Pancreas Transplantation

Experiments in pancreas transplantation began long before the discovery of insulin. In 1891, pieces of dog pancreas were autotransplanted beneath the skin and were shown to prevent diabetes after removal of the intra-abdominal pancreas. Subsequent experimentation with intrasplenic transplantation did not succeed because of graft necrosis. In 1916, a sliced human pancreas was transplanted into two patients, but the grafts were wholly absorbed. The first pancreatic xenotransplantation was performed in 1893 in London; a 15-year-old boy underwent subcutaneous implantation of a pancreas.

Despite extensive animal experimentation, pancreatic transplantation did not become a reality until 1966, when W.D. Kelly performed the first human, whole-organ pancreatic transplantation to treat type 1 diabetes mellitus. Because of poor outcomes, few procedures were conducted until 1978. Much of the early work was performed by Sutherland and colleagues at the University of Minnesota. With improved immunosuppressive regimens and newer surgical techniques, the 1980s ushered in a new era in pancreas transplantation.[4]  According to the International Pancreas Transplant Registry, nearly 10,000 pancreatic transplantations were recorded by 1998.

Most pancreatic transplantations are performed in patients with type 1 diabetes mellitus, who lack of insulin production.[5, 6] The most common indication is kidney failure; therefore, pancreas transplantation is typically performed simultaneously with kidney transplantation.[7, 8, 9, 10] In some patients with hypoglycemic unawareness or other diabetic complications, isolated pancreas transplantation has been performed. However, the results have been somewhat inferior to those of the combined procedure.

In patients undergoing pancreas transplantation, various technical concerns must be considered, including whether or not the venous drainage should be into the systemic circulation or into the portal vein.[4] Another controversial topic is whether the exocrine secretions should be drained enterically or into the bladder as initially described. The complications of graft pancreatitis and bladder leakage that plagued early experiences with pancreas transplantation have largely been resolved as a result of both better technical expertise and fewer rejection- and immunosuppression-related complications.

Type 1 diabetes mellitus is an autoimmune disease in which the insulin-producing pancreatic beta cells are destroyed selectively. Even with the increasing utilization of continuous glucose monitors (CGM) and insulin pumps, no practical mechanical insulin-delivery method exists that replaces pancreatic insulin secretion well enough to produce a near-constant euglycemic state without risk of hypoglycemia. Therefore, individuals with type I diabetes must manually regulate blood glucose levels by subcutaneous insulin injection or infusion and, as a consequence, typically exhibit wide deviations in 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 treatment methods.

One such treatment, pancreas transplantation, has the potential to achieve better glycemic control and alter the progression of long-term complications. Successful pancreas transplantation accomplishes the following:

• Produces a normoglycemic and exogenous insulin–independent state
• Reverses some of the diabetic changes in the native kidneys of patients with very early diabetic nephropathy
• Prevents recurrent diabetic nephropathy, in patients undergoing SPK transplantation
• Stabilizes and potentially partially reverses peripheral sensory neuropathy
• Stabilizes advanced diabetic retinopathy
• Significantly improves patients' quality and quantity of life

The insulin released by the endocrine pancreas graft is secreted into the bloodstream. The exocrine pancreas produces about 800-1000 mL of fluid per day, which must be diverted into the bladder or the bowel. This pancreatic fluid is rich in bicarbonate, so if the pancreas graft is attached to the bladder, the fluid loss 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 rejection, patients must take immunosuppressive medications daily for the rest of their lives. Long-term immunosuppression elevates the risk of viral and fungal infections and some types of malignancy.

An estimated 34.2 million people in the United States have diabetes and over 58,000 individuals annually develop end-stage kidney disease with diabetes as the primary cause.[11] Although almost 2400 candidates were on the waitlist for pancreas transplants (13.4% PTA, 76.6% SPK, 10% PAK) at the end of 2019, only about 1000 pancreas transplantations were performed.[1] The number of transplants is limited in part by the number of high-quality donor organs available for transplantation. See Table 1 below for a breakdown of patient characteristics.

