Care of the Pancreas Transplant Recipient
Robert M. Esterl Jr
Gregory A. Abrahamian
David E.R. Sutherland
Raja Kandaswamy
Type 1 diabetes mellitus has two treatments: (a) exogenous insulin administration or (b) beta cell replacement by pancreas or islet transplantation. The former is burdensome to the patient and gives imperfect glycemic control, predisposing to secondary complications of the eyes, nerves, kidneys, and other systems. The latter, when successful, establishes a constant euglycemic state but requires major surgery—at least for the pancreas transplant—and immunosuppression to prevent rejection, predisposing to complications as well, often compounded by those that are preexisting from diabetes.
The Diabetes Control and Complications Trial [1] showed that intensive insulin therapy (multiple injections per day with doses adjusted by frequent blood sugar determinations) decreased, although rarely normalized, glycosylated hemoglobin levels (HbA1C) and reduced the rate of secondary complications [2]. The threshold for totally eliminating the risks of secondary diabetic complications was perfect glycemic control, an objective that cannot be achieved by even the most sophisticated exogenous insulin-delivery devices available today. Pancreas transplantation induces insulin independence in diabetic recipients without the risk of hypoglycemia and can ameliorate secondary complications. With major advances in the area of management of pancreas transplantation (Table 184.1), the success rate has progressively increased during the past five decades [3]. Today’s recipients have a high probability of achieving insulin independence for years, if not indefinitely.
Historically, islet transplants have been less successful than pancreas transplants for a variety of reasons, but the gap is narrowing. In the late 1990s at the University of Alberta, insulin independence was achieved by sequential transplantation of islets from multiple donors and the use of a steroid-free, nondiabetogenic, immunosuppressive regimen [4]. In another series from the University of Minnesota with a similar immunosuppressive regimen, single-donor islet transplants induced insulin independence [5]. In this series, the donors had a high body mass index and the recipients had a low body mass index, so that the net number of islets transplanted per unit weight was similar in the Alberta and Minnesota series. Islet transplants can succeed with strict donor and recipient selection, but are not yet able to supersede pancreas transplants as the mainstay of beta cell replacement. Until islet transplants can consistently succeed from a single donor, regardless of recipient size or insulin requirements, an integrated approach is likely; large donors will be used for islet transplants to recipients with low insulin needs and the remaining donors (the majority) for pancreas transplants to recipients with average- or high-insulin requirements. This strategy will maximize the number of recipients who receive allogeneic beta cells and eliminate surgical complications for at least a subset of patients.
Although short-term islet-graft survival appears promising (even with single donors) [6], long-term graft function after islet transplants (even with multiple donors) continues to be a major impediment to rapid progress. In the University of Alberta series, only 10% of islet transplant recipients were insulin independent at 5 years posttransplant [7].
The main trade-off for recipients of beta cell allografts is the need for immunosuppression. A successful graft makes the recipient euglycemic and normalizes glycosylated hemoglobin levels, but the combined risks of immunosuppression and a major pancreas transplant surgery must be weighed against the long-term risks of imperfect glycemic control with exogenous insulin injection and of development of secondary complications. A randomized prospective trial has not been done to weigh these risks. The burden of daily management of diabetes with the need for multiple sticks to monitor blood sugar levels and to inject insulin tilts the balance in favor of a pancreas or islet transplant for many diabetic patients. Furthermore, antirejection strategies are continually being modified to decrease the complications of immunosuppression. Nevertheless, only a few institutions perform pancreas transplants soon after the onset of diabetic disease [8]; most institutions delay pancreas transplantation until the recipient becomes uremic and needs a kidney transplant.
The main indications for pancreas transplants in patients with normal kidney function are progressive diabetic complications, glycemic lability, and hypoglycemic unawareness, the latter of which may emerge years after the onset of diabetes, particularly in patients with autonomic neuropathy. However, even for nonlabile diabetic patients who attempt tight control by intensive glucose monitoring, the diabetes literature shows a high rate of secondary complications that are just as morbid [9] as complications of chronic immunosuppression in pancreas transplant recipients. Thus, for patients who wish to avoid a lifetime of insulin injections and glucose monitoring and prefer the risks of immunosuppressive complications to the secondary complications of diabetes, a pancreas transplant can be an attractive alternative therapy.
