PANCREAS TRANSPLANTATION WAS first described

0163-769X/04/$20.00/0 Endocrine Reviews 25(6):919 946 Printed in U.S.A. Copyright 2004 by The Endocrine Society doi: 10.1210/er.2002-0036 Pancreas Transplantation: Indications and Consequences JENNIFER L. LARSEN Section of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198-3020 Pancreas transplantation continues to evolve as a strategy in the management of diabetes mellitus. The first combined pancreas-kidney transplant was reported in 1967, but pancreas transplant now represents a number of procedures, each with different indications, risks, benefits, and outcomes. This review will summarize these procedures, including their risks and outcomes in comparison to kidney transplantation alone, and how or if they affect the consequences of diabetes: hyperglycemia, hypoglycemia, and microvascular and macrovascular complications. In addition, the new risks introduced by immunosuppression will be reviewed, including infections, cancer, osteoporosis, reproductive function, and the impact of immunosuppression medications on blood pressure, lipids, and glucose tolerance. It is imperative that an endocrinologist remain involved in the care of the pancreas transplant recipient, even when glucose is normal, because of the myriad of issues encountered post transplant, including ongoing management of diabetic complications, prevention of bone loss, and screening for failure of the pancreas graft with reinstitution of treatment when indicated. Although long-term patient and graft survival have improved greatly after pancreas transplant, a multidisciplinary team is needed to maximize long-term quality, as well as quantity, of life for the pancreas transplant recipient. (Endocrine Reviews 25: 919 946, 2004) I. Introduction II. The Pancreas Transplant Candidate III. Indications for and Types of Pancreas Transplantation A. Simultaneous pancreas-kidney transplantation B. Pancreas-after-kidney transplantation C. Pancreas transplant alone IV. Surgical Procedure Variations, Immunosuppression, and Immediate Complications A. Bladder vs. enteric duct management (Table 3) B. Portal vs. systemic venous drainage C. Immunosuppression V. Effect of Pancreas Transplantation on Patient Survival VI. Consequences of Pancreas Transplantation on the Management of Diabetes A. Islet cell function of the pancreas graft B. Hypoglycemia and counterregulatory hormone response C. Diabetic nephropathy D. Diabetic retinopathy E. Diabetic neuropathies F. Microangiopathy G. Macrovascular disease risk factors and events H. QOL Abbreviations: A1C, Hemoglobin A1C; ACE, angiotensin-converting inhibitor; ApoE, apolipoprotein E; BD, bladder drainage; CET, cholesterol ester transfer; CMV, cytomegalovirus; ED, enteric drainage; ESRD, end-stage renal disease; HDL, high-density lipoprotein; IPTR, International Pancreas Transplant Registry; LDL, low-density lipoprotein; MMF, mycophenolate mofetil; PTLD, posttransplant lymphoproliferative disease; PVD, portal venous drainage; QOL, quality of life; SVD, systemic venous drainage; UNOS, United Network for Organ Sharing; VLDL, very low-density lipoprotein. Endocrine Reviews is published bimonthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community. VII. Clinical Management Issues of the Pancreas Transplant Patient A. Diabetes complication surveillance including vascular disease risk management B. Infection and cancer surveillance C. Bone mass screening and osteoporosis treatment D. Hypogonadism, fertility, and pregnancy after transplantation VIII. Summary I. Introduction PANCREAS TRANSPLANTATION WAS first described in 1967 (1), but initial pancreas graft and patient survival rates were dismal. A variety of factors, including advances in surgical techniques, immunosuppression, graft preservation techniques, methods of diagnosis and treatment of rejection, and management of common posttransplant complications, have led to significant improvements in graft and patient survival. As a result, the total number of pancreas transplant procedures reported to United Network of Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) continued to increase, a total of 18,843 from December 1966 to October 2002, with most (13,951) performed in the United States (Fig. 1) (2). Pancreas transplantation is actually a group of procedures, with slight differences that, in some cases, may have different, immediate, and possibly long-term complications and outcomes. In most cases, pancreas transplantation is performed in the setting of type 1 diabetes with end-stage renal disease (ESRD). The frequency of diabetes as the etiology of ESRD has doubled over the last decade so that diabetes is now the most common cause of new ESRD, which includes both type 1 and type 2 diabetes (3). Because the longevity of patients with type 1 diabetes has increased, more individuals 919

920 Endocrine Reviews, December 2004, 25(6):919 946 Larsen Pancreas Transplantation are at risk for developing ESRD, increasing the number of type 1 diabetes patients also eligible for combined or simultaneous pancreas-kidney transplant. Kidney transplant markedly improves patient survival in the diabetic ESRD patient compared with dialysis, especially when performed early (4 7). Therefore, the impact of adding a pancreas graft, as with simultaneous pancreas-kidney transplant, should compare patient survival to that of kidney transplant alone. Kidney graft failure, from whatever cause, also results in increased mortality as soon as the diabetic patient returns to dialysis (5). Thus, if kidney graft survival is lower after pancreas transplant, life expectancy will also be decreased, although not as immediate or as well tracked. This review will discuss the three main types of pancreas transplantation (see Tables 1 and 2): 1) simultaneous pancreas-kidney transplant, in which the pancreas and kidney are transplanted from the same deceased donor; 2) pancreasafter-kidney transplant, in which a cadaveric, or deceased, donor pancreas transplant is performed after a previous, and different, living or deceased donor kidney transplant; and 3) pancreas transplant alone for the patient with type 1 diabetes FIG. 1. Total pancreas transplants reported to the IPTR and UNOS from 1966 