Table 1. Characteristics of adult recipients of pancreas transplantation, United States, 2019 ^[1] (Open Table in a new window)

Assessment of pancreas graft outcome rates has been hampered by lack of uniformity in the criteria for graft failure. Some programs do not report a failed graft if C peptide production continues, whereas others report a graft failure if the recipient is no longer insulin independent. To resolve this problem, the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) established a uniform definition for pancreas graft failure, which includes any of the following criteria:

• Removal of a transplanted pancreas
• Re-registration for a pancreas transplant
• Registration for an islet transplant after undergoing pancreas transplant
• Death

Total insulin use of 0.5 units/kg/day or more for 90 consecutive days can also be used to define pancreas graft failure. However, this may be problematic if the recipient's starting insulin dose was less than 0.5 units/kg/day.

The new pancreas graft failure definition was implemented in February 2018. It was used in the first full year of pancreas graft survival data in the OPTN/Scientific Registry of Transplant Recipients 2020 Annual Data Report.[1]

Nevertheless, the number of recipients alive with a functioning pancreas allograft has contin­ued to rise over the past decade and exceeded 19,000 in June 2019. Mortality has decreased consistently among all pancreas transplant groups as a result of safer and more effective immunosuppressive regimens. Five-year survival rates for patients transplanted in 2011-2012 were 87.8% for PAK, 79.5% for PTA, and 91.7% for SPK.

For SPK, the 5-year survival rates were similiar in patients with type 1 and type 2 diabetes (91.1% and 93.1% respectively), despite the older age and comorbidity associated with type 2 diabetes. This is likely due to selecting candidates with type 2 diabetes whose cardiovascular status can tolerate the high operative risks.[1]

In one published retrospective study, differences in mortality were examined in consecutive patients with diabetes who were older than 50 years compared with well-matched recipients younger than 50 years undergoing pancreas transplantation (the majority were simultaneous kidney-pancreas transplants) at a high-volume European center. Despite US data suggesting an increased risk of mortality in recipients older than 45 years compared with patients younger than 45 years, it is becoming clear that carefully selected patients with diabetes who are older than 50 years can undergo successful pancreas transplantation with similar patient and allograft survival outcomes.[12]  

This trend toward considering pancreas transplantation in older recipients appears to have begun earlier in the United States and is now gaining momentum in Europe. It must be emphasized that careful cardiac evaluation is essential to this patient selection process.

Effect of pancreas transplantation on secondary complications of diabetes

Recipients of successful pancreas transplantation maintain normal plasma glucose levels without exogenous insulin therapy. This results in the normalization of glycosylated hemoglobin levels and has 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.

One long-term follow-up study of 15 years showed that pancreas transplantation in patients with type 1 diabetes mellitus and end-stage kidney failure has long-term functional viability. However, some deterioration in pancreas function should be expected, as shown in oral glucose tolerance test results.[13]

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 with recipients of kidney transplantation alone.[14, 15]  Virtually all patients with a successful pancreas transplantation report that managing their life, even with the added need for immunosuppression, has become much easier. Successful pancreas transplantation will not elevate all patients with diabetes to the general population's level of health and functioning. Still, transplant recipients consistently report significantly better quality of life than 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 kidney pathology, including mesangial expansion and widening of the glomerular basement membrane, in patients with type 1 diabetes and kidney transplantation alone. The onset of pathological lesions can be detected within a few years of kidney transplantation. Clinical deterioration of kidney allograft function can lead to loss 10-15 years after transplantation.

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 and 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 for 5-10 years after transplantation. 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 kidney 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 partly because of the reduction in uremic neuropathy. However, pancreas transplantation alone in preuremic patients also has also been shown to improve diabetic neuropathy. Many patients report subjective improvements in peripheral sensation 6-12 months after pancreas transplantation. Interestingly, the reversal of autonomic neuropathy in patients with type 1 diabetes with pancreas transplantation has been associated with better patient survival rates than in patients with failed or no transplantation.[16]

Pancreas transplantation does not have an immediate dramatic beneficial effect on established 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 with diabetic recipients of kidney transplantation only.[17] Longer-term studies of 5-10 years have not been reported.

Candidates for pancreas transplantation require evaluation for the following complications of diabetes:

• Kidney disease
• Retinopathy
• Coronary artery, cerebral vascular, and peripheral vascular disease
• Gastropathy
• Neuropathy

Kidney disease

A significant number of pancreas transplantation candidates have preexisting advanced kidney disease. Therefore, coincident extrarenal disease should be assumed present. Candidates for PTA transplants must be evaluated for the likelihood of progression of kidney dysfunction once nephrotoxic immunosuppression is started, as these patients may eventually need a kidney transplant as well. Some of the relative benefits of SPK transplant (shorter waiting time for a kidney than for kidney alone candidates and improved pancreas graft function compared with PTA recipients) may warrant waiting for eventual SPK rather than proceeding with PTA.

