Whole-organ pancreas and pancreatic islet transplantation

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Chapter 101 Whole-organ pancreas and pancreatic islet transplantation

Overview

Type 1 diabetes mellitus, formerly known as juvenile diabetes, is characterized by hyperglycemia as a result of the nearly complete destruction of the insulin-producing β-cells of the pancreatic islets of Langerhans. The loss of β-cells is the result of a T-cell–mediated autoimmune attack that typically occurs during childhood or early adolescence. Insulin replacement can lead to acceptable control of blood glucose levels; however, affected individuals are subject to the development of various secondary complications that include cardiac disease, stroke, retinopathy and blindness, nephropathy and renal failure, peripheral and autonomic neuropathy, and amputation (Atkinson & Eisenroth, 2001). Although tight glycemic control has been shown to decrease the number of diabetes-related secondary complications, it also has been shown to lead to an increased number of dangerous hypoglycemic episodes (Diabetes Control and Complications Trial [DCCT] Research Group, 1993).

Transplantation therapy for type 1 diabetes was developed as an alternative to insulin administration with the additional theoretic benefit of reducing or eliminating the development of secondary complications of the disease. Both whole-organ pancreas and isolated pancreatic islets are being transplanted into select individuals with type 1 diabetes. Whole-organ transplantation is already an established and widely available therapy, whereas clinical islet transplantation remains under investigation in diabetic individuals.

Whole-Organ Pancreas Transplantation

History and Early Results

On December 20, 1893, P. Watson Williams grafted three pieces of a sheep pancreas into the subcutaneous tissues of a diabetic child, who died 3 days later of unrelenting diabetic ketoacidosis (Williams, 1894). This first attempt to treat diabetes with transplantation, although unsuccessful, preceded decades of animal experimentation, in which investigators developed the methods necessary to perform a vascularized pancreas transplant; pancreas transplantation was subsequently used as a model to study diabetes and glucose homeostasis.

The first clinical vascularized pancreas transplantation was performed on December 17, 1966, by William Kelly and Richard Lillehei at the University of Minnesota. The patient had temporary insulin independence but eventually required graft removal and ultimately died of postoperative complications (Kelly et al, 1967). The subsequent early experience with pancreas transplantation at Minnesota and at a few other centers was characterized by some technical success, but no graft functioned beyond 1 year, and the enthusiasm for this procedure dwindled.

During 1975, only six pancreas transplantations were performed worldwide. However, the introduction of cyclosporine as an immunosuppressive medication and further technical refinements allowed for better outcomes following pancreas transplantation such that throughout the 1980s and early 1990s, the number of pancreas transplants performed increased dramatically: almost 1500 pancreas transplantations were performed in the United States during 2004. This number has declined slightly for the past several years, with fewer than 1200 pancreas transplantations performed in the United States during 2010.

Indications and Patient Selection

The majority of patients who undergo pancreatic transplantation have type 1 diabetes mellitus and renal failure. In these individuals, pancreas transplantation is performed with a simultaneous kidney transplantation (SPK; 72% of cases) or after a successful kidney transplantation (PAK; 20% of cases). The normal glucose control achieved by the pancreas transplant may protect the transplanted kidney from recurrent diabetic nephropathy and is beneficial from an overall quality of life perspective. In a small proportion of patients with diabetes that is very brittle and difficult to manage, but with preserved renal function, pancreas transplantation alone (PTA; 8% of cases) is performed. It should be noted that SPK and PAK recipients require immunosuppressive therapy to protect both the kidney and pancreas from rejection, whereas in the case of PTA recipients, the need for immunosuppression is solely for the pancreas itself. This difference becomes important when weighing the risk/benefit ratio for each type of recipient.

Potential pancreas recipients are carefully screened for contraindications to transplantation, such as an ongoing infectious process or malignancy. These candidates almost always have medical comorbidities as a result of secondary complications from diabetes; therefore a thorough assessment of a candidate’s cardiovascular status is essential. Cardiac contraindications to pancreas transplantation include the presence of noncorrectable coronary artery disease, significantly decreased ejection fraction, or myocardial infarction within the preceding 6 months. Recipient age is also important, and in some programs, recipients older than 50 years are not considered candidates because of an increased risk of perioperative complications.

Donor Operation

Selection of an appropriate deceased pancreas donor includes standard donor selection criteria. In addition, a bias exists toward using organs from younger, leaner, and more hemodynamically stable deceased donors. Donors with hemodynamic instability or those that require high doses of vasopressors are considered higher risk. In addition, pancreata with significant steatosis are usually avoided, because they are associated with a greater likelihood of postoperative complications, such as pancreatitis, peripancreatic fat necrosis, and infection. Based on these selection criteria, which are relatively stringent compared with those applied to the liver or kidney, only a fraction of deceased donors are deemed suitable for whole-organ pancreas donation. In the United States, there were 8022 deceased donors during 2009. Of these, only 1233 pancreata were transplanted (15%), compared with 6101 livers (76%) and 10,442 kidneys.

