Pancreas Transplantation Treatment & Management

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.

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.