This Article Abstract Full Text (PDF) A correction has been published Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Larsen, J. L. Search for Related Content PubMed PubMed Citation Articles by Larsen, J. L.

Pancreas Transplantation: Indications and Consequences

Section of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198-3020

Correspondence: Address all correspondence and requests for reprints to: Jennifer L. Larsen, M.D., Department of Internal Medicine, 983020 Nebraska Medical Center, Omaha, Nebraska 69198-3020. E-mail: jlarsen{at}unmc.edu

	Abstract

Top Abstract I. Introduction II. The Pancreas Transplant... III. Indications for and... IV. Surgical Procedure... V. Effect of Pancreas... VI. Consequences of Pancreas... VII. Clinical Management Issues... VIII. Summary References

 
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.

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

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

Top Abstract I. Introduction II. The Pancreas Transplant... III. Indications for and... IV. Surgical Procedure... V. Effect of Pancreas... VI. Consequences of Pancreas... VII. Clinical Management Issues... VIII. Summary References

View larger version (25K): [in this window] [in a new window]   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.

Kidney transplant markedly improves patient survival in the diabetic ESRD patient compared with dialysis, especially when performed early (4, 5, 6, 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) pancreas-after-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 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.

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/m² (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

Top Abstract I. Introduction II. The Pancreas Transplant... III. Indications for and... IV. Surgical Procedure... V. Effect of Pancreas... VI. Consequences of Pancreas... VII. Clinical Management Issues... VIII. Summary References

 
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).

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, 19, 20, 21, 22, 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.

	III. Indications for and Types of Pancreas Transplantation

Top Abstract I. Introduction II. The Pancreas Transplant... III. Indications for and... IV. Surgical Procedure... V. Effect of Pancreas... VI. Consequences of Pancreas... VII. Clinical Management Issues... VIII. Summary References

 
A. Simultaneous pancreas-kidney transplantation
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 pancreas-kidney transplant has been performed as described above, but has the disadvantage of lower islet mass and greater risk to the living donor (13, 14).

View larger version (23K): [in this window] [in a new window]   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 ).]

View larger version (32K): [in this window] [in a new window]   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-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 ).]

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-after-kidney 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 pancreas-after-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).

	IV. Surgical Procedure Variations, Immunosuppression, and Immediate Complications

Top Abstract I. Introduction II. The Pancreas Transplant... III. Indications for and... IV. Surgical Procedure... V. Effect of Pancreas... VI. Consequences of Pancreas... VII. Clinical Management Issues... VIII. Summary References

 
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).

View larger version (80K): [in this window] [in a new window]   FIG. 4. Pancreas transplantation with BD of exocrine secretions and SVD.

View larger version (104K): [in this window] [in a new window]   FIG. 5. Pancreas transplantation with ED of exocrine secretions and PVD.

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, 50, 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 very-low-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 pancreas-kidney 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 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 cell-depleting 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

Top Abstract I. Introduction II. The Pancreas Transplant... III. Indications for and... IV. Surgical Procedure... V. Effect of Pancreas... VI. Consequences of Pancreas... VII. Clinical Management Issues... VIII. Summary References

 
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, 71, 72, 73). Age can affect outcome, as recipients over age 40 have lower patient survival after simultaneous pancreas-kidney or pancreas-after-kidney 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 pancreas-kidney 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 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 pancreas-kidney 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 pancreas-kidney 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 living-donor kidney transplant alone after 10 yr, and both pancreas-after-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

Top Abstract I. Introduction II. The Pancreas Transplant... III. Indications for and... IV. Surgical Procedure... V. Effect of Pancreas... VI. Consequences of Pancreas... VII. Clinical Management Issues... VIII. Summary References

 
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, 50, 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, 50, 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, euglycemic-hyperinsulinemic 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 low-frequency 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 ß-cells of a healthy pancreas graft display both normal first- and second-phase insulin secretion in response to iv glucose (50, 80, 88, 89, 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.

Increased proinsulin secretion relative to insulin or C peptide can be an early marker of ß-cell injury or failure. Several (83, 94, 95, 96), although not all (80, 90), investigators reported that proinsulin was increased after pancreas transplant. However, fasting insulin and proinsulin concentrations and proinsulin/insulin ratio fall over the first 24 months after transplant, with no evidence of deterioration of glucose control (83). Proinsulin to insulin and proinsulin to C peptide ratios are also similar to those reported in kidney transplant recipients (94, 95). Thus, the elevation in proinsulin after pancreas transplant most likely reflects mild insulin resistance and decreased renal clearance rather than deteriorating pancreatic graft function.

Glucagon secretion immediately after transplant reflects both graft and native pancreas function. Fasting glucagon concentrations the first month after pancreas transplant can be three to four times normal, but decrease over the first 24 months after transplant, to slightly increased concentrations, similar to those of kidney transplant recipients who are given similar immunosuppression (81, 83, 97, 98, 99). Oral glucose suppresses glucagon secretion in pancreas transplant recipients more than controls, but is similar to that of nondiabetic kidney transplant recipients (81, 99, 100). Most importantly, glucagon secretion in response to hypoglycemia recovers after transplant, returning to normal in some studies (101), or less than normal, but improved in others, compared with type 1 diabetic controls (90, 97).

Several tests can serve as markers of those at risk for graft failure from whatever cause. In one study, an oral glucose tolerance test, performed on average 1.7 yr after simultaneous pancreas-kidney transplant that showed impaired glucose tolerance (using World Health Organization criteria), predicted risk of graft failure within 10 yr (102). Cytomegalovirus (CMV) infection also predicted greater risk of graft failure (P < 0.05). Mean 24-h glucose greater than 127 mg/dl at 1 yr was better than any other measure evaluated after transplant to predict those at high risk (93%) for pancreas graft failure within 4 yr (103).

In summary, glucose normalizes immediately after pancreas transplant, at the expense of hyperinsulinemia if SVD is used. Insulin secretion demonstrates oscillations despite denervation, as well as normal first- and second-phase secretion responses, unless there is a decrease in graft function or increased insulin resistance. C peptide concentrations are often slightly elevated, both basally and after mixed meal stimulus, but similar to those of nondiabetic kidney transplant recipients. Although fasting proinsulin is increased, it does not necessarily represent failing graft function, and glucagon response to hypoglycemia improves over time.

B. Hypoglycemia and counterregulatory hormone response
Many patients with longstanding diabetes have a history of severe hypoglycemic episodes before transplant. These episodes result, initially, from a decreased to absent glucagon response to hypoglycemia followed by a diminished epinephrine response to hypoglycemia over time. Glucose recovery in response to insulin-induced hypoglycemia is markedly improved after pancreas transplant compared with nontransplanted diabetic controls (97, 104). By 3 months after pancreas transplant, glucagon secretion and hepatic glucose production in response to hypoglycemia also return to normal (101, 104). Although epinephrine and GH responses to hypoglycemia improve after pancreas transplant, these do not return to normal (104, 105). Most importantly, hypoglycemia symptom score also returns to normal after pancreas transplant (105).

Episodic hypoglycemia was reported in a minority of recipients in the early months after pancreas transplant (82, 106, 107, 108, 109). In one study, seven of 12 individuals with repeated, documented hypoglycemic episodes had a hyperglycemic response to Sustacal followed by hypoglycemia in two, positive antiinsulin antibodies, and low free to total insulin concentrations, suggesting the possible role of antiinsulin antibodies in their hypoglycemia (82). In another study, only one of 10 reported to have symptomatic hypoglycemia episodes was found to have antiinsulin antibodies, but also had documented hypoglycemia after a mixed meal, 4 or more years after transplant (109). Glucose concentration after a 24-h fast was lower in the symptomatic group compared with those without symptoms of hypoglycemia, but the cause of the hypoglycemic symptoms was not established in another series (108). A recent case of hypoglycemia after pancreas transplant was reported to have nesidiodysplasia, another potential cause of hypoglycemia (110). Gastroparesis, the acute effects of corticosteroids on insulin secretion in the early posttransplant period, and improving counterregulation with improved recognition of hypoglycemic symptoms have also been proposed as contributing factors to the hypoglycemic symptoms reported in some patients after pancreas transplant. Symptoms generally diminish over time in most.

In summary, glucagon and symptom response to hypoglycemia return to normal or near normal over time, and epinephrine and GH responses improve but are not normal after pancreas transplant. Hypoglycemic symptoms and documented events are uncommon and tend to diminish over time but may be due to a variety of factors. It should be cautioned that glucagon secretion in response to hypoglycemia does not improve with either allo- or autotransplantation of islets into the liver, in human or animal studies, as described with pancreas transplant, and may be related to their location in the liver (111, 112). Thus, islet transplantation, commonly performed for treatment of hypoglycemia, may not be as effective a treatment for this indication.

C. Diabetic nephropathy
Risk of microvascular complications of diabetes is linked to glucose concentration (113). Thus, normalizing glucose after successful pancreas transplant might be expected to stabilize or reverse microvascular complications. Recurrent diabetic nephropathy is observed as early as 2 yr after kidney transplant in a diabetic recipient or upon failure of the pancreas graft after simultaneous pancreas-kidney transplant (114, 115, 116). Diabetic nephropathy has never been reported in a kidney graft when the graft is accompanied by a functioning pancreas graft. In fact, histological evidence of diabetic nephropathy in native kidneys can resolve between 5 and 10 yr after successful pancreas transplant in type 1 diabetes recipients as documented by prospective renal biopsies (38, 117). In summary, diabetic nephropathy can be prevented by a functioning pancreas graft, and pathological changes of diabetes can reverse over time after more than 5 yr of normal pancreas function.

D. Diabetic retinopathy
Most pancreas transplant candidates have had laser surgery for retinopathy before transplant (118, 119). This damage cannot be reversed. In fact, some patients experience short-term worsening of retinopathy immediately after transplant much like that described after sudden "tight" glucose control (120, 121, 122, 123). Some small and early studies did not show significant improvements in retinal complications after simultaneous pancreas-kidney transplant compared with pancreas transplant recipients who had lost graft function, type 1 diabetes controls, or kidney transplant alone (118, 124, 125, 127, 128, 130). Longer term studies that followed simultaneous pancreas-kidney transplant for 3 or more years demonstrated more consistent improvements including less progression of established neuropathy, fewer new vitreous hemorrhages, improved visual acuity, and less need for further laser surgeries compared with kidney transplant alone (118, 119, 120, 129, 130). In one study, 89% of those with unstable retinopathy were stable at follow-up with mean time since transplant of 5 yr, and all those with stable diabetic retinopathy were still stable (131).

One exception was a study of 20 simultaneous pancreas-kidney transplant recipients compared with 12 kidney transplants or simultaneous pancreas-kidney transplant recipients who had lost pancreas graft function. A number of the eyes, 48% of both groups, were excluded from analysis at the outset because of end-stage eye disease. Mean A1C of the pancreas transplant group was 6.2–6.5%, higher than most successful pancreas transplant patients, which usually have an A1C of 5%; therefore, many recipients were not always normoglycemic. Mean time of follow-up was not stated but was implied to be more than 3 yr. Blood pressure control and rate of smoking were also not stated. Neither the pancreas- or kidney-transplant group experienced many improvements in eye pathology or events, and there was no difference between the groups over time (132). Thus, patients with advanced retinopathy may or may not benefit from pancreas transplant, and normoglycemia is likely required for a benefit to be observed. The only report of changes in diabetic retinopathy after solitary pancreas transplant suggested early improvements observable within 6 months although there was no control group and only a small number of patients were studied (133).

However, cataracts can worsen after pancreas transplant and may be the most common long-term eye disease identified after transplant (128). From 40–55% of pancreas transplant recipients have been reported to require cataract surgery within 5 or more years, although many cataracts began before transplant (131, 134, 135).

In summary, diabetic retinopathy may worsen initially after pancreas transplantation with sudden improvement in glucose concentration; therefore, evaluation and treatment of preexisting retinopathy is important when pancreas transplant surgery is being considered. After 3 or more years of pancreas graft function, less retinal surgery is required after simultaneous pancreas-kidney transplant compared with kidney transplant alone in patients who do not already have end-stage eye disease. Lifelong eye surveillance examinations are required in all pancreas transplant recipients as laser surgery may still be required, particularly early after transplant surgery. Also, screening eye exams are needed to evaluate cataracts that can form or progress, particularly in any patient treated with corticosteroids.

E. Diabetic neuropathies
Both diabetes and renal failure can cause sensory neuropathy; therefore, peripheral sensory and motor neuropathy is present in the vast majority of individuals with diabetic ESRD. Symptoms of neuropathy were found in 86% and abnormal neurological exam in 94% of simultaneous pancreas-kidney transplant candidates in one large study (136). Peripheral sensory neuropathy improves after both simultaneous pancreas-kidney transplant and kidney transplant alone, but recipients of simultaneous pancreas-kidney transplant have even greater improvements compared with kidney transplant alone by 4–8 yr after transplant (70, 137, 138, 139, 140, 141). In fact, continued improvement in sensory and motor neuropathies can be observed as late as 10 yr after transplant (140). Equal improvements in sensory and motor neuropathy can occur after all three pancreas transplant procedures, suggesting that glucose concentration is the most important variable by which to observe these improvements (140). However, if the pancreas fails, nerve conduction velocity can worsen again to pretransplant levels within 2 yr (141). Those treated with nifedipine or angiotensin-converting enzyme (ACE) inhibitors were observed to have greater improvement, and those with prolonged uremia before transplant, obesity, or impaired renal graft function after transplant had less improvement overall (142). Weakness, due to a variety of factors including the effects of immunosuppression, prolonged hospitalization, and infection can worsen in the first year even with improved nerve conduction velocities, so does not always reflect neuropathy (143).

Diabetic autonomic neuropathies take longer to develop, are more variable from person to person, and can be much more difficult to quantitate. Reported prevalence of autonomic neuropathy at time of pancreas transplant varies from 76–100% depending on the population being studied (simultaneous pancreas-kidney vs. pancreas transplant-alone candidates) as well as what testing is performed (77, 144). Having autonomic neuropathy already marks an individual at higher risk for mortality as discussed above (74, 76, 77). Autonomic neuropathies can also complicate posttransplant care. For example, gastroparesis can change the timing of drug absorption so that assumptions about optimal dosing or timing of immunosuppression medication concentrations may not be correct. Cyclosporine, in particular, can slow gastric emptying even in nondiabetic renal failure patients so it may not be an ideal choice for the patient diagnosed with prolonged gastric emptying times (145). MMF can cause diarrhea, including an enterocolitis-associated diarrhea, so it may not be the drug of choice in individuals with preexisting diabetic diarrhea or other autoimmune diarrhea such as sprue or inflammatory bowel disease (146).

Whether or how much pancreas transplant alters the course of autonomic neuropathies is still controversial. Improvements are more modest, if present at all, or may not be observed in all individuals in the same study. These differences between studies and between individuals within a given study may reflect the severity of dysfunction at time of transplant, as suggested by the far greater cardiac autonomic neuropathy of pancreas-kidney recipients at the outset compared with nondiabetic kidney recipients in one report. Thus, although both groups improved, the rate of change or final function achieved over time could not reasonably be compared (147). However, the differences between studies may also reflect the amount of time needed to observe changes because these types of neuropathies often take a long time to develop. In support of this last possibility, peripheral neuropathy scores clearly improved within 12–24 months after pancreas transplant, but only mild improvements in autonomic neuropathy scores were observed after 42 months, and these changes were not significantly different (137). Additional variables may alter the results of testing used to define these neuropathies, independent of the impact of changes in glucose concentration. This is particularly true of gastric emptying studies in which recent immobilization and pharmacological agents, including narcotics, cannibinoids, clonidine, and immunosuppressant medications, can affect gastric emptying times (145, 148, 149, 150).