The procurement of the pancreas must be performed in conjunction with the liver procurement, carefully delineating the blood supply to the liver to ensure that both organs can be removed and transplanted. In the vast majority of cases, blood supply should not preclude the transplantation of both organs. Initial dissection involves division of the gastrocolic ligament to expose the anterior surface of the pancreas. Visual inspection is considered to be an important element to the pancreas procurement process, because this is an opportunity to assess the organ for the presence of infiltrating fat or hematoma that might preclude transplantation. The portal triad is carefully dissected, with division of the common bile duct and the gastroduodenal artery. In addition, the common hepatic, left gastric, and splenic arteries are all dissected free of surrounding lymphatic tissues. Further dissection of the pancreas includes a Kocher maneuver, to mobilize the head, and division of the lienophrenic and lienocolic ligaments, to mobilize the body and tail. Of note, the spleen is left in continuity with the pancreas to serve as a handle to minimize manipulation of the gland itself. The duodenum is decontaminated by flushing povidone-iodine antifungal/antibiotic solution through a nasoduodenal tube.

After the patient has been systemically heparinized, the abdominal aorta is ligated at its bifurcation and is cannulated in a retrograde direction for perfusion. The liver team may also elect to place a cannula for portal perfusion through the inferior mesenteric vein. The supraceliac aorta is cross-clamped, the vena cava is vented, and the abdominal organs are flushed in situ with preservation solution, typically University of Wisconsin (UW) solution, at 4° C. In addition, topical cooling is also used.

Once the organs have been adequately flushed, the liver and pancreas are either separated in situ and removed individually from the donor, or both organs are removed en bloc and divided at the back bench. In the in situ separation situation, the liver is removed first by dividing the portal vein 1 cm cephalad to the superior margin of the pancreatic head, approximately the level of the coronary vein, and dividing the splenic artery about 3 mm beyond its origin, thus preserving the entire celiac axis with the liver.

Next, removal of the pancreas proceeds. The proximal duodenum just beyond the pylorus and the distal duodenum are divided with gastrointestinal anastomosis stapler. The small bowel mesentery that lies inferior to the pancreas is divided, and the superior mesenteric artery is divided at its origin from the aorta. Long segments of donor iliac vessels are removed to use for vascular reconstruction during back-bench preparation of the pancreas.

Back-Table Preparation of the Pancreas

Relative to other solid organs, the pancreas requires extensive preparation prior to implantation into the recipient. This back-bench preparation is performed in ice-cold preservation solution to minimize any further ischemic injury to the organ. The duodenum is often shortened with a gastrointestinal anastomosis stapler, being careful to exclude any gastric tissue and also being careful not to compromise the opening of the ampulla of Vater. The division of the small bowel mesentery in the donor is shortened by firing a stapler across this mesentery and then reinforcing the staple line with a running vascular suture. The spleen is removed by dividing the vessels in the splenic hilum, being careful not to injure the tail of the gland. Finally, the arterial inflow to the graft must be reconstructed, because the organ has two major sources of blood supply that are not in continuity: the splenic artery supplies the body and tail, and branches of the superior mesenteric artery supply the head.

In most instances, arterial reconstruction can be performed using the donor iliac artery as a bifurcated Y graft. The internal iliac artery is joined to the splenic artery, and the external iliac artery is joined to the superior mesenteric artery. The common iliac artery of the donor Y graft can then be anastomosed to the recipient iliac artery, serving as the arterial inflow to the pancreas. In some instances, it is necessary to create a portal vein extension graft on the back bench using donor iliac vein; however, this technique is avoided if possible, because it may increase the risk of venous thrombosis of the graft.

Recipient Operation

The techniques used for transplanting the pancreas have changed dramatically over the past few decades. Partial segmental grafts that contained only the body and tail were once common; however, this technique is rarely used today. Exocrine secretions were previously managed by pancreatic duct ligation or by injection of a polymer that would cause duct obliteration, however, now exocrine secretions are handled by internal drainage.

In two areas of pancreas transplantation, current-day techniques differ: in the drainage of exocrine secretions and the venous drainage of the graft. Exocrine drainage is performed either via the intestinal tract or via the urinary tract. Throughout most of the 1980s and 1990s, drainage of the pancreatic secretions into the recipient bladder was the most common form of exocrine drainage. This technique is convenient for monitoring organ function by measurement of amylase levels in the urine; however, problems with hematuria, cystitis, bicarbonate loss, and dehydration are all associated with bladder drainage. These complications necessitate surgical revision to enteric drainage in up to 20% of bladder-drained pancreas recipients (Stratta, 2005). Based on these issues, and on the lower rejection rates observed with newer immunosuppressive medications, the majority of transplant centers now perform enteric drainage of the exocrine secretions. This enteric drainage is either directly into a loop of jejunum in a side-to-side fashion or into a Roux-en-Y limb of jejunum.

