Antifungal agents may be administered for up to 1-3 months postoperatively, and antiviral prophylaxis may include a 3- to 6-month course of ganciclovir, acyclovir, or IV immune globulin. Pneumocystis carinii pneumonia prophylaxis consists of either oral TMP-SMX or aerosolized pentamidine for 1 year posttransplantation. Antifungal agents such as fluconazole increase cyclosporine (CsA) and tacrolimus (TAC) levels (requiring decreased dosages while on antifungal therapy), so CsA and TAC dosage must be increased when antifungal therapy is discontinued.

Pancreatitis. Pancreatitis can occur in the immediate postoperative period as a result of damage to the pancreas during cold ischemic preservation or from handling of the organ during surgery. The longer the cold ischemia time, the greater the risk of pancreatitis. Pancreatitis that occurs in the immediate perioperative period is usually self-limiting.[1] When pancreatitis occurs several weeks postoperatively, it is most likely due to reflux of urine (often infected) into the pancreatic duct of a bladder-drained pancreas. The typical clinical presentation is tenderness over the graft site, low-grade fever, and increased serum amylase level. Endocrine function is not affected. Fluid high in exocrine enzyme content seeps from and accumulates around the pancreas. This can continue for 1-2 weeks and can be prevented or decreased by tube drainage of the operative site.

The differential diagnosis is acute rejection. The treatment is the same for any patient with pancreatitis. If severe, laparotomy may be necessary to evacuate peripancreatic fluid collections or resection of necrotic areas on the surface of the organ.

Pancreatitis may also result from constipation, abdominal distention, and ileus, called reflux pancreatitis. Ultrasound examination reveals an edematous pancreas.[53] Reflux pancreatitis is treated with continuous bladder drainage for several days, antibiotics, IV fluids, and limited oral intake. Constipation is treated with oral laxatives and enemas. Prevention is very important and includes increased fiber in the diet, adequate fluid intake, stool softeners, and regular bowel elimination. Reflux pancreatitis usually resolves within a few days to weeks.

A 58-year-old SPK recipient was admitted 1 month after transplantation with fever and right upper quadrant pain. Her white blood cell count was 21.3 X 103/mcL. An abdominal ultrasound showed a small peripancreatic fluid collection. Octreotide and antibiotics were started. Her serum amylase and lipase peaked at 345 U/mL and 1597 U/mL, respectively. The patient did not respond to antibiotics or restriction of oral intake. A repeat CT scan showed a 1-cm abscess just above the right iliac crest. The abscess was surgically drained and the patient improved clinically.

Cystitis and urethritis. Cystitis, urethritis, and urinary tract infection are common in bladder-drained pancreas transplant recipients and recipients with a neurogenic bladder. Monitoring for postvoid residual urine and a voiding cystourethrogram are done in patients with a suspected neurogenic bladder. Pancreatic exocrine secretions irritate and inflame the bladder mucosa, resulting in hematuria and discomfort that may become chronic. The patient can also become dysuric. In the early postoperative period, hematuria may be a sign of rejection, a viral infection, or a side effect of prophylactic anticoagulation therapy.[45] Cystoscopic evaluation may be necessary to rule out ulceration of or anastomotic bleeding from the duodenal segment.[1]

Continuous urinary drainage can improve inflammation, hematuria, and dysuria.[1] Prophylactic antibiotics are prescribed for approximately 1 year posttransplantation and may continue for several years, depending on the severity of the patient's neurogenic bladder. Urinary tract analgesics such as phenazopyridine, antibiotics, and hydration are other important components of patient care. Urethral stricture from chronic urethritis can occur and is more common in men.[53] Persistent problems may require enteric conversion.

Prior to discharge from the hospital, the patient is educated about preventive urinary hygiene: wiping front to back, voiding after intercourse, not suppressing the urge to void, and urinating every 2 hours even if there is no urge. The patient may have to be taught self-catheterization.

Intrapancreatic abscess. Intrapancreatic abscess can develop several weeks after transplantation and is thought to be due to chronic rejection or viral infection. Signs and symptoms include persistent fever, pain over the graft site, and the gradual development of hyperglycemia. Serum amylase levels are not affected. An intrapancreatic abscess requires pancreatectomy.