Patients with prolonged diabetes often manifest hypoglycemia unawareness with decreased symptoms and epinephrine output in response to hypoglycemia. These are both considered forms of autonomic neuropathy. After pancreas transplant, symptomatic response to hypoglycemia is normalized. Epinephrine response to hypoglycemia is also improved but does not return to normal (104, 105).

Heart rate variation, gastric emptying time, and skin temperature regulation have all been reported to improve after simultaneous pancreas-kidney transplant (70, 120, 138, 151). In some cases, new methods of measuring change had to be developed and validated to evaluate these responses (152). Symptoms sometimes improve independently of documented objective changes, but whether these reflect changes that current methods are not yet sensitive enough to identify is unknown (151). Improvements do not occur in all recipients, or in all studies (140, 151). For example, cardiorespiratory responses did not improve in any recipient 2–4 yr after pancreas transplant (153), and heart rate variation, one method of quantifying cardiac autonomic neuropathy, showed no improvement by 25 months after transplant or between serial examinations at 20 and 43 months after transplant in another (154). However, improvements in autonomic neuropathies may require more time. For example, R-R interval variation was not changed after 2 yr (138), whereas after 10 yr the same investigators described greater improvements after simultaneous pancreas-kidney transplant than kidney transplant alone (70).

In summary, improvements in sensory and motor neuropathy occur after both simultaneous pancreas-kidney and kidney transplant alone. However, greater improvements have been reported after simultaneous pancreas-kidney transplant with ongoing improvements up to 10 yr after transplant. Autonomic neuropathies may take longer to improve, 10 yr or more, and may be only partially reversible or not reversible at all in some cases. Yet some autonomic neuropathy parameters are improved in some studies, particularly hypoglycemia awareness, autonomic response to hypoglycemia, and cardiac autonomic neuropathies.

F. Microangiopathy
Microangiopathy represents the effects of long-term diabetes (and hyperglycemia) on vascular endothelium, as well as neurovascular response, with implications for healing response. Simultaneous pancreas-kidney transplant improves fluorescein escape rate in the nailfold capillary microcirculation, conjunctival microcirculation as assessed by intravital microscopy, vascular reactivity after suprasystolic occlusion, and microcirculation as assessed by laser Doppler and videophotometric capillaroscopy, with responses greater than after kidney transplant alone when such a comparison was made (155, 156, 157). However, at least one group did not find any difference in a cross-sectional study between pre- and post-simultaneous pancreas-kidney transplant recipients (158). As microangiopathy can also be caused by both tacrolimus and cyclosporine (159, 160, 161) and viral infection (162), not all individuals may see benefit after transplant, even with normoglycemia. In summary, improved glucose control, as with simultaneous pancreas-kidney transplant, can improve vascular reactivity and microvascular integrity and responses, but other factors after transplant may prevent or minimize these improvements in some.

G. Macrovascular disease risk factors and events
Immunosuppression agents used in organ transplantation contribute to weight gain, dyslipidemia, increased blood pressure, and insulin resistance after transplant. In fact, each combination of immune suppression agents may have different effects. Thus, normalization of glucose alone may not be enough to assume cardiovascular outcomes improve in this high-risk population if other risk factors worsen. Variable prevalence of genetic, ethnic, or behavioral variables that impact cardiovascular risk, and differences in procedure and immunosuppression protocols used may also contribute to differences reported in cardiovascular risk factors and outcomes between populations and centers. With these possibilities in mind, the data of how each risk factor might be affected by pancreas transplant will be reviewed.

1. Diet and weight.
In the one study of diet before and after pancreas transplant, neither total calories nor distribution of calories between carbohydrates, fats, and protein changed after successful pancreas transplant (163). Most studies report minimal, if any, effects of pancreas transplant on weight, 0–1 kg/yr (163, 164), although greater weight gain can be observed in individuals with preexisting obesity and in centers with greater ethnic diversity where risk of insulin resistance may also be greater (165). Type 2 diabetes patients who receive simultaneous pancreas-kidney transplant have not only a greater body mass index at time of transplant, but are also more likely to experience weight gain after transplant although this has not been well documented (31).

2. Hypertension.
Blood pressure after transplant is affected by a variety of factors. First, the immunosuppressive drugs themselves contribute to hypertension. Cyclosporine and corticosteroids have the greatest negative impact (166, 167, 168). Second, the transplant procedure can affect blood pressure. Blood pressure decreases after simultaneous pancreas-kidney transplant with BD, even with cyclosporine- and corticosteroid-based immunosuppression, in part, because of the salt and water loss that accompanies BD of the exocrine duct (66, 163, 169). In fact, after pancreas transplant with ED, blood pressure may not improve at all (170). Blood pressure can increase after pancreas transplant alone, even with BD, in a study using cyclosporine-based immunosuppression and in which renal insufficiency resulted (171). However, in another study of solitary pancreas transplant in which PVD and tacrolimus-based immunosuppression were used, renal function was unchanged, and blood pressure was improved (172). Thus, potential variables that impact direction of blood pressure change after pancreas transplant could include the procedure (simultaneous pancreas-kidney transplant vs. pancreas transplant alone), exocrine duct management (BD vs. ED), renal function or renovascular complications of the surgery, and choice of immunosuppression medications. Finally, differences in blood pressure can be "iatrogenic" if medications are changed or terminated, and blood pressure goals are not monitored.

3. Lipids and lipoproteins.
Multiple variables can also impact lipid concentrations before and after pancreas transplant. Most of the commonly used immunosuppressant medications, cyclosporine, tacrolimus, sirolimus, and corticosteroids, have adverse effects on lipid profile in many patients, particularly those predisposed to dyslipidemia. The two agents with the least impact on lipid metabolism are MMF and azathioprine. Many centers are using more sirolimus (rapamycin) in combination with calcineurin inhibitors without corticosteroids. However, sirolimus itself, or in combination with a calcineurin inhibitor or steroids, may be associated with greater dyslipidemia than other choices (173, 174, 175, 176, 177). Diabetic patients may even be more susceptible to sirolimus-associated dyslipidemia (177).

Simultaneous pancreas-kidney transplant, which restores insulin secretion and improves renal function, does improve lipid profile. In general, most studies observed lower fasting triglycerides, increased high-density lipoprotein (HDL), increased low-density lipoprotein (LDL) particle size, increased lipoprotein lipase activity, and improved postprandial lipemia compared with kidney transplant alone (62, 165, 178, 179, 180, 181, 182). One study reported no improvement in elevated triglycerides after pancreas transplant performed with SVD, but considerable weight gain was also reported at this center after transplant, which might explain these differences (60).

Lipoprotein composition may not be normal even if fasting lipids improve and may differ between those receiving pancreas transplant performed with PVD vs. SVD. As described previously, SVD causes systemic hyperinsulinemia, which can increase CET activity in other settings. In pancreas transplant recipients, increased CET activity increases unesterified cholesterol in the lipoprotein surface composition of HDL2, HDL3, and LDL, that is not observed with PVD (53, 60, 62, 165). Although greater improvements in LDL and VLDL subcomponents are reported after PVD, compared with SVD, the groups were not completely matched for other potential variables that could affect lipoprotein profile, including immunosuppressant doses and serum creatinine (60).

In contrast to simultaneous pancreas-kidney transplant, solitary pancreas transplant may not always improve fasting lipids. Triglycerides were higher 1 yr after pancreas transplant alone in one study using predominantly cyclosporine-based immunosuppression and SVD, which correlated with both immunosuppression dose and a decrease in renal function after transplant (171). However, in a more recent study using tacrolimus-MMF-based immunosuppression and PVD, LDL-cholesterol improved, and triglycerides were unchanged. Most importantly, serum creatinine did not increase significantly in this study after transplant (172).

Genetic differences may also contribute to differing susceptibility to dyslipidemia both before and after pancreas transplant. Insulin resistance and associated dyslipidemia may be greater in the individual with a family history of diabetes who is treated with corticosteroids. Apolipoprotein E (ApoE) gene polymorphism is another genetic cause of dyslipidemia as ApoE is important for clearance of VLDL remnants by the liver. ApoE gene polymorphism increases risk of diabetic nephropathy in some, but not all, studies; therefore, this genetic polymorphism may be more common in the pancreas transplant candidate population (183). In fact, presence of ApoE4 allele was associated with higher triglycerides and lower HDL before pancreas transplant, compared with those with a normal ApoE genotype (E3/E3). ApoE2 allele had no impact on lipids before transplant, and neither abnormal ApoE allele affected lipid profile after simultaneous pancreas-kidney transplant, when lipids improved in general (184).

4. Macrovascular disease and events.
The most common cause of death in diabetes and transplant patients is vascular disease. As described above, individual vascular risk factors may increase or decrease depending on genetic predisposition, differences in behaviors (e.g., weight gain or persistent smoking), specific immunosuppressants used, type of procedure performed, and pancreas graft and renal function after transplant. Thus, because macrovascular disease increases with age alone, it can still progress after pancreas transplant even with reported improvements in lipids, blood pressure, and glucose. The rate of progression will depend, in part, on presence of ongoing risk factors and may depend on severity of previous disease as well. The factors that best predict rate of progression include preexisting vascular disease, older age, ongoing smoking, hyperphosphatemia, hypoalbuminemia, and longer duration of pretransplant dialysis (164). Although the focus of changes in macrovascular disease and events after pancreas transplant often concentrates on cardiovascular events, amputation remains an ongoing concern and significant cause of morbidity after transplantation and is another reflection of macrovascular disease. Preexisting vascular disease and greater duration of pretransplant dialysis are also risk factors for these macrovascular events as well (185).

Carotid intima media thickness correlates with future vascular disease risk and is greater in pancreas transplant candidates compared with age-matched normals or type 1 diabetes patients without renal failure (23). Carotid intima media thickness improved by 2 yr after simultaneous pancreas-kidney transplant, independent of significant changes in lipids, blood pressure, or use of hypolipidemic agents in this cohort (44, 64). Simultaneous pancreas-kidney transplant also reduced the progression of coronary artery disease as determined by mean segment diameter loss on coronary angiography compared with those whose graft had failed (65).

Left ventricular ejection fraction, peak filling rate to peak ejection rate ratio, and endothelial-dependent dilation of the brachial artery also improved after simultaneous pancreas-kidney transplant recipients compared with type 1 diabetes patients who received kidney transplant alone (186, 187). Diastolic dysfunction normalized by 4 yr in simultaneous pancreas-kidney transplant recipients but not kidney transplant-alone recipients (72). Fewer cardiovascular events, specifically acute myocardial infarction and acute pulmonary edema, are reported to occur after simultaneous pancreas-kidney transplant compared with type 1 diabetes recipients receiving kidney transplant alone (71). Although these studies report considerable benefits, the two groups being compared, cadaveric kidney transplant recipients and simultaneous pancreas-kidney transplant recipients, likely started with different cardiovascular risk even before transplant, which was not compared in these studies but has been reported in others (73, 78). Unfortunately, no studies have compared these same parameters between living-donor kidney and simultaneous pancreas-kidney transplant recipients to determine whether or not they start with or experience the same improvements in these cardiovascular parameters as they have similar patient survival.

There was initial concern that peripheral vascular disease was increased after pancreas transplant, compared with kidney transplant alone (188, 189). However, others have shown that pancreas transplant neither worsened nor improved peripheral vascular disease events or progression, although amputations are often the endpoint used to assess changes in peripheral vascular disease (190, 191). It should be noted that amputation can result from peripheral vascular disease but also from an injury or infection resulting from preexisting neuropathy and/or immunosuppression. In fact, foot infections are reported to be the second most common cause of infection after pancreas transplant, after CMV (192). Thus, amputations may continue for years after pancreas transplant, even with excellent glucose control and even if peripheral vascular disease improves. Risk of amputation is greatest in those with longer duration of pretransplant dialysis and history of amputation before transplant (185). Overall, these studies do not resolve the question of whether peripheral vascular disease is better or worse after pancreas transplantation.

Few studies have been performed in solitary-pancreas transplant or pancreas-after-kidney transplant recipients to determine whether changes in macrovascular disease will be the same. Cardiac ultrasound after solitary pancreas transplant showed improved systolic and diastolic function parameters by 6 months compared with pretransplant measurements in patients with demonstrated improved blood pressure (172). However, if blood pressure and lipids increase and renal function decreases, as reported in some pancreas-alone recipients, the results may not be the same.

In summary, the type of pancreas transplant procedure; changes in renal function; genetic predisposition to hypertension, dyslipidemia, or insulin resistance; the types of immunosuppressants used and their relative dose; changes in behavior as with weight gain or smoking cessation; and even donor and graft variables that contribute to delayed or decreased renal function, or frequency of rejection that increases the need for immune suppression may all impact risk over time. However, the results to date suggest that macrovascular disease improves in most patients after simultaneous pancreas-kidney transplant, but inadequate data are available to comment on change in risk after pancreas transplant alone or pancreas-after-kidney transplant.

H. QOL
Early QOL surveys show that successful pancreas transplant recipients experience improvements in QOL in all categories compared with kidney transplant alone (193, 194, 195, 196). More recent studies show that changes in QOL may also depend on what the desired goal is. For example, QOL improves after both simultaneous pancreas-kidney and kidney transplant alone when the recipient received the procedure they were expecting. Individuals who received a combined pancreas-kidney transplant but experienced pancreas graft failure were far less positive about a change in QOL even if the kidney graft still functioned, because of the disparity from expectation (197). This was confirmed in another study in which individuals who experienced failure of either organ reported more fatigue and lower functioning than either simultaneous pancreas-kidney or kidney transplant-alone groups where they felt they were offered and chose the transplant operation they received (198). Such a disparity in expectations might also occur when an individual strongly desired a pancreas-kidney transplant, but was listed for a kidney transplant alone because of the transplant team’s concerns that the individual could not withstand the more complex procedure; was offered and strongly encouraged to take a living-kidney transplant because it was available; or received only a cadaveric kidney transplant after being listed for pancreas-kidney in a circumstance where a good match was available but the pancreas from the same person was not usable after it was harvested.

Recent studies compared matched recipients receiving kidney transplant alone and separated diabetes QOL from overall QOL. Simultaneous pancreas-kidney transplant recipients had more days in the hospital and in the intensive care unit, and more readmissions to the hospital in the first 3 months compared with kidney transplant-alone recipients. In this small study, there was a trend toward fewer cardiac and peripheral vascular disease events with pancreas-kidney transplant, but these differences were not significant. As a result, overall QOL was not different, although diabetes-related QOL was significantly improved (199). Another study showed improvements in physical health in both simultaneous pancreas-kidney transplant and kidney transplant-alone recipients, but greater improvements in diabetes-related disease parameters after simultaneous pancreas-kidney transplant than kidney transplant alone. However, the kidney transplant-alone recipients demonstrated a greater improvement in the emotional-mental health subscore than simultaneous pancreas-kidney transplant recipients that was not easily explained (200).