2001. Number of simultaneous pancreas kidney (SPK), pancreas-after-kidney (PAK), and pancreas transplant-alone (PTA) procedures are shown. [Adapted with permission from A. Gruessner and D. Sutherland: Clinical transplants 2001 (edited by J. Cecka and E. Terasaki) UCLA Immunogenetics Center, Los Angeles, 2001, pp 41 72 (17).] Cad, Cadaveric; Cat., category. who usually has severe, frequent hypoglycemia, but adequate kidney function. The indications for each procedure will be discussed, but contraindications to pancreas transplant are often the same for all procedures. Pancreas transplant alone and pancreas-after-kidney transplant candidates must have stable, adequate kidney function at the time of transplant, as both the transplant operation and immunosuppression can otherwise cause an immediate further decline of renal function. Absolute contraindications to transplantation of any type include active malignancy or infection, recently treated malignancy not meeting the minimum disease-free observation period as suggested by the Clinical Practice Guidelines of the American Society of Transplantation (8), psychiatric disease so severe or unstable that the stress of a large surgery would likely result in marked decompensation, and subjects unable or unwilling to take immunosuppressant medications regularly such that graft failure would be certain. Immediate complications that can occur with all types of pancreas transplant include rejection, thrombosis, pancreatitis, and infection. Exocrine pancreatic duct leaks and allograft pancreatitis are usually due to technical failures, preservation injury, or infection, leading to fluid collections, pseudocysts, or abscesses surrounding the pancreatic graft. The technical failure rate refers to graft failure attributed to an immediate complication of surgery. The technical failure rate is lowest with simultaneous pancreas-kidney transplant, but also varies with the location of the exocrine duct, bladder vs. enteric. Lower technical failure rates occur with bladder drainage (BD) than enteric exocrine duct drainage (ED) for both simultaneous pancreas- kidney (7.4% vs. 9.8%; P 0.03) and pancreas-after-kidney (9.5 vs. 14.1%; P 0.03) transplant procedures. There were no differences in rates for BD vs. ED with pancreas transplant alone (12.5 vs. 13.7%; P 0.77), but rates were higher overall for this procedure compared with the other two pancreas transplant procedures (2). Thrombosis is the most common cited cause of graft failure. Vascular thrombosis can also accompany rejection and pancreatitis. Although thrombosis is often attributed to a technical failure, rarely is pathology evaluated to confirm the cause. In a recent evaluation of all cases of massive pancreatic graft thrombosis, unrecognized hyperacute rejection was much more common than previously appreciated; therefore, rejection may, in fact, be the most common cause (9). Complications and need TABLE 1. Types of pancreas and kidney transplantation Procedure Type of diabetes Type of organ donor Presence of renal failure Kidney transplant alone Type 1 or type 2 Deceased, living related, or Yes living unrelated donor Simultaneous pancreas kidney (or combined pancreas-kidney) transplant Type 1 usually; the indications for type 2 have not been established Pancreas and kidney grafts usually from the same deceased donor Yes Pancreas-after-kidney transplant Type 1 Deceased or living donor (related or unrelated) followed by deceased-donor pancreas graft Yes, but not at the time of pancreas transplant Pancreas transplant-alone (or solitary pancreas transplant) Type 1 Deceased donor; rarely livingdonor hemipancreatectomy No

Larsen Pancreas Transplantation Endocrine Reviews, December 2004, 25(6):919 946 921 TABLE 2. Demographics of U.S. pancreas transplants reported to UNOS as of October 2002 for 1996 2002 a Simultaneous pancreas kidney Pancreas after kidney Pancreas transplant alone P value b No. (%) c 6032 (78) 1081 (14) 471 (6) Age (yr) 39.3 7.9 41.1 7.5 38.8 9.0 0.0001 % Male 59 58 39 0.0001 % Minorities 12 7 3 0.0001 Duration of diabetes (yr) 26 8 28 7 24 10 0.0001 % Performed with ED 65 50 46 0.0001 Median waiting list time (d) 302 140 105 0.0001 1-yr patient survival (%) 95 95 98 1-yr pancreas graft survival (%) 84 78 78 1-yr kidney graft survival (%) 92 94 N/A a Transplant number, prevalence and demographics shown are for transplants performed 1996 2002. Graft and patient survival statistics shown are for 1998 2002 only. [Adapted with permission from A.C. Gruessner and D.E. Sutherland: Clin Transpl 41 77, 2002 (2).] b Denotes significant differences between the three pancreas transplant types. c The remaining 2% include recipient category unknown, or pancreas transplant in combination with another organ other than kidney (2%). for reoperations, as well as rejection episodes, are all greater with simultaneous pancreas-kidney transplant than kidney transplant alone. However, the specific complications, and their frequency, can vary with the specific procedure being performed, as will be discussed with each procedure below. Living donor pancreas transplant is one type of pancreas transplant that will not be discussed in detail, as it represents only 0.5% of pancreas transplants performed (2). In this procedure, a hemipancreatectomy is performed on a living donor, often a relative of the recipient, and then implanted as a segmental graft in a recipient with diabetes. Islet cell mass in the recipient is less than with a whole-organ transplant. The University of Minnesota has the largest series and reports a 1- and 5-yr patient survival of 90%, and a 1-yr pancreas graft survival of 75% (10). The potential risk of diabetes in the donor, who also now has a smaller pancreas, continues to be a concern. In one series, six of 104 living donors from 1978 1997 required diabetes treatment or had an elevated hemoglobin A1C (A1C) after donation, a 5% diabetes rate. However, no details were given on whether additional screening for asymptomatic diabetes or impaired glucose tolerance was performed or how long the donors were followed to determine whether this rate represents the entire risk (10). In a random group of eight living pancreas donors who were 9 18 yr after their