Most pancreas transplant candidates have advanced diabetic nephropathy and require a kidney transplant also. The risks of immunosuppression are already assumed because of the kidney transplant, so a simultaneous or sequential pancreas transplant does not pose significant additional risks other than surgical ones [8]. Although most pancreas transplants are performed in type 1 diabetics with impending or chronic renal failure, some pancreas transplants occur in renal allograft recipients who meet the criteria for type 2 diabetes who want to eliminate the need for exogenous insulin [10].
Pancreas Transplant Recipient Categories
Pancreas transplant candidates are divided into three categories: uremic (need a kidney transplant), posturemic (have a functioning kidney transplant), and nonuremic (do not need a kidney transplant, at least yet). For candidates who are
uremic, the options are to receive kidney and pancreas transplants either simultaneously in the same operation or sequentially in separate operations. Which option to take is usually based on the availability and suitability of living and deceased donors for one or both organs at that particular time.
uremic, the options are to receive kidney and pancreas transplants either simultaneously in the same operation or sequentially in separate operations. Which option to take is usually based on the availability and suitability of living and deceased donors for one or both organs at that particular time.
Table 184.1 Major Advances in the Management of Pancreas Transplantation | |||||||||||||||
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Accordingly, there are three broad categories of pancreas transplants: simultaneous pancreas kidney (SPK) transplant, pancreas after kidney (PAK) transplant, and pancreas transplant alone (PTA).
SPK transplants: Most SPK transplants are performed with both organs from the same deceased donor. Because a large number of patients wait on the UNOS list for a kidney organ, unless priority is given to SPK candidates, waiting times tend to be long (years). To avoid two operations and long waiting times, a simultaneous kidney and segmental pancreas transplant from a living donor can be done, but only a few centers offer this option. With successful islet transplantation from a living donor [11], a simultaneous living donor islet-kidney transplant may become a viable option in the future. If a living donor is willing or is medically suitable to give a kidney organ only, another option is a simultaneous living donor kidney and deceased donor pancreas transplant [12]. For this option, the living kidney donor and the recipient must be available at a moment’s notice, because the deceased donor pancreas must be transplanted soon after procurement. Alternatively, a recipient of a scheduled living donor kidney transplant could receive a simultaneous deceased donor pancreas organ if it became available fortuitously. If not, and only a living donor kidney is transplanted, the recipient becomes a PAK candidate.
PAK transplants: For diabetic patients who have already received a kidney transplant from a living or deceased donor, a PAK transplant can be performed. Most PAK transplants today are performed from a deceased donor in a patient who previously received a living kidney transplant. Although a PAK transplant requires that a uremic diabetic patient undergoes two operations to achieve both a dialysis-free and insulin-independent state, the two transplants done separately are “smaller” procedures than a combined transplant. The time interval between the living donor kidney transplant and the deceased donor pancreas transplant depends on several factors, including recipient recovery from the kidney transplant and donor availability, but the outcomes are similar for all time intervals greater than 1 month duration. Because of the lack of priority of patients who wait for a SPK versus a kidney alone, the PAK is now becoming the most popular pancreas transplant category at many institutions [13,14].
PTA: For recipients with adequate kidney function, a solitary pancreas transplant can be performed from either a living or deceased donor. Because the waiting time for a solitary deceased pancreas is relatively short at the present time, living donor solitary pancreas transplants are done infrequently, but are typically indicated if a candidate has a high panel-reactive antibody and a negative cross-match to a living donor. PTA candidates have problems with glycemic control, hypoglycemic unawareness, and frequent insulin reactions but fairly normal renal function. A successful PTA not only obviates these problems, but also probably improves the quality of life, and may ameliorate secondary diabetic complications, thus increasing the applicability of PTA [13,14,15].
Although the numbers of SPK transplants have remained fairly constant for nearly two decades, the numbers of solitary pancreas transplants (PAK and PTA) have nearly quadrupled [16]. From 2004 to 2008, the most common category of pancreas transplant was the SPK (73%), followed by the PAK (19%) and the PTA (9%); in the PAK category, 76% of the kidney organs came from living donors [3]. Although rare, pancreas transplants can also occur as multiorgan transplants in patients with unique medical problems [17].