In summary, diabetes-related QOL is clearly improved by the addition of a pancreas to kidney transplant. However, overall QOL depends on the specific expectation of the patient for a specific transplant operation and whether or not it was achieved as well as on postsurgical morbidity experienced, which is often greater in pancreas-kidney transplant recipients.

	VII. Clinical Management Issues for the Pancreas Transplant Patient

Top Abstract I. Introduction II. The Pancreas Transplant... III. Indications for and... IV. Surgical Procedure... V. Effect of Pancreas... VI. Consequences of Pancreas... VII. Clinical Management Issues... VIII. Summary References

 
A. Diabetic complication surveillance including vascular disease risk management
1. Assessment of hyperglycemia after pancreas transplant.
Glucose control often worsens after kidney transplant alone in type 1 diabetic patients. However, successful pancreas transplant usually results in a normal glucose without additional insulin therapy by the time the operation is completed. A1C is usually normal by 1 month after transplant unless rejection has occurred (51). Intermittent or temporary elevations in glucose can accompany high doses of immunosuppression agents, particularly with acute rejection. Once euglycemia has been achieved after pancreas transplant, the recurrence of chronic hyperglycemia requiring insulin therapy usually suggests one of the following: 1) graft failure due to acute or chronic rejection, pancreatitis, or thrombosis; 2) insulin resistance with new-onset type 2 diabetes; 3) immunosuppressant-induced islet cell toxicity; 4) immune-mediated islet cell destruction as with recurrent type 1 diabetes; or 5) a combination of the above. Most late hyperglycemia is attributed to chronic rejection, which, after technical failure, is the second most common cause of hyperglycemia (201). Resolution of diabetic complications has been tied to establishing normoglycemia, and treatment may be needed to prevent progression of diabetic complications, but the treatment may vary depending on the cause.

Fasting glucose and A1C should be a minimal screen for evidence of glucose intolerance at all clinic visits. If A1C is elevated or fasting glucose exceeds 100 mg/dl [based on the most recent guidelines for impaired fasting glucose (202)], unassociated with a recent rejection episode, an oral glucose tolerance test with insulin concentrations should be performed to evaluate for graft failure or new-onset type 2 diabetes.

New-onset type 2 diabetes usually represents a genetic predisposition to insulin resistance aggravated by immune suppressant medications, significant weight gain, or both. Islet function is still intact as insulin and C peptide concentrations are elevated. The prevalence of type 2 diabetes as a cause of hyperglycemia after pancreas transplant is unknown because few centers evaluate insulin or C peptide concentrations with recurrence of hyperglycemia. Posttransplant diabetes from insulin resistance is described in 7–25% of other organ transplant groups (203); therefore, a similar risk is likely to occur after pancreas transplant, as well, particularly with rapid weight gain, coexistent obesity, or family history of diabetes (204). Optimal treatment of type 2 diabetes after pancreas transplant has not been established. Insulin may protect islet function until more specific treatment strategy becomes effective (e.g., antirejection therapy, weight loss, oral hypoglycemic agents, changing dose or type of immunosuppression). Unfortunately, there is a disincentive to begin insulin therapy in many transplant centers because use of insulin is the definition used to denote graft failure. Instead, oral agents are often used alone without consistent follow-up of whether or not the therapy results in good glucose control.

Many of the immune suppressant medications inhibit insulin secretion from a variety of cell lines as well as human islets, including, and particularly, cyclosporine and tacrolimus, but some report that MMF and sirolimus (or rapamycin) can also inhibit insulin secretion as well (205, 206, 207, 208, 209, 210, 211, 212, 213). Corticosteroids cause insulin resistance in all settings, which can result in later decreases in insulin secretion, but have also been shown to directly affect insulin release from islets (213, 214, 215, 216, 217). It has not been well established whether or not the calcineurin inhibitors cause an insulin resistance state, with effects on insulin action, separate from decreased insulin secretion. Calcineurin inhibitors, particularly at high doses, can cause temporary or permanent structural islet changes, including apoptosis, that may impair insulin secretion long-term (68, 69). Rapamycin (or sirolimus) binds to mammalian target of rapamycin, part of the insulin signal transduction cascade, but whether it affects glucose metabolism in people is unknown. Some, but not all, studies have shown that rapamycin inhibits insulin secretion (212, 218, 219), but at the same time, rapamycin has been reported to improve glucose metabolism in animal studies (220, 221). In summary, corticosteroids and the calcineurin inhibitors may contribute to hyperglycemia that is sometimes characterized as "insulin resistance" or "graft failure" after transplant. Whether sirolimus, by itself or in combination with other agents, also contributes to hyperglycemia in this clinical setting still needs to be established.

Finally, even recurrent type 1 diabetes has been raised as a potential cause of hyperglycemia after pancreas transplant. Antiislet and antiglutamic acid decarboxylase (GAD-65) antibodies reappear in patients after pancreas and islet transplantation (108, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233). Higher titers of immune markers also correlate with higher risk of graft failure (228, 234, 235). Although criteria for recurrent type 1 diabetes have not been established, it is currently suspected as an uncommon cause of hyperglycemia after pancreas transplant (237).

2. Diabetic complication surveillance.
Ongoing surveillance for diabetic complications is necessary even after successful pancreas transplant. Lifelong annual surveillance eye exams are recommended, because diabetic retinopathy does not always stabilize immediately, corticosteroids can cause cataracts, opportunistic infections of the eyes are not rare after transplant, and if hyperglycemia recurs, retinopathy can also worsen. The feet, which are often neglected, should still be examined regularly by the patient and the health care team just as before transplant. Neuropathy does not resolve quickly, and peripheral vascular disease may or may not improve. With ongoing neuropathy, and possible concomitant vascular disease, the risk of injury is still increased, and immunosuppressants can delay healing and decrease the response to infection. Good foot practices with daily self-exam, moisturization as indicated, and protective foot wear in those with established neuropathy or peripheral vascular disease should be reinforced at follow-up visits.

3. Macrovascular disease risk management.
Pancreas transplant recipients should be considered at high risk for vascular disease whether or not any previous vascular disease has been identified. A fasting lipid profile should be performed at least annually or with any change in immunosuppressant dosing. Lipid treatment goals are the same as before transplant, and the same as anyone with established vascular disease based on National Cholesterol Education Program-Adult Treatment Panel III guidelines (238). 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors are the first-line agents for treatment of hypercholesterolemia and may have other benefits as these agents can decrease graft loss in other organ transplant groups (239, 240). There are multiple reports of myositis when these agents are used in conjunction with calcineurin inhibitors. However, if the dose is increased gradually, the overall risk is still low. A recent comparison of multiple statins in small, nonrandomized groups of renal transplant patients did not demonstrate a particular difference in toxicity between the agents (241).

Dyslipidemia after transplant is, in part, due to the effects of immune suppressant medications, which differ in their impact on dyslipidemia. Thus, changing drug therapy can ameliorate the severity of dyslipidemia in some cases, such as replacing cyclosporine with tacrolimus (242), withdrawing steroids in patients treated with tacrolimus-MMF (243), using tacrolimus-MMF over tacrolimus-sirolimus (176), or removing sirolimus from a cyclosporine-prednisone-sirolimus regimen (173, 177).

Hypertension management is also important to prevent graft loss and cardiovascular events. Hypertension is commonly aggravated after kidney transplant and may depend on the specific procedure used after pancreas transplant. Increased blood pressure can result from direct effects of immunosuppression, particularly cyclosporine-based regimens, transplant renal artery stenosis, rejection (acute or chronic), high renin release from the diseased kidneys when they have been left in place, weight gain, and recurrence of intrinsic renal disease. Uncontrolled hypertension accelerates both kidney failure and vascular disease. Thus, achieving a blood pressure target is as important after transplant as it was in the diabetic patient before transplant. The presumed blood pressure goal in diabetic patients, even after transplant, should be less than 130/80 mm Hg, although it can be more difficult to achieve, and little data have affirmed whether this is the ideal goal.

Weight control, salt restriction, and exercise should be considered with pharmacological therapy for treatment of hypertension. Smoking cessation is strongly encouraged because it can contribute to hypertension and vascular disease progression in posttransplant patients (164). Patients treated with cyclosporine may benefit by changing to another agent. In the long term, ACE inhibitors or angiotensin receptor blockers are often prescribed because they can decrease future vascular events in both diabetic and nondiabetic patients and have few side effects, and the ACE inhibitors are cost effective (244, 245, 246). However, ACE inhibitors are more likely to cause hyperkalemia when used in conjunction with calcineurin inhibitors, and both ACE inhibitors and angiogensin II receptor blockers are generally avoided during the first months after kidney transplant. Calcium channel blockers are also effective and may protect against the hypertensive effects of the calcineurin inhibitors, but can increase cyclosporine blood levels, which should be monitored.

B. Infection and cancer surveillance
Immunosuppression increases the risk for a number of different kinds of infection, and most, if not all, pancreas and simultaneous pancreas-kidney transplant patients will have some type of infection episode in the first year after transplant (247). The infections can be serious, with deaths from infection greater in simultaneous pancreas-kidney than kidney transplant-alone recipients (248). Infection is the second most common cause of readmission in the first 3 months after pancreas transplant (249) and the most common cause of readmission over the long term (59). Early infections can occur with reactivation of preexisting disease, which can include tuberculosis, subclinical infections, including bladder infections, or infections related to their transplant wound or iv catheters. Frequency of early infections may depend on type of duct drainage procedure used, as bladder infections, CMV, and fungal infections are lower with ED than BD, but time to first infection is the same (250). Viral infections, CMV in particular, are a particular concern in the first 6 months after transplant. CMV can be acquired at any time in the peri- or posttransplant period, and once present, remains throughout life. CMV can cause a variety of symptoms, including unexplained fever, and may predispose to both acute and chronic rejection of the organ as well as other opportunistic infections and possibly vascular disease. Because chemoprophylaxis decreases the rate of acquiring CMV after transplant, it is part of most posttransplant order sets. Later, depending, in part, on doses of immunosuppression required because of frequent rejection or poor graft function, opportunistic infections or chronic viral infections, as well as greater susceptibility to community-acquired infections of all kinds, are more likely.

All pancreas transplant recipients should have received a pneumococcal vaccine, and annual influenza vaccinations are recommended. Hepatitis B vaccination has also been suggested. In the patient with preexisting diabetic neuropathy and peripheral vascular disease, as is present in most transplant recipients, infections of the feet are more likely and with immunosuppression can progress more rapidly from superficial to deep-tissue infections and osteomyelitis. Thus, all infections, even what appear to be superficial, and particularly those located in the feet, should be evaluated rapidly and followed closely until they resolve.

Risk of cancer is also increased with chronic immunosuppression. The two most common reported cancers are skin cancers followed by lymphoproliferative disease, also called posttransplant lymphoproliferative disease (PTLD). The latter represents a spectrum of diseases, but non-Hodgkin’s lymphoma, usually B cell type, is most common. PTLD can present in a single site or in multiple sites including bone marrow, brain, gastrointestinal tract, allograft, or liver. Epstein-Barr virus infection, in particular, increases its incidence. Antiviral prophylaxis, used predominantly for CMV prophylaxis, may also prevent Epstein-Barr virus infection and associated PTLD. Recent studies have suggested a higher incidence of PTLD after simultaneous pancreas-kidney transplant than kidney transplant-alone recipients (251). However, incidence of PTLD reported to UNOS from larger single centers suggests that the incidence of PTLD in pancreas transplant recipients is likely closer to 1–2%, which is comparable to kidney transplant alone (252, 253). Treatment of PTLD usually requires decreasing or stopping immunosuppression therapy. If graft function is lost, retransplantation does not necessarily result in recurrence (254). Other cancers that are more common are those associated with viral infection, including hepatitis B- and C-associated hepatocellular carcinoma, and papillomavirus-associated carcinoma of the cervix, vulva, and perineum. Overall risk of death among all pancreas transplant recipients from either malignancy or PTLD is low (<0.6%) (2).

All transplant candidates should be screened for preexisting malignancies using established recommendations because immunosuppressant medications enhance the growth of any cancers already present. Individuals previously diagnosed with cancer may require 2–5 yr of observation before they should be listed for transplant, even when they are assumed to be cured. Many examples have shown that recurrence of many cancers are far more rapid in the presence of immunosuppression. Any suspected or recurrent malignancy should be reported and biopsied because, too often, cancers are mistaken for other disease. In some cases, immunosuppression will need to be withdrawn until the cancer is successfully treated and may result in graft failure. Other preventive measures include consistent use of sun screens, regular pelvic examinations, and use of barrier contraception for sexually active women.

C. Bone mass screening and osteoporosis treatment
Bone loss and bone fractures are common consequences of solid-organ transplantation. Whereas the effects of corticosteroids are well known, calcineurin inhibitors also have direct effects on bone (255, 256, 257, 258). Factors such as hypogonadism, vitamin D deficiency, adynamic bone disease, previous or ongoing parathyroid disease, previous uncontrolled diabetes, and thyroid function abnormalities may all contribute to pretransplant bone loss. Adynamic bone disease refers to the low-turnover bone disease found commonly in uremia. Fractures after simultaneous pancreas-kidney transplant are common, 45–49% within the first 2 yr (259, 260, 261), which is one of the highest fracture rates reported for any organ transplant recipient group. Retrospective, cross-sectional studies of all kidney transplant recipients suggested the factors that predicted the greatest risk of fracture were increased age, diabetes, which included simultaneous pancreas-kidney transplant recipients, long duration of pretransplant kidney failure, history of pretransplant fracture, and being female (262, 263, 264). Fractures continue to accumulate in some recent long-term organ transplant studies (264, 265), with a cumulative incidence for all kidney transplant recipients of 60% by 15 yr in one study (263). Yet decreased bone density, although common (80% in one study of long-term kidney transplant recipients), may not significantly change over time after the first year post transplant (266).

With the frequency of both decreased bone density and fracture in this setting, bone density should be screened before or immediately after transplant and then annually with dual energy x-ray absorptiometry. Heel ultrasonography, because of convenience, is increasingly used for bone density screening in normal populations, but should not be used in high-risk transplant candidates or patients because it has both a high false-positive and false-negative rate of identification of those at risk (267). Osteomalacia was found in some pancreas transplant recipients with bone biopsy (268), as corticosteroids can decrease vitamin D absorption. Vitamin D (at least 800 IU/d) and calcium (1200–1500 mg/d) should be prescribed, and 25-hydroxyvitamin D concentration should be measured periodically with additional dosing as indicated. Parathyroid disease does not always resolve immediately; therefore, if still present 1 yr after transplant, surgical therapy may be indicated, particularly with osteoporosis.