surgery, 50% had diabetes (mean age 50), with greatest risk in individuals with body mass index 27.8 kg/m 2 (11). More extensive testing using oral glucose tolerance tests and 24-h blood glucose and urine C peptide profiles was performed in 28 donors before and 1 yr after hemipancreatectomy (12). In this study, seven of 28 had evidence of abnormal glucose tolerance by oral glucose tolerance test, but none were found to have diabetes at the time of the study. Most concerning was that mean glucose was higher and urine C peptide was significantly lower 1 yr after hemipancreatectomy. These studies suggest a greater future risk of diabetes in donors after hemipancreatectomy, although the degree of risk still needs to be better defined. Additional centers are performing this operation, as well as simultaneous living-donor pancreas-kidney transplant, first described in 1996 (13). A recent report of six cases of simultaneous living-donor pancreas-kidney transplant from one center reported a 1-yr pancreas graft survival rate of 83% (14). In this study, all donors had normal glucose tolerance at 1 yr, but this is likely too early to determine the entire risk to the donor. Long-term benefits to the recipient of living-donor pancreas transplant of any kind, if established, must be balanced against both short- and long-term risks to donors and recipients before this procedure can be advocated. Islet transplantation, the subject of considerable ongoing discussion and investigation, has no long-term data ( 5 yr) to compare with whole-organ pancreas transplant outcomes, so it will not be included in this review. II. The Pancreas Transplant Candidate Before a discussion of the pancreas transplant procedures and their consequences, it is useful to review who the usual pancreas transplant candidate or recipient is. Usually, the pancreas transplant candidate has type 1 diabetes, although 6% of recipients are reported to have type 2 diabetes (2), as some institutions will consider patients with type 2 diabetes as candidates for pancreas transplant. The specific criteria for defining a candidate as having type 1 or type 2 diabetes varies from institution to institution. Women are more protected from diabetic nephropathy than men in the setting of poor metabolic control (15), and male gender has been implicated in many studies as a contributing risk factor for diabetic nephropathy (16). Thus, it is not surprising that more men than women are candidates for and receive simultaneous pancreas-kidney or pancreas-after-kidney transplant procedures (Table 2). Yet more women than men receive pancreas transplant alone, suggesting that women may be at higher risk for frequent hypoglycemia as a complication of diabetes, the most common indication for this procedure. The average age of pancreas transplant recipients has gradually increased at all centers for all transplant types. When the period of 1987 1992 was compared with 1999 2001, recipients over the age of 45 increased from 9% to 24% for simultaneous pancreas-kidney transplant, 9% to 29% for pancreas-after-kidney transplant, and 11% to 25% for pancreas transplant alone, although pancreas transplant-alone recipients are generally younger than other recipients (2). Pancreas transplant recipients with type 2 diabetes are generally older than those with type 1 (45 vs. 39 yr; P 0.001) (17).

922 Endocrine Reviews, December 2004, 25(6):919 946 Larsen Pancreas Transplantation Most pancreas transplant recipients are Caucasian because Caucasians are also at highest risk for developing type 1 diabetes. Yet the number of non-caucasian pancreas transplant recipients is increasing. For example, African-Americans represented 4% of recipients in 1987 1990 and 8% of recipients in 1996 2000 (17). The mean duration of diabetes before transplant is 23 27 yr, depending on the category (Table 2). Almost by definition, all pancreas transplant candidates have had diabetic complications to be eligible for transplant: simultaneous pancreas-kidney or pancreas-after-kidney transplant candidates already have ESRD, and pancreas transplant alone candidates usually have frequent, severe hypoglycemic episodes that result from one or more complications. Macrovascular disease, whether or not symptomatic, is present in most, as markers of vascular disease such as carotid intima media thickness, and C reactive protein are increased in kidney and pancreas transplant candidates compared with age-matched controls or type 1 diabetes patients without nephropathy (18 23). Whether diabetic complications stay the same, accelerate, or regress after pancreas transplant is one of the most important questions to be answered and will be discussed in Section VI. Patients with type 1 diabetes and ESRD have the choice of three transplant procedures: kidney transplant alone, simultaneous pancreas-kidney transplant, or kidney transplant followed by pancreas transplant (pancreas-after-kidney transplant), where the kidney graft is obtained from either a living or deceased donor. Kidney transplant alone is the most common transplant performed in diabetes patients with ESRD, overall, but simultaneous pancreas-kidney is the most common pancreas transplant procedure, with 78% of the 13,330 pancreas transplants reported to the UNOS between 1987 and 2002 (Figs. 1 and 2) (2). Although there is no consensus statement specifying all indications, the usual indication for this procedure at most centers is a type 1 diabetes patient with ESRD and adequate cardiac reserve who either has no option for a living kidney donor or desires to receive both organs simultaneously rather than waiting for a pancreas after the kidney transplant is completed. In simultaneous pancreas-kidney transplant, the pancreas and kidney are usually obtained from the same deceased donor; therefore, changes in kidney function can be used to determine whether rejection is occurring in either organ. Uncommonly, a cadaveric pancreas graft is transplanted at the same time as a living donor kidney to avoid two hospitalizations while reaping the benefits of living-donor kidney transplant (24). Even less commonly, simultaneous living-donor pancreaskidney transplant has been performed as described above, but has the disadvantage of