The venous drainage of the graft is either to the systemic circulation, via an iliac vein or the inferior vena cava, or to the portal circulation. Portal venous drainage has the theoretic advantage of delivering insulin in a more physiologic manner, because insulin undergoes a “first pass” through the liver, and the hyperinsulinemia that results from systemic drainage is avoided (Gaber et al, 1995). There is also an immunologic advantage of portal drainage that has been observed in several experimental studies, in which the delivery of foreign antigen via the portal system results in diminished immune responses. Despite these potential advantages, no demonstrable difference has been found in outcomes between human transplants drained by the portal vein and those drained by the systemic vein, and systemic venous drainage is how the majority of pancreas transplantations are performed.

There are two common locations in the abdomen where the transplant is placed based on the type of venous drainage planned: either in the pelvis, most commonly the right side, for systemic venous drainage or in the midabdomen for portal venous drainage. When the graft is placed in the pelvis, the donor portal vein is anastomosed to the external iliac vein, the common iliac vein, or the inferior vena cava. In this pelvic position, the graft is oriented with the duodenum in an inferior position, if bladder drainage is planned (Fig. 101.1A), or with the duodenum in either the superior (Fig. 101.1B) or inferior position if enteric drainage is planned. Alternatively, for portal venous drainage, the pancreas is placed in the mid-abdomen below the transverse colon with the duodenum oriented superiorly. The portal vein of the pancreas is anastomosed to a major branch of the superior mesenteric vein, found in the small intestine mesentery, in an end-to-side fashion (Fig. 101.2). Enteric drainage for exocrine secretions must be used with the portal venous drainage technique. With either venous drainage technique, the donor arterial conduit to the pancreas graft is anastomosed in an end-to-side manner to the recipient common or external iliac artery.

Complications

The major complications following pancreas transplantation are often technical in nature. Pancreas graft thrombosis, arterial or venous, is more frequent after pancreas transplantation than after other solid-organ transplants, and the reported incidence is approximately 10%. Thrombosis usually occurs within the first week following transplantation and likely reflects the relatively low blood flow through the organ. In most instances of thrombosis, graft removal is necessary (Humar et al, 2000). Early pancreatitis occurs in 10% to 20% of cases and is largely a reflection of ischemic damage to the gland during preservation and reperfusion injury. Hyperamylasemia and graft edema are characteristic, and graft pancreatitis is usually treated nonsurgically with octreotide. Leakage at the site of pancreatic exocrine drainage is another early complication, with management often dictated by the method of drainage. Bladder-drained transplants with a small leak at the duodenocystostomy can often be managed by Foley catheter drainage of the bladder, allowing the site of leakage to heal over time. Enteric-drained transplants with a leak at the duodenojejunostomy will often result in peritonitis and usually require operative intervention to control the leak.

Rejection following pancreas transplantation was once a very common occurrence. Pancreas rejection is often difficult to diagnose, and a variety of indicators are used to help make the diagnosis. These include tenderness over the area of the pancreas allograft, increased serum amylase and lipase, decreased urinary amylase excretion (if bladder drainage is used), biopsy of the pancreas, and hyperglycemia. It is noteworthy that hyperglycemia is a late indicator of rejection, and the pancreas is often difficult to salvage once hyperglycemia has occurred. If SPK transplantation is performed, renal allograft dysfunction can often assist with the diagnosis of pancreatic rejection, because the rejection process is often occurring in both organs. As a result of the high incidence of rejection and the difficulty in making the diagnosis, pancreas transplant recipients usually receive potent induction immunosuppression with a T–cell depleting agent and maintenance therapy with tacrolimus, mycophenolate mofetil, and corticosteroids.

The total amount of immunosuppression pancreas recipients receive is among the highest of any solid-organ transplantation. As a result, they are more susceptible to the complications of immunosuppressive therapy. These complications include infection with opportunistic bacteria, viruses, and fungi; malignancy; gastrointestinal complications; and others. The high incidence of these complications makes effective prophylaxis strategies important.

Results

Patient and graft survival following pancreas transplantation have improved significantly in recent years. Depending upon the type of transplantation—SPK, PAK, or PTA—patient survival is approximately 96% to 98% at 1 year and 85% to 89% at 5 years after transplantation. Graft survival varies according to the type of transplantation performed (Fig. 101.3). For SPK recipients, 1-, 5-, and 10-year pancreas graft survival rates are 85%, 73%, and 55%, respectively. For PAK recipients, the respective rates are 80%, 53%, and 37%. Finally, for PTA recipients, rates of pancreas graft survival are 76%, 52%, and 35%, respectively (Axelrod et al, 2010).

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FIGURE 101.3 Pancreas graft survival rates (unadjusted) at 1 year, 3 years, 5 years, and 10 years following whole-organ transplantation by transplant category.

(Modified from Axelrod DA, et al, 2010: Kidney and pancreas transplantation in the United States, 1999-2008: the changing face of living donation. Am J Transplant 10:987-1002, Copyright 2010 Blackwell Publishing, with permission.)

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