Resistance training can be effective in some types of transplant recipients to prevent vertebral osteoporosis, but pharmacological intervention is likely to be required in most (269). There is no general agreement about timing (before or immediately after transplant or with evidence of bone loss after transplant), the preferred or most effective agent, or the duration of that intervention. There are no published studies of bone loss prevention in pancreas transplant recipients. In other transplant groups, the studies are conflicting. Calcium and/or vitamin D alone are effective in preventing bone loss and fracture rates in some, but not all, cardiac transplant patients (270, 271), and in one study, were more effective than etidronate (272). Intravenous pamidronate started 6–18 months after transplant significantly increased bone density in a nonrandomized trial (271) but was no different than calcitriol and calcitonin 18 months after cardiac transplant in another (273). One dose of pamidronate before liver transplant was ineffective at preventing bone loss 12 months after transplant (274), whereas two doses of iv pamidronate, at time of transplant and 1 month later, prevented bone loss at 12 months after renal transplant compared with placebo (275). Intravenous pamidronate infusions every 3 months decreased fracture rate after lung transplant (268) but increased bone density with no change in fracture rate in another group of lung transplant patients (277). Oral etidronate or alendronate reduces bone loss and/or parameters of high bone turnover after renal or cardiac transplant (278, 279, 280, 281, 282) but may not result in different outcomes than treatment with calcitriol (266). These observations were reinforced by a prospective randomized study comparing the effects of alendronate (10 mg/d) and calcitriol (5 mg/d) on bone loss and fracture after cardiac transplantation, compared with controls (283). There was no significant difference in bone density or fracture rates of patients treated with these two agents at 1 yr after transplant. However, only alendronate had a significant effect on bone loss at the spine compared with the control group, whereas both agents significantly prevented bone loss in the femoral neck compared with controls. Risk of calciuria was also greater with calcitriol treatment than alendronate (27% vs. 7%).

The first study to evaluate zoledronic acid therapy in transplant patients showed improvement in bone density at 6 months following two doses given at 2 wk and 3 months after kidney transplant, but there was no sustained effect on bone density 3 yr later compared with placebo (284). Calcitonin had no impact on bone histomorphometry after liver transplant in one study (285) or on bone mass and bone fractures after liver transplant for primary biliary cirrhosis in another (286). There are no studies showing efficacy of residronate on fracture rate or bone loss after transplant.

In summary, all pancreas transplant recipients should be screened for osteoporosis, ongoing parathyroid disease, and vitamin D status, and adequate calcium and vitamin D replacement should be prescribed. Most transplant recipients should receive additional therapy, usually oral or iv bisphosphonates, with established low bone mass or fractures. Bisphosphonates may also be beneficial to prevent bone loss after transplant, although this needs to be more clearly established. Because osteoporosis and fractures are so common in this patient population, further studies are needed to determine the best prevention strategies. Whether the current trend of using lower doses of corticosteroids, or in some cases no corticosteroids, for immunosuppression will change the prevalence or severity of metabolic bone disease in the future has yet to be determined. However, metabolic bone disease has already been shown to vary with calcineurin inhibitor dose, and other factors also impact bone turnover in this setting; therefore, use of steroid-free protocols alone is unlikely to prevent bone loss after transplantation.

D. Hypogonadism, fertility, and pregnancy after transplantation
Hypogonadism has been reported in both men and women with ESRD, with frequency reported to be greater with those who are on hemodialysis for a longer time. Etiology is attributed to abnormal hypothalamic-pituitary axis function, in part, because of the hyperprolactinemia that accompanies renal failure (287, 288, 289, 290, 291, 292).

Hypogonadism improves in men after kidney transplant (287, 290, 291, 293). Oligospermia after transplant is uncommon in those treated with cyclosporine or tacrolimus and, when present, generally represents primary seminiferous tubule dysfunction evident before transplant (290). There is less evidence of how or if rapamycin can affect reproductive status after transplant, but there is at least one case of rapamycin causing both decreased sperm number and increased abnormal forms after kidney transplant with a normal rapamycin concentration. The sperm analysis of this patient returned to normal after rapamycin was replaced with tacrolimus (294). Thus, fertility in men generally improves after kidney transplantation. There is only one study that has evaluated hypogonadism before and after pancreas-kidney transplant, and hypogonadism was uncommon in these men both before and after transplant (295).

In women, the results are not as straightforward. Menstrual function generally improves after kidney transplant, although menstrual irregularity often remains (296, 297, 298). Corticosteroids and weight gain can cause features of polycystic ovarian syndrome, in those predisposed, which, in turn, can result in menstrual irregularity and decreased fertility. Cyclosporine, more than tacrolimus, can also cause hypogonadism; therefore, immunosuppression may contribute to the ongoing reproductive abnormalities in some (256). In women, pelvic surgery may compromise ovarian blood supply, resulting in primary hypogonadism after transplant. Stress, including surgeries or infections, can temporarily disrupt the reproductive system in women, in particular. Thus, many causes likely contribute to the ongoing reproductive dysfunction in women after transplant. In the only study evaluating hypogonadism in women before and after pancreas-kidney transplant, half of the women had hypogonadism before transplant, both primary and secondary, but 70% still had abnormal reproductive hormones 1 yr after transplant; these included one new case of primary hypogonadism, thought to be unrelated to surgery, and one case of ovarian hyperstimulation that improved with lowering the cyclosporine dose. Changes in reproductive function were unrelated to changes in prolactin concentration, but hyperprolactinemia was still present at 1 yr after transplant in some patients (295).

The consequences of hypogonadism are potentially greater, because hypogonadism in both men and women has been shown to contribute to the bone loss observed in a variety of transplant patients (258, 268, 270, 299). Because hypogonadism is often unrecognized and untreated (270, 295), symptoms of this disorder should be routinely elicited in men and women after transplant, and reproductive hormones should be measured in anyone with significant bone loss. Women of premenopausal age (before age 50), with a history of ovariectomy or premature ovarian failure, should be considered for hormone replacement therapy after the immediate hospitalization, if there are no contraindications. Gonadal replacement therapy should not be used routinely to treat temporary secondary hypogonadism due to stress, but should be considered for treatment of primary or permanent secondary hypogonadism, in either men or women. The risk of thrombosis accompanying hormone replacement therapy in female transplant recipients has not been established. Usual health care maintenance activities should include monitoring for sex steroid-dependent cancers with mammography, pelvic examination and pap smear in women, and prostate exam and serum prostatic-specific antigen in men after transplant, particularly in those receiving sex hormone replacement therapy.

Despite ongoing reproductive dysfunction, fertility can and does improve in both men and women after transplant. Female recipients, in particular, should be counseled about risks of pregnancy after transplant. Yet, in a recent survey of sexual concerns of transplant patients, the majority (two thirds) received no instruction about sexuality or fertility after transplant (300).

The National Transplant Pregnancy Registry was established to track the outcomes of all reported pregnancies of transplant patients and, more recently, paternity after transplant, as well. A total of 34 women with pancreas-kidney transplants have had 47 pregnancies (Table 4) (301). Based on this data, pregnancy in a female pancreas-transplant recipient should be treated as a "high-risk" pregnancy. Adverse outcomes to the mother and the baby are greater in pancreas-kidney transplant recipients than those reported after kidney transplant alone. Graft failure and infections are the greatest concerns for the mother, whereas abortion, small size and prematurity, and neonatal complications are the greatest concern for the baby, although no significant increase in fetal malformations has been reported to date (Table 4) (301, 302, 303). Because sex steroids can change the metabolism of many immunosuppression medications, doses may need to be altered through the pregnancy.

For all these reasons, pregnancies should be planned, and the transplant team should be involved in the management of the pregnant transplant recipient. Women desiring pregnancy should be encouraged to wait until immunosuppression doses are stable and their risk of rejection is reduced. In general, women should consider waiting for pregnancy until after the first year of transplant when risks to both the mother (and the newly grafted organ) and the baby are presumed to be lower with reduced risk of rejection and lower medication doses, but there are no data to confirm this. Risk to babies fathered by men who are transplant recipients is being monitored, but no adverse effects have yet been reported.

Cyclosporine can be excreted into breast milk, but concentrations in the breast-fed infant are quite variable, from undetectable to therapeutic, and not necessarily related to the maternal dose or concentration (236). Measurement of tacrolimus in breast milk has only been reported in one person, and the concentration was quite low (126). The overall risk to the breast-fed infant when the mother is taking immunosuppression medications is still unknown, but if breast-feeding is practiced, concentrations of the medications should be monitored in the infant, based on these results.

Long-term risk to the infant is also an area of concern. White blood cell count in the baby can be low immediately after birth, but later returns to normal with no known long-term risk to the immune system. Yet delayed risk, including risk transmitted to the child’s offspring, cannot be excluded. If pregnancy is not desired, a discussion of birth control options should be offered early. Surgical methods of birth control are preferred because the risks of birth control pills (e.g., thromboembolic disease) and intrauterine devices (e.g., infection) may be greater in a transplant than a nontransplant patient.

In summary, hypogonadism and fertility can improve after transplant in both men and women. Menstrual irregularity is still common after pancreas-kidney transplant in women, whether due to the continued stress and morbidity of the first postoperative year, direct effects of the immunosuppressive agents on the reproductive axis, weight gain, or aggravated insulin resistance in some patients already predisposed, is less clear. Desire for future pregnancy should be discussed in advance with the transplant team to discuss optimal timing and to anticipate changing the type of immunosuppression in some patients. There are immediate risks to both the mother and the infant in the pancreas-kidney transplant recipient who becomes pregnant, and there are still concerns about long-term risks to the infant after prenatal or postnatal immunosuppressant exposure. All these concerns should be discussed with prospective parents.

	VIII. Summary

Top Abstract I. Introduction II. The Pancreas Transplant... III. Indications for and... IV. Surgical Procedure... V. Effect of Pancreas... VI. Consequences of Pancreas... VII. Clinical Management Issues... VIII. Summary References

 
Pancreas and kidney transplant procedures have specific indications, benefits, and risks. Pancreas transplant has become more common as long-term success has improved and risks have decreased. Yet, pancreas transplant remains a complex procedure that requires an experienced transplant team, especially as immunosuppression regimens continue to change. Compared with being on dialysis, simultaneous pancreas-kidney transplant offers a distinct advantage with respect to mortality and QOL issues related to diabetic complications. As living-donor kidney transplant alone often means earlier transplant and possibly similar patient and graft survival, at 10 yr, this procedure should also be considered strongly when available. Pancreas-after-kidney transplant, when successful, can improve microvascular complications compared with kidney transplant alone, but immediate mortality may be greater particularly if the recipient has good renal function and a living-donor kidney transplant. Thus, a careful discussion of the procedure and possible outcomes should be provided to a potential candidate. Solitary pancreas transplantation is done less frequently by fewer centers. Although it can dramatically change QOL for some who live in fear of severe, recurrent hypoglycemic reactions unresponsive to other therapies, it may also increase immediate risk of mortality because of the complexity of the surgery and the risks of immunosuppression.

A diabetologist or endocrinologist should work closely with the pancreas and kidney transplant team, whenever possible, to optimize glucose management before transplant; to prevent further diabetic complications after transplant including vascular risk factor management and simple foot care; to prevent or treat bone loss; and to help decide when and how to reinitiate therapy for hyperglycemia, if and when it recurs. Birth control, hormone replacement therapy, and pregnancy are all more complex in the transplant patient and should be discussed proactively. Multidisciplinary transplant centers that include specialists experienced and involved in surveillance of diabetic and organ transplant complications (e.g., posttransplant diabetes, hypertension, dyslipidemia, and osteoporosis), in addition to those experienced in immunosuppression and postoperative care, are needed for the best, long-term outcomes of the diabetic patient undergoing either pancreas or kidney transplant.

	Acknowledgments

 
I am indebted to Mary West for her secretarial assistance.

	Footnotes

 
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.

	References

Top Abstract I. Introduction II. The Pancreas Transplant... III. Indications for and... IV. Surgical Procedure... V. Effect of Pancreas... VI. Consequences of Pancreas... VII. Clinical Management Issues... VIII. Summary References

 