lower islet mass and greater risk to the living donor (13, 14). Patient survival is generally high after all pancreas transplant procedures, including simultaneous pancreas-kidney, and comparable to kidney transplant alone (Fig. 2), but simultaneous pancreas-kidney transplant has the best 1-yr and long-term pancreas graft survival rate of any pancreas transplant procedure. Whereas 1-yr pancreas graft survival rates were the same for simultaneous pancreas-kidney (83%), pancreas-after-kidney (82%), or pancreas transplant alone (80%) performed 1999 2001 (Fig. 3) (17), simultaneous pancreaskidney transplant had a slightly greater 1-yr as well as longterm graft survival rate in those reported 1999 2002, 84% vs. 78%, for the other two categories (2). A number of centers report even higher ( 90%) 1-yr pancreas graft survival rates after simultaneous pancreas-kidney transplant than the av- III. Indications for and Types of Pancreas Transplantation A. Simultaneous pancreas-kidney transplantation FIG. 2. Patient survival after whole-organ cadaveric pancreas transplantation as reported to the IPTR and UNOS from 1966 2001. Rates for simultaneous pancreas-kidney (SPK), pancreas-after-kidney (PAK), and pancreas transplant-alone (PTA) procedures are shown. [Adapted with permission from A. Gruessner and D. Sutherland: Clinical transplants 2001 (edited by J. Cecka and E. Terasaki) UCLA Immunogenetics Center, Los Angeles, 2001, pp 41 72 (17).] FIG. 3. Pancreas graft survival after whole-organ cadaveric pancreas transplantation as reported to the IPTR and UNOS from 1966 2001. Rates for simultaneous pancreas-kidney (SPK), pancreas-afterkidney (PAK), and pancreas transplant-alone (PTA) procedures are shown. [Adapted with permission from A. Gruessner and D. Sutherland: Clinical transplants 2001 (edited by J. Cecka and E. Terasaki) UCLA Immunogenetics Center, Los Angeles, 2001, pp 41 72 (17).]

Larsen Pancreas Transplantation Endocrine Reviews, December 2004, 25(6):919 946 923 erage for all UNOS data (25). Finally, simultaneous pancreaskidney transplant has equal or better 1-yr patient and kidney graft survival rates compared with kidney transplant alone in diabetic recipients (Fig. 2) (26). Thus, simultaneous pancreas-kidney transplant does not have a negative impact on the success of the kidney graft. The retransplant rate is the number of individuals, out of the total, who have had a previous transplant of the same type; the retransplant rate after simultaneous pancreas-kidney transplant has remained quite stable at 1% (2). Transplant outcomes may be affected by several recipient factors, including age. In a recent cohort study of transplants performed 1995 2000, age over 40 increased mortality in both simultaneous pancreas-kidney and pancreas-after-kidney recipients, but not pancreas alone recipients, as had been reported previously (27). However, when transplants performed 1999 2002 were analyzed, age over 45 yr did not negatively affect patient or pancreas graft survival in all transplant categories (2). Women have also recently been reported to have greater early pancreas graft loss ( 6 months) than men in a small study of pancreas-kidney transplants unrelated to rejection and without any difference in kidney graft loss (28). African-Americans are reported to have higher rates of acute and chronic rejection than Caucasians after kidney transplant alone (29), but there is no reported difference between African-Americans and Caucasians in graft survival of either graft after simultaneous pancreas-kidney transplant (30). A small number of simultaneous pancreas-kidney transplant recipients (6%) have type 2 diabetes (2). At one center, patient, pancreas, and kidney graft survival were also similar between African- American and Caucasian recipients as well as between type 1 and type 2 diabetes recipients, where 40% of African-American and 16% of Caucasian recipients had type 2 diabetes as defined by C peptide more than 0.8 ng/ml (31). UNOS data also confirm that type 1 and type 2 diabetic recipients of simultaneous pancreas-kidney transplant have the same 1-yr patient and pancreas graft survival (2, 17). Recipients with type 1 and type 2 diabetes are reported to have the same A1C, and frequency of requiring insulin or oral hypoglycemic agents after simultaneous pancreas-kidney transplant in this center, too, although neither these data nor weight changes after transplant were shown (31). B. Pancreas-after-kidney transplantation This is the second most common pancreas transplant procedure (Fig. 1 and Table 2). The indication for this procedure is a patient with type 1 diabetes who has identified a living donor for kidney transplant and wants to plan a later pancreas-after-kidney transplant, or the type 1 diabetes patient who already has a kidney transplant that has stable graft function, desires the potential benefits of normoglycemia, and has the cardiac reserve to undergo the procedure. The initial kidney transplant can be obtained from either a deceased or living donor, but a living donor is preferred, when available, because it offers the best short- and long-term patient and graft survival for diabetic recipients (32). As a result, the number of living-donor kidney transplants has increased. Pancreas graft survival with pancreas-afterkidney transplant has also improved, which has further increased the interest in this procedure. The number of pancreas-after-kidney transplants has increased from 11% of all transplants in 1987 1998 to 18% in 1999 2000, whereas the number of simultaneous pancreas-kidney transplants performed has stayed the same, limited by the number of available deceased kidney donors (33). Ideally, pancreas-after-kidney transplant should be performed when the kidney graft is stable. However, outcomes are not different between those receiving a pancreas graft early ( 4 months), compared with later ( 4 months), after kidney transplant (34). One-year patient survival rate with pancreas-after-kidney transplant is comparable to other pancreas transplant categories above (96%). In 2001, 1-yr pancreas graft survival with pancreas-after-kidney transplant was reported to be similar to simultaneous pancreas-kidney transplant, but long-term graft survival is still