Diabetic retinopathy

Diabetic retinopathy is a frequent 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. However, it is essential to confirm that a patient with significant vision loss has an adequate support system to ensure help with travel and immunosuppressive medications.

Coronary artery disease

A significant comorbidity to consider in patients with type I diabetes with diabetic nephropathy is coronary artery disease (CAD). Patients with diabetes and 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 the development of CAD, including hypertension, hyperlipidemia, and smoking. They may have asymptomatic myocardial ischemia because of neuropathy associated with diabetes. The prevalence of significant (> 50% stenosis) CAD in patients with diabetes who are starting treatment for ESRD is estimated to be 45-55%.[18]

Cerebral vascular disease

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.

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 essential to prevent rejection of the transplants. Episodes of volume depletion with associated azotemia frequently occur in patients with simultaneous pancreas-kidney (SPK) transplants. Patients typically require careful treatment, including motility agents such as metoclopramide, cisapride, or erythromycin.

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 undergoing 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 and reflux into the donor duodenum. This may adversely affect renal allograft function, 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 transplants predisposed to volume depletion. Therefore, careful reassessment of the posttransplantation antihypertensive medication requirement is required.

Sensory and motor neuropathies

These conditions are common in patients with longstanding diabetes. This may have implications for rehabilitation after transplantation. It also indicates the potential risk of a foot injury 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 essential pretransplantation consideration, with important implications for ensuring a high degree of medical compliance.

The emphasis of the pretransplantation 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 or a pattern of noncompliance.

Pretransplant cardiac risk screening is needed in all pancreas transplant candidates. At a minimum, a 12-lead electrocardiogram and ECHO are required. Given risk factors for CAD, most patients will require stress testing or anatomic study of potential coronary lesions. Such studies may include stress echocardiogram, stress nuclear medicine studies, coronary C.T., or cardiac catheterization. Appropriate testing is often made in conjunction with cardiology and center-specific protocols.

Laboratory studies should include blood chemistries, liver function tests, CBC count, coagulation profile, urinalysis, urine culture, and cytospin (when indicated). A C-peptide level may distinguish if the candidate has type I or type II diabetes. In addition, test for the following infections:

• 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 reagent (syphilis)
• HIV serology
• Purified protein derivative (tuberculosis skin test with anergy panel, when indicated)

Imaging studies performed in the pre-transplantation evaluation are chest radiography and potentially ultrasound or computed tomography (CT) evaluation of target (iliac) vessels to look for vascular calcification or narrowing.

Determining donor human leukocyte antigen (HLA) typing, presence of anti-HLA donor-specific antibodies, 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 simultaneous pancreas-kidney [SPK] transplantation) prior to procurement of the organs. 

The timing of allocation of the pancreas to a specific patient relative to the procurement of the organ has important implications. Early allocation allows the transplantation center performing the pancreas transplantation the choice to arrange for organ recovery and transportation. It will enable recipients to be admitted to the hospital and be prepared for surgery prior to organ recovery, thus avoiding last-minute reallocation of organs and minimizing the cold-ischemia time of the pancreas prior to implantation. Pancreas allografts do not tolerate cold ischemia as well as kidney allografts.

Ideally, the pancreas should be revascularized within 12 hours after cross-clamping at procurement. Finally, early allocation also allows identification of highly matched (zero-mismatch) donor-recipient pairs or highly sensitized recipients before procurement, minimizing cold-ischemia time if the organs need to be transported across the country.

The surgical techniques for pancreas transplantation are diverse, and no standard methodology is used by all programs. However, the principles are consistent, 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.

Arterial revascularization is usually performed via a Y-graft reconstruction using a segment of donor iliac artery. The donor external and internal iliac arteries are anastomosed to the superior mesenteric artery and splenic artery of the donor graft. Then the common iliac artery of the donor Y-graft is anastomosed end-to-side to the recipient right common or external iliac artery. The graft may be positioned with the head of the pancreas graft cephalad or caudad.