1. Kelly WD, Lillehei RC, Merkel FK, Idezuki Y, Goetz F 1967 Allotransplantation of the pancreas and duodenum along with the kidney in diabetic nephropathy. Surgery 61:827–837[Medline]
2. Gruessner AC, Sutherland DE 2002 Pancreas transplant outcomes for United States (US) and non-US cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of October 2002. Clin Transpl 41–77
3. Collins AJ, Kasiske B, Herzog C, Chen SC, Everson S, Constantini E, Grimm R, McBean M, Xue J, Chavers B, Matas A, Manning W, Louis T, Pan W, Liu J, Li S, Roberts T, Dalleska F, Snyder J, Ebben J, Frazier E, Sheets D, Johnson R, Li S, Dunning S, Berrini D, Gno H, Solid C, Arko C, Daniels F, Wang X, Forrest B, Gilbertson D, St Peter W, Frederick P, Eggers P, Agodoa L2003 Excerpts from the United States Renal Data System 2003 Annual Data Report: atlas of end-stage renal disease in the United States. Am J Kidney Dis 42:A5–A7
4. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, Held PJ, Port FK 1999 Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 341:1725–1730[Abstract/Free Full Text]
5. Ojo A, Wolfe RA, Agodoa LY, Held PJ, Port FK, Leavey SF, Callard SE, Dickinson DM, Schmouder RL, Leichtman AB1998 Prognosis after primary renal transplant failure and the beneficial effects of repeat transplantation: multivariate analyses from the United States Renal Data System. Transplantation 66:1651–1659
6. Meier-Kriesche HU, Port FK, Ojo AO, Rudich SM, Hanson JA, Cibrik DM, Leichtman AB, Kaplan B 2000 Effect of waiting time on renal transplant outcome. Kidney Int 58:1311–1317[CrossRef][Medline]
7. Mange KC, Joffe MM, Feldman HI 2001 Effect of the use or nonuse of long-term dialysis on the subsequent survival of renal transplants from living donors. N Engl J Med 344:726–731[Abstract/Free Full Text]
8. Kasiske BL, Vazquez MA, Harmon WE, Brown RS, Danovitch GM, Gaston RS, Roth D, Scandling JD, Singer GG 2000 Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation. J Am Soc Nephrol 11(Suppl 15):S1–S86
9. Drachenberg CB, Papadimitriou JC, Farney A, Wiland A, Blahut S, Fink JC, Philosophe B, Schweitzer E, Lal T, Anderson L, Bartlett ST 2001 Pancreas transplantation: the histologic morphology of graft loss and clinical correlations. Transplantation 71:1784–1791[CrossRef][Medline]
10. Humar A, Gruessner RW, Sutherland DE 1997 Living related donor pancreas and pancreas-kidney transplantation. Br Med Bull 53:879–891[Abstract/Free Full Text]
11. Robertson RP, Lanz K, Sutherland D, Seaquist E 2002 Relationship between diabetes and obesity 9 to 18 years after hemipancreatectomy and transplantation in donors and recipients. Transplantation 73:736–741[CrossRef][Medline]
12. Kendall DM, Sutherland DE, Najarian JS, Goetz FC, Robertson RP 1990 Effects of hemipancreatectomy on insulin secretion and glucose tolerance in healthy humans. N Engl J Med 322:898–903[Abstract]
13. Gruessner R, Sutherland D 1996 Simultaneous kidney and segmental pancreas transplants from living related donors—the first two successful cases. Transplantation 61:1265–1268[CrossRef][Medline]
14. Zielinski A, Nazarewski S, Bogetti D, Sileri P, Testa G, Sankary H, Benedetti E 2003 Simultaneous pancreas-kidney transplant from living related donor: a single-center experience. Transplantation 76:547–552[CrossRef][Medline]
15. Zhang L, Krzentowski G, Albert A, Lefebvre PJ 2003 Factors predictive of nephropathy in DCCT Type 1 diabetic patients with good or poor metabolic control. Diabet Med 20:580–585[CrossRef][Medline]
16. Jacobsen P, Rossing K, Tarnow L, Rossing P, Mallet C, Poirier O, Cambien F, Parving HH 1999 Progression of diabetic nephropathy in normotensive type 1 diabetic patients. Kidney Int (Suppl)71:S101–S105
17. Gruessner A, Sutherland D 2001 Analysis of United States (US) and Non-US Pancreas Transplants Reported to the United Network for Organ Sharing (UNOS) and the International Pancreas Transplant Registry (IPTR) as of October 2001. In: Cecka J, Terasaki E, eds. Clinical transplants 2001. Los Angeles: UCLA Immunogenetics Center; 41–72
18. Sarnak MJ, Poindexter A, Wang SR, Beck GJ, Kusek JW, Marcovina SM, Greene T, Levey AS 2002 Serum C-reactive protein and leptin as predictors of kidney disease progression in the Modification of Diet in Renal Disease Study. Kidney Int 62:2208–2215[CrossRef][Medline]
19. De Santo NG, Cirillo M, Perna A, De Santo LS, Anastasio P, Pollastro MR, De Santo RM, Iorio L, Cotrufo M, Rossi F 2001 The heart in uremia: role of hypertension, hypotension, and sleep apnea. Am J Kidney Dis 38:S38–S46
20. Lowbeer C, Stenvinkel P, Pecoits-Filho R, Heimburger O, Lindholm B, Gustafsson SA, Seeberger A 2003 Elevated cardiac troponin T in predialysis patients is associated with inflammation and predicts mortality. J Intern Med 253:153–160[CrossRef][Medline]
21. Ichihara A, Hayashi M, Ryuzaki M, Handa M, Furukawa T, Saruta T 2002 Fluvastatin prevents development of arterial stiffness in haemodialysis patients with type 2 diabetes mellitus. Nephrol Dial Transplant 17:1513–1517[Abstract/Free Full Text]
22. Vlassara H 1994 Serum advanced glycosylation end products: a new class of uremic toxins? Blood Purif 12:54–59[Medline]
23. Larsen JL, Lynch T, Al-Halawani M, Miller SA, Cushing KA, Baxter BT, Stratta RJ 1995 Carotid intima-media thickness by ultrasound measurement in pancreas transplant candidates. Transplant Proc 27:2996[Medline]
24. Farney A, Cho E, Schweitzer E, Dunkin B, Philosophe B, Colonna J, Jacobs S, Jarrell B, Flowers JL, Bartlett ST 2000 Simultaneous cadaver pancreas living-donor kidney transplantation: a new approach for the type 1 diabetic uremic patient. Ann Surg 232:696–703[CrossRef][Medline]
25. Secchi A, Carlo VD, Pozza G 1994 Pancreas transplantation. Lancet 343:607–608 (Letter to the editor)[Medline]
26. Cecka JM 2000 The UNOS Scientific Renal Transplant Registry—2000. Clin Transpl 1–18
27. Venstrom JM, McBride MA, Rother KI, Hirshberg B, Orchard TJ, Harlan DM 2003 Survival after pancreas transplantation in patients with diabetes and preserved kidney function. JAMA 290:2817–2823[Abstract/Free Full Text]
28. Colling C, Stevens R, Lyden E, Lane J, Mack-Shipman L, Wrenshall L, Larsen J 2004 Greater early pancreas graft loss in women compared to men after simultaneous pancreas-kidney transplantation. Clin Transplant, in press
29. Gjerston D 1995 Multifactorial analysis of renal transplants reported to the United Network for Organ Sharing Registry: a 1994 update. In: Terasaki P, Cecka J, eds. Clinical transplants 1994. Los Angeles: UCLA Tissue Typing Laboratory; 519–539
30. Douzdjian V, Bhaskar S, Baliga P, Gugliuzza K, Rajagopalan P 1997 Effect of race on outcome after kidney and kidney-pancreas transplantation in type 1 diabetic patients. Diabetes Care 20:1310–1314[Abstract]
31. Light J, Sasaki T, Currier C, Barhyte D 2001 Successful long-term kidney-pancreas transplants regardless of C-peptide status or race. Transplantation 71:152–154[CrossRef][Medline]
32. Gaston RS, Alveranga DY, Becker BN, Distant DA, Held PJ, Bragg-Gresham JL, Humar A, Ting A, Wynn JJ, Leichtman AB 2003 Kidney and pancreas transplantation. Am J Transplant 3(Suppl 4):64–77
33. Gruessner A, Sutherland D 2000 Pancreas transplant outcomes for United States (US) cases reported to the United Network for Organ Sharing (UNOS) and non-US cases reported to the International Pancreas Transplant Registry (IPTR) as of October, 2000. In: Terasaki CA, ed. Clinical transplants 2000. Los Angeles: UCLA Immunogenetics Center; 45–72
34. Humar A, Ramcharan T, Kandaswamy R, Matas A, Gruessner RW, Gruessner AC, Sutherland DE 2001 Pancreas after kidney transplants. Am J Surg 182:155–161[CrossRef][Medline]
35. American Diabetes Association 2000 Pancreas transplantation for patients with type 1 diabetes. Diabetes Care 23:117[Medline]
36. Brennan DC, Stratta RJ, Lowell JA, Miller SA, Taylor RJ 1994 Cyclosporine challenge in the decision of combined kidney-pancreas versus solitary pancreas transplantation. Transplantation 57:1606–1611[Medline]
37. Lane JT, Ratanasuwan T, Mack-Shipman R, Taylor RJ, Leone JP, Miller SA, Lyden ER, Larsen JL 2001 Cyclosporine challenge test revisited: does it predict outcome after solitary pancreas transplantation? Clin Transplant 15:28–31[Medline]
38. Fioretto P, Steffes MW, Sutherland DE, Goetz FC, Mauer M 1998 Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 339:69–75[Abstract/Free Full Text]
39. Sollinger HW, Stratta RJ, D’Alessandro AM, Kalayoglu M, Pirsch JD, Belzer FO 1988 Experience with simultaneous pancreas-kidney transplantation. Ann Surg 208:475–483[Medline]
40. Corry RJ, Nghiem DD, Schulak JA, Beutel WD, Gonwa TA 1986 Surgical treatment of diabetic nephropathy with simultaneous pancreaticoduodenal and renal transplantation. Surg Gynecol Obstet 162:547–555[Medline]
41. Schang T, Timmermann W, Thiede A, Najarian JS, Sutherland DE 1991 Detrimental effects of fluid and electrolyte loss from duodenum in bladder-drained pancreas transplants. Transplant Proc 23:1617–1618[Medline]
42. Del Pizzo J, Jacobs S, Bartlett S, Sklar G 1998 Urological complications of bladder-drained pancreatic allografts. Br J Urol 81: 543–547
43. Hickey DP, Bakthavatsalam R, Bannon CA, O’Malley K, Corr J, Little DM 1997 Urological complications of pancreatic transplantation. J Urol 157:2042–2048[CrossRef][Medline]
44. Larsen J, Ratanasuwan T, Burkman T, Colling C, Lynch T, Erickson J, Lyden E, Miller S, Lane J, Mack-Shipman L2004 Pancreas transplantation improves vascular disease in patients with type 1 diabetes. Diabetes Care 27:1706–1711
45. Orsenigo E, Cristallo M, Socci C, Castoldi R, Secchi A, Colombo R, Invernizzi L, Fiorina P, Naspro R, Di Carlo V 2002 Urological complications after simultaneous renal and pancreatic transplantation. Eur J Surg 168:609–613[CrossRef][Medline]
46. Stephanian E, Gruessner RW, Brayman KL, Gores P, Dunn DL, Najarian JS, Sutherland DE 1992 Conversion of exocrine secretions from bladder to enteric drainage in recipients of whole pancreaticoduodenal transplants. Ann Surg 216:663–672[Medline]
47. Sindhi R, Stratta R, Taylor R 1995 Experience with enteric conversion after pancreas transplantation with bladder drainage. Transplant Proc 27:3014–3015[Medline]
48. Sindhi R, Stratta RJ, Lowell JA, Sudan D, Cushing KA, Castaldo P, Jervis JT 1997 Experience with enteric conversion after pancreatic transplantation with bladder drainage. J Am Coll Surg 184:281–289[Medline]
49. Robertson RP, Abid M, Sutherland DE, Diem P 1989 Glucose homeostasis and insulin secretion in human recipients of pancreas transplantation. Diabetes 38(Suppl 1):97–98
50. Diem P, Abid M, Redmon JB, Sutherland DE, Robertson RP 1990 Systemic venous drainage of pancreas allografts as independent cause of hyperinsulinemia in type I diabetic recipients. Diabetes 39:534–540[Abstract]
51. Stratta RJ, Taylor RJ, Zorn BH, Ozaki C, Larsen JL, Duckworth WC, Langnas AN, Wood RP, Wahl TO, Marujo WC, Li S, Shaw Jr BW 1991 Combined pancreas-kidney transplantation: preliminary results and metabolic effects. Am J Gastroenterol 86:697–703[Medline]
52. Gaber AO, Shokouh-Amiri MH, Hathaway DK, Hammontree L, Kitabchi AE, Gaber LW, Saad MF, Britt LG 1995 Results of pancreas transplantation with portal venous and enteric drainage. Ann Surg 221:613–622; discussion 622–624[Medline]
53. Bagdade JD, Ritter MC, Kitabchi AE, Huss E, Thistlethwaite R, Gabfr O, Lambeth H 1996 Differing effects of pancreas-kidney transplantation with systemic versus portal venous drainage on cholesteryl ester transfer in IDDM subjects. Diabetes Care 19:1108–1112[Abstract]
54. Stratta R, Gaber O, Shoukouh-Amiri MH, Reddy KS, Egidi MF, Grewal HP, Gaber LW 2000 A prospective comparison of systemic-bladder versus portal-enteric drainage in vascularized pancreas transplantation. Surgery 127:217–226[CrossRef][Medline]
55. Rosenlof L, Earnhardt R, Pruett T, Stevenson WC, Douglas MT, Cornett GC, Hanks JB 1992 Pancreas transplantation: an initial experience with systemic and portal drainage of pancreatic allografts. Ann Surg 215:586–595[Medline]
56. Philosophe B, Farney A, Schweitzer E, Colonna JA, Jarrell BE, Krishnamurthi V, Wiland AM, Bartlett ST 2001 Superiority of portal venous drainage over systemic venous drainage in pancreas transplantation. Ann Surg 234:689–696[CrossRef][Medline]
57. Petruzzo P, Da Silva M, Feitosa LC, Dawahra M, Lefrancois N, Dubernard JM, Martin X 2000 Simultaneous pancreas-kidney transplantation: portal versus systemic venous drainage of the pancreas allografts. Clin Transplant 14:287–291[CrossRef][Medline]
58. Katz HH, Nguyen TT, Velosa JA, Robertson RP, Rizza RA 1994 Effects of systemic delivery of insulin on plasma lipids and lipoprotein concentrations in pancreas transplant recipients. Mayo Clin Proc 69:231–236[Medline]
59. Lo A, Stratta RJ, Hathaway DK, Egidi MF, Shokouh-Amiri MH, Grewal HP, Winsett R, Trofe J, Alloway RR, Gaber AO 2001 Long-term outcomes in simultaneous kidney-pancreas transplant recipients with portal-enteric versus systemic-bladder drainage. Am J Kidney Dis 38:132–143[Medline]
60. Hughes TA, Gaber AO, Amiri HS, Wang X, Elmer DS, Winsett RP, Hathaway DK, Hughes SM 1995 Kidney-pancreas transplantation. The effect of portal versus systemic venous drainage of the pancreas on the lipoprotein composition. Transplantation 60:1406–1412[Medline]
61. Carpentier A, Patterson B, Uffelman KD, Giacca A, Vranic M, Cattral MS, Lewis GF 2001 The effect of systemic versus portal insulin delivery in pancreas transplantation on insulin action and VLDL metabolism. Diabetes 50:14102–11413
62. Foger B, Konigsrainer A, Palos G, Ritsch A, Trobinger G, Menzel HJ, Lechleitner M, Doblinger A, Konig P, Utermann G, Margreiter R, Patsch JR 1996 Effects of pancreas transplantation on distribution and composition of plasma lipoproteins. Metabolism 45:856–861[CrossRef][Medline]
63. Zavaroni I, Bonora E, Pagliara M, Dall’Aglio E, Luchetti L, Buonanno G, Bonati PA, Bergonzani M, Gnudi L, Passeri M, Reaven G 1989 Risk factors for coronary artery disease in healthy persons with hyperinsulinemia and normal glucose tolerance. N Engl J Med 320:702–706[Abstract]