better with simultaneous pancreas-kidney (Fig. 3) (2, 17). One-year kidney graft survival is higher in pancreas-after-kidney transplants compared with simultaneous pancreas-kidney transplant, perhaps because of greater use of living-donor kidney grafts, but also the transplant procedure itself selects for recipients whose kidney function is stable and adequate after kidney transplant (17, 34). C. Pancreas transplant alone Pancreas transplant alone is the least common pancreas transplant procedure performed (5%; Table 1). Frequent, severe, hypoglycemic events are the most common indication for this procedure. The American Diabetes Association position statement suggests that indications for pancreas transplant (in the absence of kidney failure) are frequent, acute and severe metabolic complications (hypoglycemia, hyperglycemia, and ketoacidosis) requiring medical attention as well as clinical and emotional problems with exogenous insulin therapy that are so severe as to be incapacitating; and consistent failure of insulin-based management to prevent acute complications, and centers performing this procedure generally evaluate possible candidates on a case-by-case basis (35). Pancreas transplant-alone recipients are the youngest of all pancreas transplant recipients, which may explain why they also have the best 1-yr patient survival rate (Fig. 2; 99% in 1999 2001). One-year pancreas graft survival rate improved to 80% in 2001, similar to that reported after both pancreasafter-kidney transplants and simultaneous pancreas-kidney transplants, but is slightly lower at 78% in 2002 (Fig. 3) (2, 17). Optimally, creatinine clearance should be more than 70 ml/ min to be considered for pancreas-only transplant, as a rapid decline in renal function can occur with impaired renal function, especially when cyclosporine-based immunotherapy is used (36, 37). Even with careful patient selection, kidney function may still deteriorate over time. At 1 yr, 2 8% of pancreas transplant-alone recipients underwent kidney transplant (17). Yet, by 10 yr after solitary pancreas transplant, the pathological changes of diabetes can reverse (38).

924 Endocrine Reviews, December 2004, 25(6):919 946 Larsen Pancreas Transplantation IV. Surgical Procedure Variations, Immunosuppression, and Immediate Complications A. Bladder vs. enteric duct management (Table 3) Location of the graft s exocrine duct is one variable in the pancreas transplant procedure. Drainage of the exocrine duct into the urinary bladder was first described by Sollinger et al. (39), and then modified by Corry et al. (40) to include a small button of duodenum to reinforce the anastomosis with the urinary bladder (Fig. 4). With BD, urine amylase can be used as a marker of graft function. Biopsies of the pancreas graft are also easily obtained across the bladder wall through a cystoscope with this procedure. In early pancreas transplants, when rates of rejection were high, these were seen as advantages as they facilitated frequent monitoring for pancreas graft rejection. Even now, with pancreas transplant alone or pancreas-after-kidney transplant, where the kidney cannot be used to monitor pancreas rejection, BD may still be useful. However, this procedure also creates potential complications. Metabolic acidosis occurs in most, and extracellular volume depletion is common, occasionally severe enough to require hospitalization; both complications are due to the loss of sodium bicarbonate-rich pancreatic secretions into the urine (41). Oral sodium bicarbonate therapy is required in almost all and minimizes these complications in most. Additional problems that can complicate BD include bladder leak, reflux pancreatitis, particularly with neurogenic bladder, chemical cystitis/urethritis, frequent bladder infections, duodenitis in the connecting segment, bladder tumors, bladder calculi, urethral stricture, urethral erosion, epididymitis, prostatitis, and prostatic abscess (42, 43). Frequency of urological complications is high, 50 77%, but rarely results in graft or patient loss (42, 43, 45). The alternative to BD is ED of the exocrine duct. In this procedure, the pancreatic duct is inserted into the small bowel using a small button of duodenum or with a Rouxen-Y limb (Fig. 5) (46, 47). Roux-en-Y was used predominantly in early ED procedures, but most centers no longer prefer a Roux-en-Y connection (2). There is less need for monitoring the pancreas graft, overall, because immunosuppression has improved and frequency of rejection episodes has decreased after pancreas transplant of all types. Thus, more new transplants are using ED at the outset, particularly with simultaneous pancreas-kidney transplant (77%), but also pancreas-after-kidney transplant (54%), and pancreas transplant alone (54%) as reported to UNOS from 1999 2002 (2). As long-term negative consequences of BD continue to emerge, many previous BD transplants have also been converted to ED, 9% by 1 yr and 15% by 3 yr for transplants performed 1996 2000 (2). Indications for enteric conversion surgery are frequent episodes of severe extracellular volume depletion, severe metabolic acidosis, urological complica- FIG. 4. Pancreas transplantation with BD of exocrine secretions and SVD. TABLE 3. Variations in pancreas transplant procedures Variation Advantages Disadvantages Exocrine duct Extensive surgical experience Dehydration and metabolic acidosis common BD Easier access to pancreas graft for biopsy Urological complications and related morbidity common Urine amylase can be used to monitor graft function Better outcomes with pancreas after kidney or pancreas alone ED More physiological: exocrine secretions reabsorbed into gut Leaks can result in intraabdominal sepsis, which may require removal of graft More difficult to biopsy pancreas with suspected rejection Venous drainage Long surgical experience Causes systemic hyperinsulinemia SVD Can be combined with either BD or ED PVD Physiological delivery of insulin to the liver; may improve lipid metabolism Patient and graft survival worse in some series Requires ED for duct management