Anastomotic Leak

A serious complication of enteric pancreas transplantation is a duodenal segment leak. This may occur early or late after surgery. Early duodenal segment leaks usually result from technical problems or ischemia, while late duodenal segment leaks are generally due to rejection or infection. However, late leaks may also develop as a result of ischemia of the duodenal staple line.[45] Anastomotic leaks occur in the first few weeks after transplantation and can lead to the formation of an external pancreatic fistula with discharge of clear fluid and/or peripancreatic abscess. Signs and symptoms include leukocytosis, fever, and tenderness over the graft. Endocrine function is not affected. The differential diagnosis includes acute rejection, pancreatitis, and intestinal obstruction. If an exterior fistula develops, the diagnosis is easily made by the high amylase content in the drainage and reddening of the skin at the exterior site due to contact with digestive enzymes. A leak can be confirmed by ultrasound or computed tomography scan. Treatment of early leaks usually includes percutaneous placement of drains or surgical exploration with drainage. An anastomotic leak and/or fistula can take weeks to resolve.[1] Enteric conversion is the treatment for late leaks.[45]

Eighteen months after SPK transplantation, a patient presented with elevated serum amylase and lipase levels and a complaint of right lower quadrant pain over the graft site associated with fever and diarrhea. Previous history included diagnoses of pancreatitis and biopsy-proven mild acute rejection of the pancreas in the preceding 6 months. Renal function remained stable with a serum creatinine level of 0.8 mg/dL and estimated creatinine clearance of 95.2 mL/min. The patient was hospitalized and an exploratory laparotomy revealed a duodenal segment leak and pancreatic fistula. The duodenal segment leak was repaired, patched, and drained externally and with a Roux limb enterostomy tube. Peritoneal lavage with antibiotics was performed intraoperatively. The patient received a 3-week course of antibiotic therapy for gram-negative bacteria in the pancreas drainage. Subsequently, the patient had an episode of pancreatitis and 3 months later presented with gram-negative sepsis. Appropriate antibiotic therapy was initiated and an exploratory laparotomy with peritoneal lavage and drainage was performed. During the course of hospitalization, fluid leakage from the midline surgical incision occurred, which was found to have a high content of amylase and lipase confirming the presence of a persistent cutaneous pancreatic leak. A graft pancreatectomy was performed.

Rejection

Rejection of the transplanted graft may occur at any time from within seconds to years after transplantation. Rejection that occurs immediately is hyperacute rejection, which is caused by the presence of preformed circulating cytotoxic antibodies in the recipient's blood. Hyperacute rejection is diagnosed in the operating room immediately upon vascularization of the graft. The pancreas becomes grossly edematous and ischemic. Hyperacute rejection results in immediate graft loss. Fortunately, hyperacute rejection is extremely rare. Acute rejection is a cellular immune response involving mononuclear, cytotoxic, helper T cells, monokines, and lymphokines. Acute rejection usually occurs from approximately 1 week to 3 months after transplantation, but can occur earlier or later. Acute rejection is the only type of rejection that can be treated, but if left untreated, it eventually leads to graft loss. Chronic rejection can occur at any time after approximately 3 months after transplantation. Chronic rejection is mediated by T cells and B cells. Chronic rejection leads to insidious, progressive loss of graft function.

Acute Rejection

The pancreas is a highly immunogenic organ. In spite of advances in immunosuppressive therapy, acute rejection continues to be the primary cause of graft loss during the first posttransplant year.[5] According to the IPTR,[5] the rate of 1-year graft loss from immunologic causes (rejection or recurrence of autoimmune disease) prior to the introduction of TAC and mycophenolate mofetil (MMF), from 1998 to 2000, was 2%, 6%, and 12% for SPK, PAK, and PTA, respectively, compared with 6%, 12%, and 27% for SPK, PAK, and PTA, respectively. The use of TAC and MMF has significantly decreased the rate of acute pancreas graft rejection.

Prevention of rejection is a primary goal of care of the pancreas transplant recipient. Most centers include induction therapy with an antilymphocyte agent in their immunosuppressive regimens. In addition, triple-agent immunosuppression with: (1) a calcineurin inhibitor (CsA or TAC); (2) an antiproliferative agent (azathioprine [AZA] or MMF; and (3) corticosteroids is the standard maintenance regimen. During the initial transplant hospitalization, CsA or TAC trough levels and CD2 or CD3 counts (depending on the induction agent used) are monitored daily until discharge from the hospital or completion of induction therapy. Routine long-term monitoring of CD2 or CD3 counts is not conducted because of the high cost; however, counts may be performed when pancreas rejection is suspected or if the absolute lymphocyte count rises, particularly if the pancreas biopsy is difficult to obtain.

Acute Rejection in Solitary Pancreas Transplantation (PTA or PAK)

In PTA or PAK transplantation, the lack of sensitive indices for rejection makes the clinical diagnosis of acute rejection difficult. Signs and symptoms include low-grade fever, unexplained leukocytosis, and a swollen, painful graft. Alterations in C-peptide and insulin levels are not sensitive enough to detect early acute rejection. Careful attention to fasting blood glucose levels and upward trends in serum amylase, lipase, and glucose levels may be useful in the clinical detection of rejection, but are usually not apparent until late in the rejection process. Serum amylase may double or triple with rejection; however, an elevated serum amylase level may also indicate pancreatitis. In PTA or PAK transplantation with bladder drainage, a decline in the urinary amylase level precedes hyperglycemia, making urine amylase a useful marker for acute rejection.[1] However, urine amylase levels may be elevated with diuretic therapy.