64. Larsen J, Ratanasuwan T, Burkman T, Lynch T, Erickson J, Colling C, Lane J, Mack-Shipman L, Lyden E, Loseke M, Miller S, Leone J2002 Carotid intima media thickness is decreased after pancreas transplantation. Transplantation 73:936–940
65. Jukema J, Smets Y, van der Pijl J, Zwinderman AH, Vliegen HW, Ringers J, Reiber JH, Lemkes HH, van der Wall EE, de Fijter JW 2001 Impact of simultaneous pancreas and kidney transplantation on progression of coronary atherosclerosis in patients with end stage renal failure due to type 1 diabetes. Diabetes Care 25:906–911
66. Kaufman DB, Leventhal JR, Stuart J, Abecassis MM, Fryer JP, Stuart FP 1999 Mycophenolate mofetil and tacrolimus as primary maintenance immunosuppression in simultaneous pancreas-kidney transplantation: initial experience in 50 consecutive cases. Transplantation 67:586–593[Medline]
67. Oh JM, Wiland AM, Klassen DK, Weidle PJ, Bartlett ST 2001 Comparison of azathioprine and mycophenolate mofetil for the prevention of acute rejection in recipients of pancreas transplantation. J Clin Pharmacol 41:861–869[Abstract]
68. Neto A, Haapalainen E, Ferreira R, Feo CF, Misiako EP, Vennarecci G, Porcu A, Dib SA, Goldenberg S, Gomes PO, Nigro AT 1999 Metabolic and ultrastructural effects of cyclosporin A on pancreatic islets. Transpl Int 12:208–212[CrossRef][Medline]
69. Drachenberg C, Klassen D, Weir M, Wiland A, Fink JC, Bartlett ST, Cangro CB, Blahut S, Papadimitriou JC 1999 Islet cell damage associated with tacrolimus and cyclosporine: morphological features in pancreas allograft biopsies and clinical correlation. Transplantation 68:396–402[CrossRef][Medline]
70. Tyden G, Bolinder J, Solders G, Brattstrom C, Tibell A, Groth CG 1999 Improved survival in patients with insulin-dependent diabetes mellitus and end-stage diabetic nephropathy 10 years after combined pancreas and kidney transplantation. Transplantation 67:645–648[CrossRef][Medline]
71. La Rocca E, Fiorina P, Astorri E, Rossitti C, Lucignani G, Fazio Fgiudici D, Castoldi R, Bianchi G, Di Carlo V, Pozza G, Secchi A 2000 Patient survival and cardiovascular events after kidney-pancreas transplantation: comparison with kidney transplnatation alone in uremic IDDM patients. Cell Transplant 9:929–932[Medline]
72. La Rocca E, Fiorina P, di Carlo V, Astorri E, Rossetti C, Lucignani G, Fazio F, Giudici D, Cristallo M, Bianchi G, Pozza G, Secchi A 2001 Cardiovascular outcomes after kidney-pancreas and kidney-alone transplantation. Kidney Int 60:1964–1971[CrossRef][Medline]
73. Reddy KS, Stablein D, Taranto S, Stratta RJ, Johnston TD, Waid TH, McKeown JW, Lucas BA, Ranjan D 2003 Long-term survival following simultaneous kidney-pancreas transplantation versus kidney transplantation alone in patients with type 1 diabetes mellitus and renal failure. Am J Kidney Dis 41:464–470[CrossRef][Medline]
74. Navarro X, Kennedy WR, Aeppli D, Sutherland DE 1996 Neuropathy and mortality in diabetes: influence of pancreas transplantation. Muscle Nerve 19:1009–1016[CrossRef][Medline]
75. Ojo AO, Meier-Kriesche HU, Hanson JA, Leichtman A, Magee JC, Cibrik D, Wolfe RA, Port FK, Agodoa L, Kaufman DB, Kaplan B 2001 The impact of simultaneous pancreas-kidney transplantation on long-term patient survival. Transplantation 71:82–90[CrossRef][Medline]
76. Navarro X, Kennedy WR, Sutherland DE 1991 Autonomic neuropathy and survival in diabetes mellitus: effects of pancreas transplantation. Diabetologia 34(Suppl 1):S108–S112
77. Navarro X, Kennedy WR, Loewenson RB, Sutherland DER 1990 Influence of pancreas transplantation on cardiorespiratory reflexes, nerve conduction and mortality in diabetes mellitus. Diabetes 39:802–806[Abstract]
78. Bunnapradist S, Cho YW, Cecka JM, Wilkinson A, Danovitch GM 2003 Kidney allograft and patient survival in type I diabetic recipients of cadaveric kidney alone versus simultaneous pancreas kidney transplants: a multivariate analysis of the UNOS database. J Am Soc Nephrol 14:208–213[Abstract/Free Full Text]
79. Rayhill SC, D’Alessandro AM, Odorico JS, Knechtle SJ, Pirsch JD, Heisey DM, Kirk AD, Van der Werf W, Sollinger HW 2000 Simultaneous pancreas-kidney transplantation and living related donor renal transplantation in patients with diabetes: is there a difference in survival? Ann Surg 231:417–423[CrossRef][Medline]
80. Osei K, Henry ML, O’Dorisio TM, Tesi RJ, Sommer BG, Ferguson RM 1990 Physiological and pharmacological stimulation of pancreatic islet hormone secretion in type I diabetic pancreas allograft recipients. Diabetes 39:1235–1242[Abstract]
81. Katz H, Homan M, Velosa J, Robertson P, Rizza R 1991 Effects of pancreas transplantation on postprandial glucose metabolism. N Engl J Med 325:1278–1283[Abstract]
82. Tran M, Larsen JL, Duckworth WC, Ruby EI, Miller SA, Frisbie K, Taylor K, Taylor RJ, Stratta RJ 1994 Anti-insulin antibodies are a cause of hypoglycemia following pancreas transplantation. Diabetes Care 17:988–993[Abstract]
83. Larsen JL, Stratta RJ, Miller SA, Hirst K, Ozaki C, Taylor RJ, Duckworth WC 1993 Evidence that fasting hyperproinsulinemia after combined pancreas-kidney transplantation diminishes over time. Transplantation 56:1533–1537[Medline]
84. Kissler HJ, Gepp H, Tannapfel A, Schwille PO 2000 Effect of venous drainage site on insulin action after pancreas transplantation in the rat–is there insulin resistance and a risk for atherosclerosis? Metabolism 49:458–466[CrossRef][Medline]
85. Blackman JD, Polonsky KS, Jaspan JB, Sturis J, Van Cauter E, Thistlethwaite JR 1992 Insulin secretory profiles and C-peptide clearance kinetics at 6 months and 2 years after kidney-pancreas transplantation. Diabetes 41:1346–1354[Abstract]
86. Sonnenberg GE, Hoffmann RG, Johnson CP, Kissebah AH 1992 Low- and high-frequency insulin secretion pulses in normal subjects and pancreas transplant recipients: role of extrinsic innervation. J Clin Invest 90:545–553[CrossRef][Medline]
87. O’Meara NM, Sturis J, Blackman JD, Byrne MM, Jaspan JB, Roland DC, Thistlethwaite JR, Polonsky KS 1993 Oscillatory insulin secretion after pancreas transplant. Diabetes 42:855–861[Abstract]
88. Robertson RP, Diem P, Sutherland DE 1991 Time-related, cross-sectional and prospective follow-up of pancreatic endocrine function after pancreas allograft transplantation in type 1 (insulin-dependent) diabetic patients. Diabetologia 34(Suppl 1):S57–S60
89. Osei K, Cottrell D, Henry ML, Tesi RJ, Ferguson RM, O’Dorisio TM 1992 Minimal model analysis of insulin sensitivity in glucose mediated glucose disposal in type I (insulin dependent) diabetic pancreas allograft recipients. Diabetologia 35:676–680[CrossRef][Medline]
90. Landgraf R, Nusser J, Riepl RL, Fiedler F, Illner WD, Abendroth D, Land W 1991 Metabolic and hormonal studies of type 1 (insulin-dependent) diabetic patients after successful pancreas and kidney transplantation. Diabetologia 34(Suppl 1):S61–S67
91. Cottrell D, Henry M, O’Dorisio T, Tesi R, Ferguson R, Osei K 1992 Sequential metabolic studies of pancreas allograft function in type 1 diabetic recipients. Diabet Med 9:438–443[Medline]
92. Elmer DS, Hathaway DK, Bashar Abdulkarim A, Hughes TA, Shokouh-Amiri H, Gaber LW, Gaber AO 1998 Use of glucose disappearance rates (kG) to monitor endocrine function of pancreas allografts. Clin Transplant 12:56–64[Medline]
93. Ostman J, Bolinder J, Gunnarsson R, Btattstrom C, Tyden G, Wahren J, Groth CG 1989 Effects of pancreas transplantation on metabolic and hormonal profiles in IDDM patients. Diabetes 38(Suppl 1):88–93
94. Christiansen E, Roder M, Tibell A, Hales CN, Madsbad S 1998 Effect of pancreas transplantation and immunosuppression on proinsulin secretion. Diabet Med 15:739–746[CrossRef][Medline]
95. Babazono T, Teraoka S, Tomonaga O, Iwamoto Y, Omori Y 1998 Circulating proinsulin levels in insulin-dependent diabetic patients after whole pancreas-kidney transplantation. Metabolism 47:1325–1330[CrossRef][Medline]
96. Weide LG, Stratta RJ, Cushing K, Groggel G 1997 Elevated fasting pro-insulin levels as a marker for impaired function after pancreas transplantation. Transplant Proc 29:678[CrossRef][Medline]
97. Diem P, Redmon JB, Abid M, Moran A, Sutherland DE, Halter JB, Robertson RP 1990 Glucagon, catecholamine and pancreatic polypeptide secretion in type I diabetic recipients of pancreas allografts. J Clin Invest 86:2008–2113[Medline]
98. Christiansen E, Tibell A, Volund A, Rasmussen K, Groth GC, Holst JJ, Pedersen O, Christensen NJ, Madsbad S 1996 Pancreatic endocrine function in recipients of segmental and whole pancreas transplantation. J Clin Endocrinol Metab 81:3972–3979[Abstract/Free Full Text]
99. Christiansen E, Tibell A, Volund AA, Holst JJ, Rasmussen K, Schaffer L, Madsbad S 1997 Metabolism of oral glucose in pancreas transplant recipients with normal and impaired glucose tolerance. J Clin Endocrinol Metab 82:2299–2307[Abstract/Free Full Text]
100. Nauck MA, Busing M, Orskov C, Siegel EG, Talartschik J, Baartz A, Baartz T, Holzer H, Hopt UT, Ebert R, Becker H-D, Creutzfeldt W 1992 Basal and nutrient-stimulated pancreatic and gastrointestinal hormone concentrations in type-1-diabetic patients after successful combined pancreas and kidney transplantation. Clin Invest 70:40–48[CrossRef][Medline]
101. Barrou Z, Seaquist ER, Robertson RP 1994 Pancreas transplantation in diabetic humans normalizes hepatic glucose production during hypoglycemia. Diabetes 43:661–666[Abstract]
102. Pfeffer F, Nauck MA, Drognitz O, Benz S, von Dobschuetz E, Hopt UT 2003 Postoperative oral glucose tolerance and stimulated insulin secretion: a predictor of endocrine graft function more than 10 years after pancreas-kidney transplantation. Transplantation 76:1427–1431[CrossRef][Medline]
103. Battezzati A, Benedini S, Caldara R, Calori G, Secchi A, Pozza G, Luzi L 2001 Prediction of the long-term metabolic success of the pancreatic graft function. Transplantation 71:1560–1565[CrossRef][Medline]
104. Bolinder J, Wahrenberg H, Persson A, Linde B, Tyden G, Grath CG, Ostman J 1991 Effect of pancreas transplantation on glucose counterregulation in insulin-dependent diabetic patients prone to severe hypoglycaemia. J Intern Med 230:527–533[Medline]
105. Kendall DM, Rooney DP, Smets YF, Salazar Bolding L, Robertson RP 1997 Pancreas transplantation restores epinephrine response and symptom recognition during hypoglycemia in patients with long-standing type I diabetes and autonomic neuropathy. Diabetes 46:249–257[Abstract]
106. Cottrell DA, Henry ML, O’dorisio TM, Tesi R, Ferguson RM, Osei K 1991 Hypoglycemia after successful pancreas transplantation in type I diabetic patients. Diabetes Care 14:1111–1113[Medline]
107. Larsen JL, Forsman JA, Miller SA, Taylor RJ, Stratta RJ 1994 Symptoms of hypoglycemia are experienced by majority of combined pancreas-kidney transplant recipients but documented hypoglycemia was infrequent. Transplant Proc 26:476–477[Medline]
108. Redmon JB, Teuscher AU, Robertson RP 1998 Hypoglycemia after pancreas transplantation. Diabetes Care 21:1944–1950[Abstract]
109. Hirshberg B, Trelezky V, Raz I 1998 Hypoglycaemia following pancreatic allograft transplantation. J Intern Med 243:389–393[CrossRef][Medline]
110. Semakula C, Pambuccian S, Gruessner R, Kendall D, Pittenger G, Vinik A, Seaquist ER 2002 Clinical case seminar: hypoglycemia after pancreas transplantation: association with allograft nesidiodysplasia and expression of islet neogenesis-associated peptide. J Clin Endocrinol Metab 87:3548–3554[Abstract/Free Full Text]
111. Gupta V, Wahoff DC, Rooney DP, Poitout V, Sutherland DE, Kendall DM, Robertson RP 1997 The defective glucagon response from transplanted intrahepatic pancreatic islets during hypoglycemia is transplantation site-determined. Diabetes 46:28–33[Abstract]
112. Kendall DM, Teuscher AU, Robertson RP 1997 Defective glucagon secretion during sustained hypoglycemia following successful islet allo- and autotransplantation in humans. Diabetes 46:23–27[Abstract]
113. The Diabetes Control and Complications Trial Research Group 1993 The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.. N Engl J Med 329:977–986[Abstract/Free Full Text]
114. Mauer S, Steffes M, Connett J, Najarian J, Sutherland D, Barbosa J 1983 The development of lesions in the glomerular basement membrane and mesangium after transplantation of normal kidneys to diabetic patients. Diabetes 32:948–952[Abstract]
115. Wilczek H, Jaremko G, Tyden G, Groth C 1995 Evolution of diabetic nephropathy in kidney grafts. Evidence that a simultaneously transplanted pancreas exerts a protective effect. Transplantation 59:51–57[Medline]
116. LeFrancois N, Petruzzo P, Sepeteanu I, Da Silva M, McGregor B, Dawahra M, Hadj-Aissa A, Dubernard JM, Touraine JL, Martin X 2001 Impact of the functioning pancreas on long-term renal function in pancreas-kidney transplantation. Transplant Proc 33:1690[CrossRef][Medline]
117. Fioretto P, Mauer SM, Bilous R, Goetz F, Sutherland D, Steffes M 1993 Effects of pancreas transplantation on glomerular structure in insulin-dependent diabetic patients with their own kidneys. Lancet 342:1193–1196[CrossRef][Medline]
118. Scheider A, Meyer-Schwickerath E, Nusser J, Land W, Landgraf R 1991 Diabetic retinopathy and pancreas transplantation: a 3-year follow-up. Diabetologia 34(Suppl 1):S95–S99
119. Koznarova R, Saudek F, Sosna T, Adamec M, Jedinakova T, Boucek P, Bartos V, Lanska V 2000 Beneficial effect of pancreas and kidney transplantation on advanced diabetic retinopathy. Cell Transplant 2000 9:903–908[Medline]
120. Landgraf R, Nusser J, Muller W, landgraf-Leurs MM, Thurau S, Ulbig M, Kampik A, Lachenmayr B, Hillebrand G, Schleibner S, Illner W-D, Abendroth D, Land W 1989 Fate of late complications in type I diabetic patients after successful pancreas-kidney transplantation. Diabetes 38(Suppl 1):33–37
121. Ulbig M, Kampik A, Thurau S, Landgraf R, Land W 1991 Long-term follow-up of diabetic retinopathy for up to 71 months after combined renal and pancreatic transplantation. Graefes Arch Clin Exp Ophthalmol 229:242–245[CrossRef][Medline]