Historical Perspectives, Evolution, and Improvements in Pancreas Transplants
The first clinical pancreas transplant was performed at the University of Minnesota in 1966 [18]. The number of transplants remained low during the 1970s, but progressively increased in the 1980s, due to the introduction of cyclosporine.
By the end of 2008, more than 30,000 pancreas transplants were reported to the International Pancreas Transplant Registry (IPTR) from more than 1,000 centers worldwide, including more that 22,000 in the United States and more than 8,000 outside the United States [3]. In 2010 more than 3,700 patients wait for a pancreas transplant on the UNOS list, and more than 1,200 pancreas transplants have been done annually in the United States [17].
By the end of 2008, more than 30,000 pancreas transplants were reported to the International Pancreas Transplant Registry (IPTR) from more than 1,000 centers worldwide, including more that 22,000 in the United States and more than 8,000 outside the United States [3]. In 2010 more than 3,700 patients wait for a pancreas transplant on the UNOS list, and more than 1,200 pancreas transplants have been done annually in the United States [17].
The early history of pancreas transplants involved various surgical techniques, many of which were developed to manage pancreatic exocrine drainage [19]. The first clinical pancreas transplant was performed by Kelly et al. as a duct-ligated, segmental graft at the University of Minnesota in December 1966 [18,20]. In 1973, Lillehei described a series of 13 pancreas transplants at the University of Minnesota where he used enteric drainage (ED) of pancreatic secretions via a cutaneous duodenostomy and a roux-en-y-duodenojejunostomy [20,21]. In the 1970s, Gliedman reported the first segmental pancreas transplant (and then a series of 11 pancreas transplants) with a pancreatic duct–ureter anastomosis for exocrine drainage [20,21,22,23]. This technique did not have widespread popularity because of leakage from the pancreatic duct–ureter anastomosis and the cut surface of the pancreas [20].
From the mid-1970s to mid-1980s, segmental pancreas transplants predominated due to a historical belief that the pancreas organ was less antigenic than the duodenal stump [20,21]. With segmental pancreas transplants, two techniques were popularized to manage pancreatic exocrine secretion, including open intraperitoneal drainage by Bewick in 1976 and the University of Minnesota in 1978 [20,24] and synthetic polymer pancreatic duct injection by Dubernard in 1978 [20,25]. In 1983, Sollinger reported the use of direct bladder drainage (BD) to manage pancreatic exocrine secretions in a segmental pancreas graft [26], and the next year he described a series of 10 segmental pancreas transplants with BD that had very few surgical complications, so BD became the predominant technique (Fig. 184.1) [20,27]. In 1982, Groth and Tyden described a segmental pancreas transplant followed by a series of whole-organ pancreas transplants with ED (Fig. 184.2) [28] and this technique ended the predominance of segmental pancreas transplants [20,29].
 Figure 184.1. Bladder-drained pancreaticoduodenal transplant alone from a cadaveric donor. |
 Figure 184.2. Enteric-drained simultaneous pancreas and kidney transplant from a cadaveric donor with systemic venous drainage. |
In 1987, Nghiem et al. described a whole-organ pancreas transplant with BD via a duodenal stump, a technique that took on widespread acceptance in both Europe and the United States. BD was especially appealing because urinary amylase levels could be tracked to monitor rejection and pancreatitis [20,30]. In mid-1980s, Starzl revived ED of the whole-organ pancreas transplant described by Lellehei 20 years previously [20,31]. In the mid-1980s to the mid-1990s, although BD was popular, urinary complications including cystitis, urethritis, hematuria, metabolic acidosis, and volume depletion led to enteric conversion of whole-organ pancreas transplants in a technique first described by Tom in 1987 [20,32].
Venous drainage of the pancreas has also evolved over the years. Portal drainage was used with segmental grafts in the 1980s [33,34,35,36]. In 1989, Mühlbacher described the first case of whole-organ pancreas transplantation with portal venous drainage and exocrine BD [37]. Until 1990s systemic venous drainage had been the norm, until portal drainage gained widespread popularity with ED [38,39] as opposed to BD [37]. By 2004, about 20% of SPK transplants had portal drainage, most commonly to the superior mesenteric vein (Fig. 184.3) and 80% of SPK had ED of pancreatic exocrine secretions [40].