The posttransplant protocol pancreas biopsy is the most sensitive and specific method for diagnosing acute rejection of the pancreas allograft (Figures 3 and 4).[54] When acute rejection is suspected, an ultrasound-guided cystoscopic transduodenal or percutaneous biopsy is done. Pancreas biopsies are graded according to the following histologic criteria: degree of inflammation, eosinophilia, acinar inflammation, ductal inflammation, endothelialitis, and necrotizing arteritis.

 

Acute Rejection in SKP Transplantation

In SPK transplant recipients, increased serum creatinine and BUN are surrogate markers for pancreas rejection because the kidney and pancreas reject simultaneously and a decline in kidney function precedes a decline in pancreas function by a few days.[2]

Treatment of Acute Rejection

Acute rejection requires hospitalization for aggressive immunosuppressive therapy, which is generally administered in the hospital setting.[41] Dosages of current immunosuppression medications are adjusted, and pulsed corticosteroid therapy and/or antilymphocyte agents are administered.

Example. A 39-year-old male PAK transplant recipient received induction therapy with daclizumab (2 doses) and maintenance immunosuppression with TAC, MMF, and prednisone. At the 2-week follow-up appointment, his lab value (serum amylase, lipase, and glucose) were normal, but his biopsy showed grade 2 rejection. Initial treatment consisted of solumedrol (3 doses, 1 gram each). A week later, serum amylase and lipase levels were elevated and a repeat biopsy revealed grade V rejection. He was treated with an antilymphocyte agent (8 doses). A biopsy 2 weeks after transplantation showed histologic resolution of acute rejection. By the 12-month follow-up, no further episodes of rejection had occurred.

Chronic Rejection

The diagnosis of chronic rejection is challenging. Chronic rejection of the pancreas allograft is manifested clinically by hyperglycemia and low C-peptide levels, and eventually results in graft loss. Chronic rejection is confirmed by biopsy. The histologic features of chronic rejection include dense septal fibrosis and acinar cell loss. The rate of graft loss after 5 years from chronic rejection is 55%.[1]
 

Best Practice Examples

At the University of Tennessee Health Science Center, research findings led to clinical practice interventions aimed at improving quality of life in transplant recipients.[55-57] Prediction models for quality of life outcomes consistently showed that hospitalization during the first 6 months posttransplantation, employment, and social support accounted for up to 50% of the variance in quality of life in kidney transplant recipients.[57] Based on these findings, a clinical pathway (Figure 5) was designed by a multidisciplinary team that included 3 factors known to positively influence quality of life: (1) prevention of adverse events, (2) facilitation of employment, and (3) enhancement of social support. Although factors identified in the prediction model were derived from a sample of nondiabetic kidney transplant recipients, a prior study also identified these factors as significant predictors of posttransplant quality of life in diabetic and nondiabetic kidney transplant recipients.[58]

In addition, clinical practice guidelines for inpatient and outpatient care provide continuity of care for pancreas transplant recipients at the University of Tennessee Health Science Center. These guidelines address patient care needs related to immunosuppressive therapy; diagnosis and treatment of rejection, including the use of protocol biopsies; management of immediate and long-term health problems related to fluid and electrolyte imbalance, hypertension, and hypercholesterolemia; and long-term care related to neurogenic bladder, erectile dysfunction, immunizations, and psychological needs.

Summary

The prevalence of diabetes is increasing and is estimated to affect more than 6.5% of the US population, up from 4.9% in 1990 -- a 33% increase.[59] By the year 2020, 250 million people will be afflicted worldwide.[60] The economic burden is equally impressive. In 1999, Medicare expenditures for ESRD were $12.7 billion and non-Medicare expenditures were $5.2 billion, bringing the total cost of the ESRD program to $17.9 billion, an increase of 7.2% from 1998.[61]

Outcomes of pancreas transplantation have continued to improve in recent years, and pancreas transplantation has become an accepted treatment of selected patients with type 1 diabetes. Pancreas conservation techniques have improved, surgical techniques continue to be perfected, current immunosuppressive protocols are yielding excellent survival rates, and quality of life is better after SKP transplantation in diabetic patients.

Funding Information
Judith Ammons, MSN, FNP, has no significant financial interests to disclose.

Patricia A. Cowan, PhD, has disclosed that she owns stock in American Home Products, a Wyeth subsidiary.

Donna K. Hathaway, PhD, has disclosed that she was a consultant for the Portel study.

Teresa C. Rutland, MSN, FNP, has no significant financial interests to disclose.

Mona N. Wicks, PhD, has no significant financial interests to disclose.

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