122. Schmidt D, Kirste G, Schrader W 1994 Progressive proliferative diabetic retinopathy after transplantation of the pancreas. A case and a review of the topic. Acta Ophthalmol (Copenh) 72:743–751
123. Sosna T, Saudek F, Dominek Z 1998 Effect of successful combined renal and pancreatic transplantation on diabetic retinopathy. Acta Univ Palacki Olomuc Fac Med 141:75–77[Medline]
124. Sutherland DE, Dunn DL, Goetz FC, Kennedy W, Ramsay RC, Steffes MW, Mauer SM, Gruessner R, Moudry-Munns KC, Morel P, Viste A, Robertson RP, Najarian JS1989 A 10-year experience with 290 pancreas transplants at a single institution. Ann Surg 210:274–285; discussion 285–288
125. Petersen MR, Vine AK 1990 Progression of diabetic retinopathy after pancreas transplantation. The University of Michigan Pancreas Transplant Evaluation Committee. Ophthalmology 97:496–500; discussion 501–502[Medline]
126. French AE, Soldin SJ, Soldin OP, Koren G 2003 Milk transfer and neonatal safety of tacrolimus. Ann Pharmacother 37:815–818[Abstract/Free Full Text]
127. Ramsay R, Goetz F, Sutherland DE, Mauer SM, Robison LL, Cantrill HL, Knobloch WH, Najarian JS 1988 Progression of diabetic retinopathy after pancreas transplantation for insulin-dependent diabetes mellitus. N Engl J Med 318:208–214[Abstract]
128. Chow V, Pai R, Chapman J, O’Connell PJ, Allen RD, Mitchell P, Nankivell BJ 1999 Diabetic retinopathy after combined kidney-pancreas retinopathy. Clin Transplant 13:356–362[CrossRef][Medline]
129. Konigsrainer A, Miller K, Steurer W, Lieselbach G, Aichberger C, Ofner D, Margreiter R 1991 Does pancreas transplantation influence the course of diabetic retinopathy? Diabetologia 34 (Suppl 1):S86–S88
130. Wang Z, Klein R, Moss S, Klein BE, Hoyer C, Burke K, Sollinger HW 1994 The influence of combined kidney-pancreas transplantation on the progression of diabetic retinopathy, a case series. Ophthalmology 101:1071–1076[Medline]
131. Pearce IA, Ilango B, Sells RA, Wong D 2000 Stabilisation of diabetic retinopathy following simultaneous pancreas and kidney transplant. Br J Ophthalmol 84:736–740[Abstract/Free Full Text]
132. Bandello F, Vigano C, Secchi A, Martinenghi S, Caldara R, Di Carlo V, Pozza G, Brancato R 1991 Effect of pancreas transplantation on diabetic retinopathy: a 20 case report. Diabetologia 34 (Suppl 1):S92–S94
133. Giannarelli R, Coppelli A, Sartini MS, Aragona M, Boggi U, Mosca F, Nardi M, Del Prato S, Marchetti P 2002 Early improvement of unstable diabetic retinopathy after solitary pancreas transplantation. Diabetes Care 25:2358–2359[Free Full Text]
134. Pai RP, Mitchell P, Chow VC, Chapman JR, O’Connell PJ, Allen RD, Nankivell BJ 2000 Posttransplant cataract: lessons from kidney-pancreas transplantation. Transplantation 69:1108–1114[CrossRef][Medline]
135. Zech JC, Trepsat D, Gain-Gueugnon M, Lefrancois N, Martin X, Dubernard JM 1991 Ophthalmological follow-up of type 1 (insulin-dependent) diabetic patients after kidney and pancreas transplantation. Diabetologia 34 (Suppl 1):S89–S91
136. Kennedy WR, Navarro X, Sutherland DE 1995 Neuropathy profile of diabetic patients in a pancreas transplantation program. Neurology 45:773–780[Abstract/Free Full Text]
137. Kennedy WR, Navarro X, Goetz FC, Sutherland DE, Najarian JS 1990 Effects of pancreatic transplantation on diabetic neuropathy. N Engl J Med 322:1031–1037[Abstract]
138. Solders G, Tyden G, Persson A, Groth CG 1992 Improvement of nerve conduction in diabetic neuropathy. A follow-up study 4 yr after combined pancreatic and renal transplantation. Diabetes 41:946–951[Abstract]
139. Muller-Felber W, Landgraf R, Scheuer R, Wagner S, Reimers CD, Nusser J, Abendroth D, Illner WD, Land W 1993 Diabetic neuropathy 3 years after successful pancreas and kidney transplantation. Diabetes 42:1482–1485[Abstract]
140. Navarro X, Sutherland DE, Kennedy WR 1997 Long-term effects of pancreatic transplantation on diabetic neuropathy. Ann Neurol 42:727–736[CrossRef][Medline]
141. Martinenghi S, Comi G, Galardi G, Di Carlo V, Pozza G, Secchi A 1997 Amelioration of nerve conduction velocity following simultaneous kidney/pancreas transplantation is due to the glycaemic control provided by the pancreas. Diabetologia 40:1110–1112[CrossRef][Medline]
142. Allen R, Al-Harbi I, Morris J, Clouston PD, O’Connell PJ, Chapman JR, Nankivell BJ 1997 Diabetic neuropathy after pancreas transplantation. Transplantation 63:830–838[CrossRef][Medline]
143. Dyck PJ, Velosa JA, Pach JM, Sterioff S, Larson TS, Norell JE, O’Brien PC, Dyck PJ 2001 Increased weakness after pancreas and kidney transplantation. Transplantation 72:1403–1408[CrossRef][Medline]
144. Solders G, Tyden G, Persson A, Groth C-G 1991 Improvement in diabetic neuropathy 4 years after successful pancreatic and renal transplantation. Diabetologia 34 (Suppl 1):S125–S127
145. Maes BD, Vanwalleghem J, Kuypers D, Ghoos Y, Rutgeerts PJ, Vanrenterghem YF 1999 Differences in gastric motor activity in renal transplant recipients treated with FK-506 versus cyclosporine. Transplantation 68:1482–1485[CrossRef][Medline]
146. Maes BD, Dalle I, Geboes K, Oellench M, Armstrong VW, Evenepoel P, Geypens B, Kuypers D, Shipkova M, Geboes K, Vanrenterghem VF2003 Erosive enterocolitis in mycophenolate mofetil-treated renal-transplant recipients with persistent afebrile diarrhea. Transplantation 75:665–672
147. Cashion AK, Hathaway DK, Milstead EJ, Reed L, Gaber AO 1999 Changes in patterns of 24-hr heart rate variability after kidney and kidney-pancreas transplant. Transplantation 68:1846–1850[CrossRef][Medline]
148. Murphy DB, Sutton A, Prescott LF, Murphy MB 1997 A comparison of the effects of tramadol and morphine on gastric emptying in man. Anaesthesia 52:1224–1229[CrossRef][Medline]
149. Pertwee RG 2001 Cannabinoids and the gastrointestinal tract. Gut 48:859–867[Abstract/Free Full Text]
150. Huilgol V, Evans J, Hellman RS, Soergel KH 2002 Acute effect of clonidine on gastric emptying in patients with diabetic gastropathy and controls. Aliment Pharmacol Ther 16:945–950[CrossRef][Medline]
151. Hathaway DK, Abell T, Cardoso S, Hartwig MS, el Gebely S, Gaber AO 1994 Improvement in autonomic and gastric function following pancreas-kidney versus kidney-alone transplantation and the correlation with quality of life. Transplantation 57:816–822[Medline]
152. Hartwig MS, Cardoso SS, Hathaway DK, Gaber AO 1994 Reliability and validity of cardiovascular and vasomotor autonomic function tests. Diabetes Care 17:1433–1440[Abstract]
153. Boucek P, Bartos V, Vanek I, Hyza Z, Skibova J 1991 Diabetic autonomic neuropathy after pancreas and kidney transplantation. Diabetologia 34(Suppl 1):S121–S124
154. Boucek P, Saudek F, Adamec M, Janousek L, Koznarova R, Havrdova T, Skibova J 2003 Spectral analysis of heart rate variation following simultaneous pancreas and kidney transplantation. Transplant Proc 35:1494–1498[CrossRef][Medline]
155. Jonerskog G, Tyden G, Bolinder J, Fagrell B 1991 Skin microvascular reactivity in fingers of diabetic patients after combined and pancreas transplantation. Diabetologia 34(Suppl 1):S135–S137
156. Abendroth D, Schmand J, Landgraf R, Illner W, Land W 1991 Diabetic microangiopathy in type 1 (insulin dependent) diabetic patients after successful pancreatic and kidney or solitary kidney transplantation. Diabetologia 34(Suppl 1):S131–S134
157. Cheung A, Perez R, Chen P 1999 Improvements in diabetic microangiopathy after successful simultaneous pancreas-kidney transplantation: a computer-assisted intravital microscopy study on the conjunctival microcirculation. Transplantation 68:927–932[CrossRef][Medline]
158. Gfesser M, Nusser J, Muller-Felber W, Abendroth D, Land W, Landgraf R 1993 Cross-sectional study of peripheral microcirculation in diabetic patients with microangiopathy: influence of pancreatic and kidney transplantation. Acta Diabetol 30:79–84[CrossRef][Medline]
159. Young BA, Marsh CL, Alpers CE, Davis CL 1996 Cyclosporine-associated thrombotic microangiopathy/hemolytic uremic syndrome following kidney and kidney-pancreas transplantation. Am J Kidney Dis 28:561–571[Medline]
160. Burke GW, Ciancio G, Cirocco R, Markou M, Roth D, Esquenazi V, Tzakis A, Miller J 1998 Tacrolimus-related microangiopathy in kidney and simultaneous pancreas-kidney recipients: evidence of endothelin and cytokine involvement. Transplant Proc 30:661–662[CrossRef][Medline]
161. Zarifian A, Meleg-Smith S, O’Donovan R, Tesi RJ, Batuman V 1999 Cyclosporine-associated thrombotic microangiopathy in renal allografts. Kidney Int 55:2457–2466[CrossRef][Medline]
162. Kosch M, Hausberg M, Suwelack B 2003 Studies on effects of calcineurin inhibitor withdrawal on arterial distensibility and endothelial function in renal transplant recipients. Transplantation 76:1516–1519[CrossRef][Medline]
163. Markowski D, Larsen J, McElligott M, Walter GA, Miller SA, Frisbie K, Stratta RJ 1996 Diet after pancreas transplantation. Diabetes Care 19:735–738[Abstract]
164. Nankivell B, Lau S-G, Chapman J, O’Connell P, Fletcher J, Allen R 2000 Progression of macrovascular disease after transplantation. Transplantation 69:574–581[CrossRef][Medline]
165. Hughes TA, Gaber AO, Amiri HS, Wang X, Elmer DS, Winsett RP, Hathaway DK, Hughes SM, Ghawji M 1994 Lipoprotein composition in insulin-dependent diabetes mellitus with chronic renal failure: effect of kidney and pancreas transplantation. Metabolism 43:333–347[CrossRef][Medline]
166. Friemann S, Feuring E, Padberg W, Ernst W 1998 Improvement of nephrotoxicity, hypertension, and lipid metabolism after conversion of kidney transplant recipients from cyclosporine to tacrolimus. Transplant Proc 30:1240–1242[CrossRef][Medline]
167. Johnson RW, Kreis H, Oberbauer R, Brattstrom C, Claesson K, Eris J 2001 Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure. Transplantation 72:777–786[CrossRef][Medline]
168. Klein IH, Abrahams A, van Ede T, Hene RJ, Koomans HA, Ligtenberg G 2002 Different effects of tacrolimus and cyclosporine on renal hemodynamics and blood pressure in healthy subjects. Transplantation 73:732–736[Medline]
169. Elliott M, Kapoor A, Parker M, Kaufman D, Bonow R, Gheorghiade M 2001 Improvement in hypertension in patients with diabetes mellitus after kidney/pancreas transplantation. Circulation 104:563–569[Abstract/Free Full Text]
170. Hricik D, Chareandee C, Knauss T, Schulak J 2000 Hypertension after kidney-pancreas transplantation: role of bladder vs enteric pancreatic drainage. Transplantation 70:494–496[CrossRef][Medline]
171. Henley SA, Akhter J, Stratta RJ, Mack-Shipman LR, Miller SJ, Frisbie K, Taylor R, Erickson JM, Leone JP, Lyden E, Ratanasuwan T, Larsen JL 1999 Lipids increase after solitary pancreas transplantation. Diabetes Care 22:320–327[Abstract/Free Full Text]
172. Coppelli A, Giannarelli R, Mariotti R, Rondinini L, Fossati V, Vistoli F, Aragona M, Rizzo G, Boggi U, Mosca F, Del Prato S, Marchetti P 2003 Pancreas transplant alone determines early improvement of cardiovascular risk factors and cardiac function in type 1 diabetic patients. Transplantation 76:974–976[CrossRef][Medline]
173. Brattstrom C, Wilczek H, Tyden G, Bottiger Y, Sawe J, Groth CG 1998 Hyperlipidemia in renal transplant recipients treated with sirolimus (rapamycin). Transplantation 65:1272–1274[Medline]
174. van Hooff JP, Squifflet JP, Wlodarczyk Z, Vanrenterghem Y, Paczek L 2003 A prospective randomized multicenter study of tacrolimus in combination with sirolimus in renal-transplant recipients. Transplantation 75:1934–1939[CrossRef][Medline]
175. Morrisett JD, Abdel-Fattah G, Hoogeveen R, Mitchell E, Ballantyne CM, Pownall HJ, Opekun AR, Jaffe JS, Oppermann S, Kahan BD 2002 Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. J Lipid Res 43:1170–1180[Abstract/Free Full Text]
176. Gonwa T, Mendez R, Yang HC, Weinstein S, Jensik S, Steinberg S 2003 Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6 months. Transplantation 75:1213–1220[CrossRef][Medline]
177. Chueh SC, Kahan BD 2003 Dyslipidemia in renal transplant recipients treated with a sirolimus and cyclosporine-based immunosuppressive regimen: incidence, risk factors, progression, and prognosis. Transplantation 76:375–382[CrossRef][Medline]
178. Larsen JL, Stratta RJ, Miller S, Ozaki C, Taylor RJ, Duckworth WD 1992 Lipid status improves following combined pancreas-kidney transplantation. Diabetes Care 15:35–42[Abstract]
179. Hricik DE, Bartucci MR, Mayes JT, Schulak JA 1992 The effects of steroid withdrawal on the lipoprotein profiles of cyclosporine-treated kidney and kidney-pancreas transplant recipients. Transplantation 54:868–871[Medline]
180. Larsen J, Larson C, Hirst K, Miller SA, Ozaki CF, Taylor RJ, Stratta RJ 1992 Lipid status after combined pancreas-kidney transplantation and kidney transplantation alone in type I diabetes mellitus. Transplantation 54:992–996[Medline]
181. La Rocca E, Secchi A, Parlavecchia M, Bonfatti D, Ragogna F, Di Carlo V, Pozza G, Ruotolo G 1995 Lipoprotein profile after combined kidney-pancreas transplantation in insulin dependent diabetes mellitus. Transpl Int 8:190–195[CrossRef][Medline]
182. Foger B, Konigsrainer A, Ritsch A, Lechleitner M, Steuer W, Margreiter R, Patsch JR 1999 Pancreas transplantation modulates reverse cholesterol transport. Transpl Int 12:360–364[CrossRef][Medline]
183. Araki S-I, Moczulski D, Hanna L, Scott L, Warram J, Krolewski A 2000 ApoE polymorphisms and the development of diabetic nephropathy in type 1 diabetes. Diabetes 49:2190–2195[Abstract/Free Full Text]
184. Balakrishnan S, Colling C, Burkman T, Erickson J, Lyden E, Maheshwari H, Mack-Sipman L, Lane J, Larsen J 2002 Apolipoprotein E gene polymorphism alters lipids before pancreas transplantation. Transplantation 74:974–977[CrossRef][Medline]
185. Woeste G, Wullstein C, Pridohl O, Lubke P, Schwarz R, Kohlhaw K, Bechstein WO 2003 Incidence of minor and major amputations after pancreas/kidney transplantation. Transpl Int 16:128–132[CrossRef][Medline]
186. Fiorina P, La Rocca E, Astorri E, Lucignani G, Rossetti C, Fazio F, Giudici D, di Carlo V, Cristallo M, Pozza G, Secchi A 2000 Reversal of left ventricular diastolic dysfunction after kidney-pancreas transplantation in type 1 diabetic uremic patients. Diabetes Care 23:1804–1810[Abstract/Free Full Text]