Larsen Pancreas Transplantation Endocrine Reviews, December 2004, 25(6):919 946 925 FIG. 5. Pancreas transplantation with ED of exocrine secretions and PVD. tions, or problems with the duodenal segment. The hospitalization generally lasts 6 30 d (mean 12 d), with ED leak being the most common complication. The results of conversion surgery are good: 100% patient survival, 96% pancreas graft survival, and resolution of nearly all the indications for the surgery by 22-month follow-up in one series (48). Simultaneous pancreas-kidney transplants performed with either BD or ED have equal pancreas graft survival, as reported to UNOS and in single-center studies (84% vs. 82%), but kidney graft survival is better with ED than BD (P 0.03) (17). In pancreas-after-kidney and pancreas-alone transplants, 1-yr pancreas graft survival is better with BD than ED (17). More graft thrombosis was reported after ED than BD in the past, but current data reported to UNOS showed no difference in this complication between ED and BD (17). B. Portal vs. systemic venous drainage The other variation in surgical procedure involves the location of the venous effluent of the pancreas graft. The first successful pancreas transplant procedure used BD of the ED, which, because of the distance, required that the graft be connected to the systemic rather than the normal portal venous system. When placed in the systemic circulation, called systemic venous drainage (SVD), the insulin secreted into the pancreatic venous effluent is not extracted immediately by the liver, as it would be if it emptied into the portal circulation. Systemic concentrations of insulin, both fasting and postprandial, are elevated as a result (49 51). Subsequently, a procedure was developed where the graft was placed in the portal circulation and the pancreatic duct was drained into the small intestine. This combined portal venous drainage (PVD) with ED procedure resulted in much lower peripheral insulin concentrations than pancreas transplant recipients with SVD (52), comparable to nondiabetic kidney transplants receiving similar immunosuppression (50, 53). The PVD with ED drainage procedure is necessarily more physiological, but there has been considerable discussion about whether it changes outcomes. In all transplants reported to UNOS, outcomes were similar after PVD and SVD (17, 54, 55), but when recipients of pancreas-after-kidney or simultaneous pancreas-kidney transplant performed in 1995 2000 were analyzed, recipients of PVD or ED had greater patient mortality (27). Because PVD recreates normal physiology more than SVD, many have thought it would be beneficial to lipid metabolism or insulin actions. Some surgeons have suggested that there are other benefits as well, but there is little evidence to support this, as outlined below. Nonrandomized, retrospective studies suggested an immune benefit of PVD over SVD with improved pancreas graft survival (56). However, when a randomized prospective study compared the two procedures, pancreas graft survival was the same (57). The most recent UNOS data suggest that 1-yr graft survival was not different between PVD and SVD for any pancreas transplant category (2). Total fasting lipid concentrations are not different between individuals receiving PVD and SVD (58, 59), but lipoprotein composition may be. Hughes et al. (60) evaluated nonrandomized groups and outlined multiple differences in lipid profiles, particularly lower apolipoprotein B content of verylow-density lipoprotein (VLDL) and intermediate-density lipoprotein, and decreased intermediate-density lipoprotein mass and free cholesterol in PVD recipients compared with SVD recipients. However, in this study, cyclosporine dose was generally lower in PVD recipients, and serum creatinine was higher in SVD recipients (statistically significant at one time point), yet no analysis was performed to determine whether cyclosporine (dose or concentration) or creatinine contributed to the differences in lipoprotein content, independent of the procedure performed. In another study, no difference in apolipoprotein B content of VLDL was observed between those receiving SVD and PVD, but no other lipoproteins were analyzed (61). The one consistent finding is that cholesterol ester transfer (CET) is increased after SVD compared with PVD, as observed with other hyperinsulinemic states, and higher than nondiabetic kidney transplant-alone recipients (53, 62). Whether increased CET contributes to atherogenesis in this setting or others has not been established. Could the chronic hyperinsulinemia following SVD itself increase vascular risk? Hyperinsulinemia correlates with vascular risk in many clinical studies, but in most of these studies, hyperinsulinemia is a marker for the more general state of insulin resistance, which is associated with many factors that contribute to atherogenesis (63). We have shown that carotid intima media thickness, a marker of overall cardiovascular risk, improves after simultaneous pancreaskidney transplant with SVD (44, 64), and others have shown that progression of atherosclerosis was slowed in simultaneous pancreas-kidney transplant recipients, despite hyperinsulinemia (65). Whether PVD would result in even greater benefits is unknown, as these kinds of studies have not been compared between PVD and SVD. Without established significant advantages of PVD over SVD, most pancreas transplant recipients still receive SVD because there is greater surgical experience with SVD over PVD, greater flexibility