Before standard techniques were developed to procure liver and pancreas grafts with intact blood supplies, segmental pancreas grafts were commonly used. Currently, whole-organ pancreaticoduodenal grafts predominate, although segmental grafts are still used for living donor pancreas transplants. The first living donor pancreas transplant was performed at the University of Minnesota in 1979 [41]. The early series of living donor pancreas transplants consisted of solitary pancreata because the rejection rates for deceased donor pancreata were so high [42]. In the 1990s, living donor pancreas transplants were predominantly performed in combination with a kidney from the same donor (Fig. 184.4) [43,44,45]. More recently, laparoscopic living donor segmental pancreatectomy has gained popularity [46]. Another approach, as previously mentioned, is to perform a living donor kidney transplant simultaneously with a deceased donor pancreas transplant [12].
Immunosuppressive regimens have made great strides over the years. Most immunosuppressive protocols use antibody
induction, followed by maintenance therapy with tacrolimus in combination with mycophenolate mofetil [40]. In the late 1990s and early 2000s some centers such as Northwestern University pushed for steroid-free regimens for pancreas transplants [20]; in fact, of the nearly 25,000 pancreas transplants reported to the IPTR, a third of those in the last 5 years were done with a steroid-free immunosuppressive regimen [20,40]. Today there are more than 140 pancreas transplant centers and 25 islet cell transplant centers in the United States [17]. Some centers have reported extensive experience, including more than 1,000 SPK transplants at the University of Wisconsin [17], and more than 1,900 pancreas transplants of all categories at the University of Minnesota [17]. Since 1980, the IPTR has collected data from all centers in the world [47] and remains an excellent resource for outcome analysis. In addition, the US Transplant Scientific Registry of Transplant Recipients (SRTR), administered through the Arbor Research Collaborative for Health, provides detailed scientific analysis of national, regional, state, and center-specific pancreas graft and patient survival [48].
induction, followed by maintenance therapy with tacrolimus in combination with mycophenolate mofetil [40]. In the late 1990s and early 2000s some centers such as Northwestern University pushed for steroid-free regimens for pancreas transplants [20]; in fact, of the nearly 25,000 pancreas transplants reported to the IPTR, a third of those in the last 5 years were done with a steroid-free immunosuppressive regimen [20,40]. Today there are more than 140 pancreas transplant centers and 25 islet cell transplant centers in the United States [17]. Some centers have reported extensive experience, including more than 1,000 SPK transplants at the University of Wisconsin [17], and more than 1,900 pancreas transplants of all categories at the University of Minnesota [17]. Since 1980, the IPTR has collected data from all centers in the world [47] and remains an excellent resource for outcome analysis. In addition, the US Transplant Scientific Registry of Transplant Recipients (SRTR), administered through the Arbor Research Collaborative for Health, provides detailed scientific analysis of national, regional, state, and center-specific pancreas graft and patient survival [48].
 Figure 184.3. Enteric-drained simultaneous pancreas and kidney transplants with portal venous drainage of the pancreas graft via the superior mesenteric vein. |
 Figure 184.4. Simultaneous segmental pancreas and kidney transplant from a living donor. Either bladder- or enteric-drained can be used, but the bladder-drained technique has a lower complication rate and is illustrated. |
Table 184.2 Summary of American Diabetes Association Recommendations for Indications for Pancreas Transplants | ||
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Indications and Contraindications for Pancreas Transplants
The indications for a pancreas transplant have evolved and expanded over the years as the results have improved. The position statement of the American Diabetes Association [49] on indications for a pancreas transplant (Table 184.2) is fairly conservative. A pancreas transplant is also indicated for patients who have developed secondary complications of diabetes including retinopathy, cardiovascular disease, nephropathy, and neuropathy. The progression of many of these complications is halted by a functioning pancreas graft.
With a functioning pancreas transplant improvements with sensory, motor, and autonomic neuropathy and paresthesias have been reported [19,50,51,52,53,54,55]. Patients with abnormal cardiorespiratory neurologic reflexes have reduced death rates after functioning pancreas transplants [50,56]. There is increased nerve conduction velocity in SPK recipients with functioning pancreas transplants versus those with failed pancreas grafts [51,57,58]. Uremic patients who undergo SPK transplants have improved symptoms of gastroparesis than in patients who have kidney transplants alone [52,59].
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