Two choices are available for venous revascularization: systemic and portal. No clinically relevant difference in glycemic control has been documented between the two choices. Approximately 15% of pancreas transplantations are currently performed with portal venous drainage and the majority (85%) with systemic venous drainage. Systemic venous revascularization commonly involves the right common iliac vein, the right external iliac vein, or the inferior vena cava above the confluence of the iliac 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 the immediate delivery of insulin to the recipient liver. This results in diminished circulating insulin levels relative to that in systemic venous-drained pancreas grafts.

The two options for exocrine drainage are bladder drainage and enteric drainage. (See the images below.) The early approach was performed by anastomosing the donor duodenum to the recipient bladder. This had the advantage of adding urinary amylase as an indicator for pancreas rejection and a somewhat lower technical failure rate.[19] However, many patients developed complications from bladder drainage, including dehydration, urinary tract infections, or bladder injury/bleeding that required a second operation to convert the transplant to enteric drainage. Thus, enteric drainage has been the standard for SPK and an increasing number of pancreas alone transplants. Currently, approximately 80% of pancreas transplantations are performed with enteric drainage; the remaining 20% are completed with bladder drainage.

Solitary pancreas transplantation with enteric drainage. Illustrated by Simon Kimm, MD. Image courtesy of Landes Bioscience.

Solitary pancreas transplantation with bladder drainage. Illustrated by Simon Kimm, MD. Image courtesy of Landes Bioscience.

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. 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 following potential complications:

• Cystitis
• Urethritis
• Urethral injury
• Balanitis
• Hematuria
• Metabolic acidosis

When pancreas transplantation is performed simultaneously with kidney transplantation, the kidney transplantation is most often performed on the recipient's left iliac vessels. Both organs may be transplanted through a midline incision and placed intraperitoneally. While the pancreas is most often placed on the recipient's right side, a left-sided transplant may be required if there are previous kidney or pancreas transplants or a more significant burden of vascular disease on the right side. The sequence of transplants often depends on the cold ischemic time already accrued.

The transplant procedure and early inpatient postoperative care are performed in the transplant center. Immunosuppression regimens are center- and patient-specific but consist of both induction and maintenance phases. Induction frequently consists of a T-cell depleting antibody (ie, anti-thymocyte globulin, ATG) and methylprednisolone. Maintenance usually consists of a calcineurin inhibitor (ie, tacrolimus) and an antimetabolite (ie, mycophenolate). Low-dose prednisone is used in some patients.  Immunosuppression must be taken for as long as the patient's transplanted organs are functioning.

Antiviral and antimicrobial therapy includes preemptive or prophylactic prevention of cytomegalovirus (CMV) infection (ie, valganciclovir).Trimethoprim-sulfamethoxazole, or an alternative agent, is used to prevent Pneumocystis jirovecii pulmonary infection. 

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 those topics.

Following successful pancreas transplantation, patients usually do not require specific dietary restrictions. Extreme contact sports probably should be avoided to prevent accidental trauma to the newly placed intra-abdominal organs.

After discharge, patients are followed for the life of their transplanted organs. Testing is performed frequently during the early postoperative period and then decreasingly over time and consists of the following:

• Electrolytes, including potassium, magnesium, and phosphorus
• Complete blood count
• Blood urea nitrogen (BUN) and serum creatinine
• Glucose
• Serum amylase and lipase
• Immunosuppressive drug blood levels (if transplant recipient is receiving cyclosporine, tacrolimus, or sirolimus)
• Surveillance for CMV, Epstein-Barr virus, and BK virus infection

Rejection

The first criteria for diagnosing acute cell-mediated allograft rejection (ACMR) were established in 2008. At the time, only tentative criteria for the diagnosis of antibody-mediated rejection (ABMR) were presented. Since then, the criteria have been reviewed and updated approximately every two years to account for ongoing advances in the understanding of ABMR.[20]

Surgical and nonimmunological complications of pancreas transplantation

Surgical complications are more common after pancreas transplantation than after 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 as acute rejection as an etiology of pancreas graft loss.

Thrombosis

Vascular thrombosis is a very early complication, typically occurring within 48 hours of the transplantation.[8]  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. To minimize the risk for graft thrombosis, careful selection of donor pancreas grafts, short cold-ischemia times, and meticulous surgical techniques are necessary.