926 Endocrine Reviews, December 2004, 25(6):919 946 Larsen Pancreas Transplantation with SVD to perform either ED or BD, and possibly less patient mortality with SVD in one report (27). C. Immunosuppression Gruessner and Sutherland (17) have recently reviewed the current immunosuppression protocols being used for pancreas transplant as reported to UNOS. The most common regimen in all pancreas transplant categories in 2000 was tacrolimus/mycophenolate mofetil (MMF; nearly 80%) with cyclosporine/mmf a distant second (5% 20%). The combination of tacrolimus/mmf has largely replaced cyclosporine/mmf because of some evidence of lower rejection rates, and better blood pressure and lipids (66), and MMF has largely replaced azathioprine because of decreased rejection rates (67). With the availability of sirolimus (rapamycin) and the successful use of sirolimus-tacrolimus for islet transplantation, increasing numbers of patients are being treated with a variety of sirolimus combinations. Of these combinations, tacrolimus-sirolimus is used the most, followed by cyclosporine-sirolimus, tacrolimus-sirolimus-mmf, MMF-sirolimus, and sirolimus only. Many centers still use corticosteroids in their immunosuppression protocol, which may allow a reduced dose of calcineurin inhibitor, but others have tried to move to a steroid-free protocol with the assumption that this will decrease risk of weight gain, glucose intolerance, dyslipidemia, and bone loss. This has not proven to be true, as calcineurin inhibitors can also cause dyslipidemia, bone loss, and glucose intolerance, including the ability to induce islet cell apoptosis as will be discussed later (68, 69). The choice and type of antibody induction therapy being used are even more variable (17). Some patients receive no antibody induction therapy (7%), but most ( 50%) receive some form of anti-cd-25 therapy. The number receiving no antibody induction is decreasing over time, and combination-antibody treatment is increasing, with nearly 50% of pancreas transplant-alone recipients receiving both T celldepleting and nondepleting antibody therapies. Outcomes were not significantly different between regimens, but there was a trend toward better 1-yr graft survival with combination therapy (90%) compared with single antibody (81 86%) or no therapy (77%) in pancreas transplant-alone recipients, although the numbers are small. The immune suppression agents are often selected to improve graft survival, but they also have differential effects on blood pressure, lipids, weight gain, and glucose metabolism as will be reviewed in Section VII below. V. Effect of Pancreas Transplantation on Patient Survival The most important outcome of a new or established procedure is its impact on patient survival. Patient survival after pancreas transplant has generally been compared with that of kidney transplant-alone recipients, pancreas transplant recipients who experience graft failure, or those waiting for a transplant in cross-sectional studies. There are limitations to the use of all of these control groups. Whole-organ simultaneous pancreas-kidney transplant with normal graft function consistently improves 7- to 10-yr patient survival compared with deceased donor kidney transplant, simultaneous pancreas-kidney transplant with loss of pancreas graft function, or dialysis in type 1 diabetes patients waiting for a transplant (27, 70 73). Age can affect outcome, as recipients over age 40 have lower patient survival after simultaneous pancreas-kidney or pancreas-afterkidney transplant than those under age 40 (27, 74). UNOS data show no specific threshold for age-related effects on patient survival after simultaneous pancreas-kidney transplant (2). In fact, recipients over age 50 may receive no benefit of simultaneous pancreas-kidney transplant on patient survival over kidney transplant alone (75). No gender or ethnic differences in patient mortality have been reported, but duration of diabetes also increases risk (74). Presence of neuropathy also predicts greater mortality in pancreas transplant recipients, but abnormal cardiorespiratory reflexes had the greatest impact on risk of mortality (74, 76, 77). Although better patient and kidney graft survival have been attributed to improved glucose control after simultaneous pancreas-kidney transplant compared with cadaveric kidney transplant, both recipient and donor graft differences may also contribute. The type 1 diabetes patient who receives a cadaveric kidney transplant is generally older, more likely to be African-American, and have a longer duration of dialysis (73, 78). The donor used for kidney transplant alone was also older than the donor used for simultaneous pancreas-kidney transplant. The harvested kidney used for kidney transplant alone also had a longer cold ischemia time, on average, than the kidney used for simultaneous pancreaskidney transplant (73, 78). Simultaneous pancreas-kidney transplant was associated with a greater rejection episode rate (15% vs. 9%) than kidney transplant alone, but despite this, the simultaneous pancreas-kidney recipients were less likely to need dialysis the first week after transplant, and had better long-term kidney graft survival compared with cadaveric kidney transplant recipients (78). Living-donor kidney transplants have better patient and kidney graft survival than deceased-donor kidney transplants, for both diabetic and nondiabetic recipients. In fact, living-donor kidney transplant offers the same 8- to 10-yr patient survival as simultaneous pancreas-kidney transplant (73, 75, 79). Simultaneous pancreas-kidney transplant results in a higher patient mortality than living-donor kidney transplant the first year. Although patient mortality beyond the first year is lower in simultaneous pancreas-kidney transplant, it is not enough to result in greater patient survival overall compared with living-donor kidney transplant (73). The outstanding patient and kidney graft survival outcomes after living-donor kidney transplant, along with increasing waiting list times for deceased donor kidneys, have caused many centers to prefer living-donor kidney transplant, when available, with or without a later pancreas transplant. Yet the risk of pancreas-after-kidney transplant may not be negligible. Patient mortality was reported to be greater at 4 yr in pancreas-after-kidney transplant recipients than in a matched cohort who had a kidney transplant and were on the waiting list for a pancreas (27). Some of the factors identified that increased mortality in pancreas-after-kidney recipients were increased recipient age and use of either PVD