Transplant pancreatitis

Pancreatitis of the allograft occurs to some degree in all patients postoperatively. Temporary elevation in serum lipase levels for 48-96 hours after transplantation is common. These episodes are transient and mild, without significant clinical consequence. Interestingly, patients undergoing simultaneous kidney-pancreas transplantation commonly have a greater degree of fluid retention for several days after transplantation than is seen with kidney transplant 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 transplanted pancreas eliminates approximately 500-1000 mL of bicarbonate-rich fluid with pancreatic enzymes into the bladder each day. Change in the pH level of the bladder accounts, in part, for an 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 is usually due to ischemia/reperfusion injury to the duodenal mucosa or to a bleeding vessel on the suture line, aggravated by the antiplatelet or anticoagulation protocols used to minimize vascular thrombosis. These cases are usually self-limited but may require a 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, cystoscopy or laparotomy may be required.

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 due to 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 are also at risk of dehydration episodes 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 hyperlipasemia 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 often resolve quickly, but the patient may require a 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 the breakdown of the duodenal segment can occur and is usually encountered within the first 2-3 months following transplantation but can occur years following transplantation. A typical presentation is the onset of abdominal pain with elevated serum lipase, which can mimic reflux pancreatitis or acute rejection. A high index of suspicion for urinary leak is necessary to make the diagnosis accurately and swiftly. Supporting imaging studies using a cystogram or computed tomography (CT) scan are often used to confirm the diagnosis.

Operative repair is often required. The degree of leakage can be determined best intraoperatively. Proper judgment can be made whether a direct repair is possible, or enteric diversion or even graft pancreatectomy is indicated.

Complications of enteric-drained pancreas transplantation

A serious complication of the enteric-drained pancreas transplantation is a leak and intra-abdominal abscess. This 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, including a CT scan, are helpful.

Percutaneous sampling of any intra-abdominal fluid collection for Gram stain and culture is beneficial. This typically reveals mixed flora, with bacteria and often fungus, particularly Candida. Broad-spectrum antibiotic therapy and percutaneous drainage may be the initial management of such leaks, but surgical exploration and repair of the enteric leak may be necessary. A decision must be made on whether the infection can be eradicated without removing the pancreas allograft. Incomplete eradication of the infection can result in progression to sepsis and clinical deterioration. Peripancreatic infections can result in development of a mycotic aneurysm at the arterial anastomosis that could cause arterial rupture. Transplantation pancreatectomy is likely indicated if a mycotic aneurysm is diagnosed.

The occurrence of intra-abdominal abscesses has been reduced by more stringent donor selection. Improved perioperative antibiosis, including antifungal agents, has contributed to the decreased incidence of intra-abdominal infection. 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.

In enteric-drained pancreas transplants, gastrointestinal bleeding may result from a combination of perioperative anticoagulation and bleeding from the suture line of the duodenoenteric anastomosis. This is commonly self-limited and will manifest as diminished hemoglobin levels and heme-positive or melanotic stool. Conservative management will suffice; the necessity for operative exploration is unusual. Delayed arterial-enteric fistulae are rarely seen but can represent a life-threatening event and should be considered when a pancreas transplant patient presents with gastrointestinal bleeding.

Banff pancreas allograft rejection grading schema

In 2017, an update to the Banff pancreas allograft rejection grading schema was published.[20]  The current criteria are outlined below.

Normal criteria are as follows:

• No inflammation  or inactive septal, mononuclear inflammation not involving ducts, veins, arteries, or acini
• No graft sclerosis
• The fibrous component is limited to normal septa, and its amount is proportional to the size of the enclosed structures (ducts and vessels).
• The acinar parenchyma shows no signs of atrophy or injury

When septal inflammation appears active, but the overall features do not fulfill the criteria for mild acute rejection, rejection is deemed indeterminate.

Acute T-cell–mediated rejection (TCMR) has three grades. Criteria are as follows:

Grade I - Mild acute TCMR: Active septal inflammation (activated blastic lymphocytes and/or eosinophils) involving septal structures: venulitis (subendothelial accumulation of inflammatory cells and endothelial damage in septal veins), ductitis (epithelial inflammation and damage of ducts) and/or focal acinar inflammation (two or fewer foci per lobule) with absent or minimal acinar cell injury.