Larsen Pancreas Transplantation Endocrine Reviews, December 2004, 25(6):919 946 927 or ED without-roux-en Y. Outcomes were not different in small vs. large transplant centers; therefore, less experienced programs were not overrepresented (27). Pancreas transplant alone was also reported to cause greater patient mortality than that observed in a matched cohort waiting for this procedure (27). There are limitations of this comparison because some individuals who are placed on the list may later, particularly in the case of pancreas transplant alone, change their minds and decide they feel well enough to forego transplantation. Mortality may not be the only variable worth considering in this particular group. Some patients have such severe, frequent hypoglycemia that they can no longer hold employment, drive, or leave their home unaccompanied because of the risk of unconsciousness or requiring third-party assistance to treat their hypoglycemic events. The social impact of these hypoglycemic episodes, including effects on short-term memory and other cognitive functions, may warrant the potential increased risk of mortality, especially when the reported overall mortality rate, even if higher than without transplant, is still quite low (1 2% at 1 yr) (2, 17). In summary, patient survival after simultaneous pancreaskidney transplant is consistently better than that observed after cadaveric-donor kidney transplant, with the possible exception of recipients over age 50. Although this advantage may, in part, be due to improved glucose after pancreaskidney transplant compared with kidney transplant alone, differences between the recipients who undergo these procedures, and between the donor grafts used for these two procedures, likely also contribute to the difference in survival described between these two procedures. Mortality after simultaneous pancreas-kidney transplant is equal to livingdonor kidney transplant alone after 10 yr, and both pancreasafter-kidney and pancreas transplant alone may increase 4-yr mortality compared with remaining on the waiting list for those procedures. In these cases, specific quality of life (QOL) concerns and impact of pancreas transplant on specific diabetic complications need to be weighed against potential early increase in mortality before these procedures are considered. VI. Consequences of Pancreas Transplantation on the Management of Diabetes A. Islet cell function of the pancreas graft 1. Glucose and glucose homeostasis. Glucose concentration and A1C normalize in most recipients immediately after successful pancreas transplant (49 51, 80, 81). Delayed onset of normoglycemia can occur with transplant of a small pancreas into a large adult, injury to the graft at the time of the donor s death or during transport, arterial or venous thrombosis of the graft, pancreatitis from any cause, or acute rejection. Transient hyperglycemia can occur within the first 6 months with acute or chronic rejection, pancreatitis, or marked increase in insulin resistance with weight gain, or immunosuppressant medication effects. If hyperglycemia persists, an evaluation for a specific cause should be undertaken. 2. Insulin, C peptide, proinsulin, and glucagon secretion. Many studies have evaluated insulin secretion and acute insulin responses after pancreas transplant. It is important to note that absolute insulin concentrations may not be comparable from study to study because there is no common standard for insulin assays, the cross-reactivity of the antibodies used is often not stated, and differences in renal function can alter C peptide clearance, in particular. Antiinsulin antibodies can persist after transplant and can increase total insulin concentrations as well (82). Only studies in whole-organ pancreas transplant recipients will be reviewed. Fasting insulin concentrations are two to three times greater than normal after pancreas transplant performed with SVD, but decrease over the first 12 24 months with decreasing immunosuppressant doses. Glucose- and arginine-stimulated insulin concentrations are also increased, but these peak, stimulated concentrations do not decrease considerably over time (49 51, 61, 80, 81, 83). Two groups most clearly demonstrated that the hyperinsulinemia with SVD results from a delay in first-pass hepatic extraction (50, 80). In contrast, only mild elevations in insulin concentration are observed with PVD, similar to nondiabetic kidney transplant patients treated with corticosteroids (52, 53). Could prolonged hyperinsulinemia due to SVD cause insulin resistance? Using a rat model of pancreas transplant that does not require immunosuppression, euglycemichyperinsulinemic clamp studies were performed, after streptozotocin-induced diabetes, to determine differences between PVD and SVD. Glucose utilization and hepatic glucose production were the same between the two procedures; therefore, hyperinsulinemia does not appear to cause insulin resistance in this setting (84). Insulin is normally secreted in patterns of both lowfrequency ultradian and high-frequency oscillations. Denervation of the pancreas graft did not affect the presence of low-frequency ultradian oscillations of insulin secretion, which were also stable over time (6 months and 2 yr), and similar to kidney transplant recipients (85). However, another group suggested that although frequency was unchanged, pulsation amplitude was increased compared with controls (86). This group also described no changes in frequency or amplitude of high-frequency pulsations, whereas another group reported both a greater frequency and amplitude of high-frequency pulsations after pancreas transplant compared with kidney transplant recipients (86, 87). The -cells of a healthy pancreas graft display both normal first- and second-phase insulin secretion in response to iv glucose (50, 80, 88 90). Blunting of first-phase insulin secretion suggests impending graft failure as it is only observed after whole-organ pancreas transplantation with damage to the pancreas graft or with increased secretory demand, as with obesity, worsened insulin resistance, or high concentrations of immunosuppressant therapy (91, 92). Although fasting C peptide concentrations are generally elevated, they are similar to those in nondiabetic kidney transplant recipients regardless of the venous drainage technique (80, 81, 93). C peptide concentrations after a mixed meal challenge have been reported to be greater than (93), less than (80), and the same as (81) those of kidney transplant recipients, so they may depend on the relative insulin resistance and/or renal insufficiency of both the pancreas and the kidney transplant controls being studied.