Grade II - Moderate acute TCMR: Multifocal (but not confluent or diffuse) acinar inflammation (three or more foci per lobule) with spotty (individual) acinar cell injury and dropout and/or mild intimal arteritis 

Grade III - Severe acute TCMR: Diffuse (widespread, extensive) acinar inflammation with focal or diffuse multicellular/confluent acinar cell necrosis and/or moderate or severe intimal arteritis and/or transmural inflammation-necrotizing arteritis

The diagnostic criteria for acute/active antibody‐mediated rejection (ABMR) are as follows:

• Histologic evidence of acute tissue injury
• C4d positivity in interacinar capillaries (≥1% of acinar lobular surface for immunohistochemistry)
• Serologic evidence of donor-specific antibodies (HLA or other antigens)

Histologic evidence is categorized into three grades as follows:

• Mild acute ABMR: Well‐preserved architecture, mild interacinar monocytic‐macrophagic or mixed (monocytic‐macrophagic/neutrophilic) infiltrates with rare acinar cell damage (swelling, necrosis)
• Moderate acute ABMR: Overall preservation of the architecture with interacinar monocytic‐macrophagic or mixed (monocytic‐macrophagic/neutrophilic) infiltrates, capillary dilatation, interacinar capillaritis, intimal arteritis, a congestion, multicellular acinar cell dropout, and extravasation of red blood cells
• Severe acute ABMR: Architectural disarray, scattered inflammatory infiltrates in a background of interstitial hemorrhage, multifocal and confluent parenchymal necrosis, arterial and venous wall necrosis, transmural/necrotizing arteritis, a and thrombosis (in the absence of any other apparent cause)

ABMR is diagnosed when all three diagnostic criteria are met.  If only 2 criteria are present, the diagnosis may be considered. ABMR is excluded if only one criterion is met.

All pancreas transplant recipients require lifelong immunosuppression to prevent a T-cell alloimmune rejection response. The US Food and Drug Administration (FDA) has approved several immunosuppressive agents; others are used off label, and additional agents are currently in clinical trials.

Two broad categories 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.

Class Summary

Induction immunotherapy consists of a short course of intensive treatment with intravenous agents. Antilymphocyte antibody induction therapeutic agents include polyclonal antisera, monoclonal antibodies, and humanized monoclonals. Polyclonal antisera, such as antilymphocyte globulin (ALG), antilymphocyte serum (ALS), and anti-thymocyte globulin (ATG) are equine, goat, or rabbit antisera directed against human lymphoid cells. These 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 are either 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-identical grafts.

Basiliximab (Simulect)

A chimeric monoclonal antibody that specifically binds to and blocks the interleukin-2 (IL-2) receptor on the surface of activated T cells.

Antithymocyte globulin, rabbit (Thymoglobulin)

A purified immunoglobulin solution produced by the immunization of rabbits with human thymocytes is used to treat acute rejection.

Alemtuzumab (Campath)

A humanized monoclonal antibody against the CD52 antigen. The anti-CD52 antibody induces lympholysis from complement-mediated lysis or other effector mechanisms.

Class Summary

Several immunosuppressive agents are currently used for maintenance immunotherapy in kidney transplant recipients. An optimal maintenance immunosuppressive protocol has not been developed. Maintenance immunosuppressive agents are required for life.

Prednisone

Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity.

Azathioprine (Imuran)

The active component of azathioprine is 6-mercaptopurine. It acts as a purine analog that interacts with DNA and inhibits lymphocyte cell division.

Mycophenolate (CellCept, Myfortic)

Inhibitor of enzyme inosine monophosphate dehydrogenase (IMPDH), which results in inhibition of lymphocyte proliferation. Approved for prevention of organ rejection in allogeneic renal allograft recipients, and used off-label in patients with pancreas transplants.

Cyclosporine (Sandimmune, Neoral)

Calcineurin inhibitor that diminishes IL-2 production in activated T cells. It binds to the intracellular immunophilin cyclophilin, interfering with the action of calcineurin, which inhibits nuclear translocation of the nuclear factor of activated T cells (NFAT).

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.

Sirolimus (Rapamune)

Inhibits lymphocyte proliferation by interfering with signal transduction pathways. Binds to immunophilin FKBP to block the action of mTOR. FDA approved for the prevention of organ rejection in patients receiving allogeneic renal allografts.