187. Fiorina P, La Rocca E, Venturini M, Minicucci F, Fermo I, Paroni R, D’Angelo A, Sblendido M, Di Carlo V, Cristallo M, Del Maschio A, Pozza G, Secchi A 2001 Effects of kidney-pancreas transplantation on atherosclerotic risk factors and endothelial function in patients with uremia and type 1 diabetes. Diabetes 50:496–501[Abstract/Free Full Text]
188. Gliedman ML, Tellis VA, Soberman R, Rifkin H, Veith FJ 1978 Long-term effects of pancreatic transplant function in patients with advanced juvenile-onset diabetes. Diabetes Care 1:1–9[Abstract]
189. Morrissey P, Shaffer D, Monaco A, Conway P, Madras P 1997 Peripheral vascular disease after kidney-pancreas transplantation in diabetic patients with end-stage renal disease. Arch Surg 132:358–361[Abstract/Free Full Text]
190. Knight RJ, Schanzer H, Guy S, Fishbein T, Burrows L, Miller C 1998 Impact of kidney-pancreas transplantation on the progression of peripheral vascular disease in diabetic patients with end-stage renal disease. Transplant Proc 30:1947–1949[CrossRef][Medline]
191. Biesenbach G, Margreiter R, Konigsrainer A, Bosmuller C, Janko O, Brucke P, Gross C, Zazgornik J 2000 Comparison of progression of macrovascular diseases after kidney or pancreas and kidney transplantation in diabetic patients with end-stage renal disease. Diabetologia 43:231–234[CrossRef][Medline]
192. Bruce DS, Newell KA, Josephson MA, Woodle ES, Piper JB, Millis JM, Seaman DS, Carnrike Jr CL, Huss E, Thistlethwaite Jr JR 1996 Long-term outcome of kidney-pancreas transplant recipients with good graft function at one year. Transplantation 62: 451–456
193. Nakache R, Tyden G, Groth CG 1989 Quality of life in diabetic patients after combined pancreas-kidney or kidney transplantation. Diabetes 38(Suppl 1):40–42
194. Zehrer CL, Gross CR 1993 Prevalence of "low blood glucose" symptoms and quality of life in pancreas transplant recipients. Clin Transplant 7:312–319
195. Gross C, Zehrer C 1992 Health-related quality of life of outcomes of pancreas transplant recipients. Clin Transplant 6:165[Medline]
196. Zehrer C, Gross C 1991 Quality of life of pancreas transplant recipients. Diabetologia 34(Suppl 1):S145–S149
197. Milde FK, Hart LK, Zehr PS 1995 Pancreatic transplantation. Impact on the quality of life of diabetic renal transplant recipients. Diabetes Care 18:93–95[Abstract]
198. Kiebert GM, van Oosterhout EC, van Bronswijk H, Lemkes HH, Gooszen HG 1994 Quality of life after combined kidney-pancreas or kidney transplantation in diabetic patients with end-stage renal disease. Clin Transplant 8:239–245[Medline]
199. Sureshkumar KK, Mubin T, Mikhael N, Kashif MA, Nghiem DD, Marcus RJ 2002 Assessment of quality of life after simultaneous pancreas-kidney transplantation. Am J Kidney Dis 39:1300–1306[CrossRef][Medline]
200. Gross CR, Limwattananon C, Matthees B, Zehrer JL, Savik K 2000 Impact of transplantation on quality of life in patients with diabetes and renal dysfunction. Transplantation 70:1736–1746[CrossRef][Medline]
201. Humar A, Khwaja K, Ramcharan T, Asolati M, Kandaswamy R, Gruessner RW, Sutherland DE, Gruessner AC 2003 Chronic rejection: the next major challenge for pancreas transplant recipients. Transplantation 76:918–923[CrossRef][Medline]
202. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus 2003 Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 26:3160–3167[Free Full Text]
203. Davidson J, Wilkinson A, Dantal J, Dotta F, Haller H, Hernandez D, Kasiske BL, Kiberd B, Krentz A, Legendre C, Marchetti P, Markell M, van der Woude FJ, Wheeler DC 2003 New-onset diabetes after transplantation: 2003 International consensus guidelines. Proceedings of an international expert panel meeting. Barcelona, Spain, 19 February 2003. Transplantation 75(Suppl 10):SS3–SS24
204. Jones Jr JW, Mizrahi SS, Bentley FR 1996 Type II diabetes after combined kidney and pancreas transplantation for type I diabetes mellitus and end-stage renal disease. Clin Transplant 10:574–575[Medline]
205. Nielsen JH, Mandrup-Poulsen T, Nerup J 1986 Direct effects of cyclosporin A on human pancreatic ß-cells. Diabetes 35:1049–1052[Abstract]
206. Draznin B, Metz S, Sussman K, Leitner J 1988 Cyclosporin-induced inhibition of insulin release. Biochem Pharmacol 37:3941–3945[CrossRef][Medline]
207. Gillison SL, Bartlett ST, Curry DL 1989 Synthesis-secretion coupling of insulin: effect of cyclosporin. Diabetes 38:465–470[Abstract]
208. Basadonna G, Montorsi F, Kakizaki K, Merrell R 1988 Cyclosporin and islet function. Am J Surg 156:191–193[CrossRef][Medline]
209. Tamura K, Fujimura T, Tsutsumi T, Nakamura K, Ogawa T, Atumaru C, Hirano Y, Ohara K, Ohtsuka K, Shimomura K, Kobayashi M 1995 Transcriptional inhibition of insulin by FK506 and possible involvement of FK506 binding protein-12 in pancreatic ß-cell. Transplantation 59:1606–1613[Medline]
210. Gillison SL, Bartlett ST, Curry DL 1991 Inhibition by cyclosporine of insulin secretion—a ß cell-specific alteration of islet tissue function. Transplantation 52:890–895[Medline]
211. Hirano Y, Mitamura T, Tamura T, Ohara K, Mine Y, Noguchi H 1994 Mechanism of FK506-induced glucose intolerance in rats. J Toxiol Sci 19:61–65
212. Bell E, Cao X, Moibi JA, Greene SR, Young R, Trucco M, Gao Z, Matschinsky FM, Deng S, Markman JF, Naji A, Wolf BA 2003 Rapamycin has a deleterious effect on MIN-6 cells and rat and human islets. Diabetes 52:2731–2739[Abstract/Free Full Text]
213. Paty BW, Harmon JS, Marsh CL, Robertson RP 2002 Inhibitory effects of immunosuppressive drugs on insulin secretion from HIT-T15 cells and Wistar rat islets. Transplantation 73:353–357[CrossRef][Medline]
214. Billaudel B, Sutter BC 1982 Immediate in-vivo effect of corticosterone on glucose-induced insulin secretion in the rat. J Endocrinol 95:315–320[Abstract/Free Full Text]
215. Gold G, Qian RL, Grodsky GM 1988 Insulin biosynthesis in HIT cells. Effects of glucose, forskolin, IBMX, and dexamethasone. Diabetes 37:160–165[Abstract]
216. Philippe J, Missotten M 1990 Dexamethasone inhibits insulin biosynthesis by destabilizing insulin messenger ribonucleic acid in hamster insulinoma cells. Endocrinology 127:1640–1645[Abstract/Free Full Text]
217. Davani B, Khan A, Hult M, Martensson E, Okret S, Efendic S, Jornvall H, Oppermann UC 2000 Type 1 11ß-hydroxysteroid dehydrogenase mediates glucocorticoid activation and insulin release in pancreatic islets. J Biol Chem 275:34841–34844[Abstract/Free Full Text]
218. Kneteman NM, Lakey JR, Wagner T, Finegood D 1996 The metabolic impact of rapamycin (sirolimus) in chronic canine islet graft recipients. Transplantation 61:1206–1210[CrossRef][Medline]
219. Fuhrer DK, Kobayashi M, Jiang H 2001 Insulin release and suppression by tacrolimus, rapamycin and cyclosporin A are through regulation of the ATP-sensitive potassium channel. Diabetes Obes Metab 3:393–402[CrossRef][Medline]
220. Berg CE, Lavan BE, Rondinone CM 2002 Rapamycin partially prevents insulin resistance induced by chronic insulin treatment. Biochem Biophys Res Commun 293:1021–1027[CrossRef][Medline]
221. O’Connor JC, Freund GG 2003 Vanadate and rapamycin synergistically enhance insulin-stimulated glucose uptake. Metabolism 52:666–674[CrossRef][Medline]
222. Lohmann T, Klemm T, Geissler F, Uhlmann D, Ludwig S, Hauss J, Witzigmann H 2002 Islet cell-specific autoantibodies as potential markers for recurrence of autoimmune type 1 diabetes after simultaneous pancreas-kidney transplantation. Transplant Proc 34:2249–2250[CrossRef][Medline]
223. Bosi E, Braghi S, Maffi P, Scirpoli M, Bertuzzi F, Pozza G, Secchi A, Bonifacio E 2001 Autoantibody response to islet transplantation in type 1 diabetes. Diabetes 50:2464–2471[Abstract/Free Full Text]
224. Bosi E, Bottazzo GF, Secchi A, Pozza G, Shattock M, Saunders A, Gelet A, Touraine JL, Traeger J, Dubernard JM 1989 Islet cell autoimmunity in type I diabetic patients after HLA-mismatched pancreas transplantation. Diabetes 38(Suppl 1):82–84
225. Gunnarsson R, Groth CG, Bottazzo GF, Lernmark A 1979 Islet autoantibodies in human pancreatic transplant recipients. Lancet 1:926[Medline]
226. Lampeter EF, Homberg M, Quabeck K, Schaefer UW, Wernet P, Bertrams J, Grosse-Wilde H, Gries FA, Kolb H 1993 Transfer of insulin-dependent diabetes between HLA-identical siblings by bone marrow transplantation. Lancet 341:1243–1244[CrossRef][Medline]
227. Jaeger C, Brendel MD, Hering BJ, Eckhard M, Bretzel RG 1997 Progressive islet graft failure occurs significantly earlier in autoantibody-positive than in autoantibody-negative IDDM recipients of intrahepatic islet allografts. Diabetes 46:1907–1910[Abstract]
228. Thivolet C, Abou-Amara S, Martin X, Lefrancois N, Petruzzo P, McGregor B, Bosshard S, Dubernard JM 2000 Serological markers of recurrent beta cell destruction in diabetic patients undergoing pancreatic transplantation. Transplantation 69:99–103[CrossRef][Medline]
229. Jaeger C, Hering BJ, Hatziagelaki E, Federlin K, Bretzel RG 1999 Glutamic acid decarboxylase antibodies are more frequent than islet cell antibodies in islet transplanted IDDM patients and persist or occur despite immunosuppression. J Mol Med 77:45–48[CrossRef][Medline]
230. Braghi S, Bonifacio E, Secchi A, Di Carlo V, Pozza G, Bosi E 2000 Modulation of humoral islet autoimmunity by pancreas allotransplantation influences allograft outcome in patients with type 1 diabetes. Diabetes 49:218–224[Abstract]
231. Brooks-Worrell BM, Peterson KP, Peterson CM, Palmer JP, Jovanovic L 2000 Reactivation of type 1 diabetes in patients receiving human fetal pancreatic tissue transplants without immunosuppression. Transplantation 69:166–172[CrossRef][Medline]
232. Da Silva M, Thivolet C, Lefrancois N, Bosshard S, Sepeteanu I, Petruzzo P, Dubernard JM, Martin X 2000 Combined analysis of autoantibodies against ß-cells for prediction of pancreas allograft failure. Transplant Proc 32:2773[CrossRef][Medline]
233. Pileggi A, Ricordi C, Alessiani M, Inverardi L 2001 Factors influencing islet of Langerhans graft function and monitoring. Clin Chim Acta 310:3–16[CrossRef][Medline]
234. Esmatjes E, Rodriguez-Villar C, Ricart MJ, Casamitjana R, Martorell J, Sabater L, Astudillo E, Fernandez-Cruz L 1998 Recurrence of immunological markers for type 1 (insulin-dependent) diabetes mellitus in immunosuppresssed patients after pancreas transplantation. Transplantation 66:128–131[CrossRef][Medline]
235. Sundkvist G, Tyden G, Karlsson F, Bolinder J 1998 Islet autoimmunity before and after pancreas transplantation in patients with type 1 diabetes mellitus. Diabetologia 41:1532–1534[CrossRef][Medline]
236. Moretti ME, Sgro M, Johnson DW, Sauve RS, Woolgar MJ, Taddio A, Verjee Z, Giesbrecht E, Koren G, Ito S 2003 Cyclosporine excretion into breast milk. Transplantation 75:2144–2146[CrossRef][Medline]
237. Petruzzo P, Andreelli F, McGregor B, Lefrancois N, Dawahra M, Feitosa LC, Dubernard JM, Thivolet C, Martin X 2000 Evidence of recurrent type 1 diabetes following HLA-mismatched pancreas transplantation. Diabete Metab 26:215–218[Medline]
238. NCEP 2002 Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106:3143–3421[Free Full Text]
239. Kobashigawa JA, Katznelson S, Laks H, Johnson JA, Yeatman L, Wang XM, Chia D, Terasaki PI, Sabad A, Cogert GA, Trosian K, Hamilton MA, Moriguchi JD, Kawata N, Hage A, Drinkwater DC, Stevenson LW 1995 Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 333:621–627[Abstract/Free Full Text]
240. Katznelson S, Wilkinson AH, Kobashigawa JA, Wang XM, Chia D, Ozawa M, Zhong HP, Hirata M, Cohen AH, Terasaki PI, Danovitch GM 1996 The effect of pravastatin on acute rejection after kidney transplantation—a pilot study. Transplantation 61:1469–1474[CrossRef][Medline]
241. Martinez-Castelao A, Grinyo J, Gil-Vernet S, Seron D, Castineiras MJ, Ramos R, Alsina J 2002 Lipid-lowering long-term effects of six different statins in hypercholesterolemic renal transplant patients under cyclosporine immunosuppression. Transplant Proc 34:398–400[CrossRef][Medline]
242. McCune TR, Thacker LR, II, Peters TG, Mulloy L, Rohr MS, Adams PA, Yium J, Light JA, Pruett T, Gaber AO, Selman SH, Jonsson J, Hayes JM, Wright Jr FH, Armata T, Blanton J, Burdick JF 1998 Effects of tacrolimus on hyperlipidemia after successful renal transplantation: a Southeastern Organ Procurement Foundation multicenter clinical study. Transplantation 65:87–92[CrossRef][Medline]
243. Gruessner RW, Sutherland DE, Parr E, Humar A, Gruessner AC 2001 A prospective, randomized, open-label study of steroid withdrawal in pancreas transplantation-a preliminary report with 6-month follow-up. Transplant Proc 33:1663–1664[CrossRef][Medline]
244. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G 2000 Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 342: 145–153
245. Heart Outcomes Prevention Evaluation Study Investigators 2000 Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 355:253–259[CrossRef][Medline]
246. Ball SG, White WB 2003 Debate: angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers—a gap in evidence-based medicine. Am J Cardiol 91:15G–21G
247. Fishman J, Rubin R 1998 Infection in organ-transplant recipients. N Engl J Med 338:1741–1751[Free Full Text]
248. Manske CL, Wang Y, Thomas W 1995 Mortality of cadaveric kidney transplantation versus combined kidney-pancreas transplantation in diabetic patients. Lancet 346:1658–1662[CrossRef][Medline]
249. Stratta RJ, Taylor RJ, Sindhi R, Sudan D, Jerius JT, Gill IS 1996 Analysis of early readmissions after combined pancreas-kidney transplantation. Am J Kidney Dis 28:867–877[Medline]
250. Pirsch JD, Odorico JS, D’Alessandro AM, Knechtle SJ, Becker BN, Sollinger HW 1998 Posttransplant infection in enteric versus bladder-drained simultaneous pancreas-kidney transplant recipients. Transplantation 66:1746–1750[CrossRef][Medline]
251. Martinenghi S, Dell’Antonio G, Secchi A, Di Carlo V, Pozza G 1997 Cancer arising after pancreas and/or kidney transplantation in a series of 99 diabetic patients. Diabetes Care 20:272–275[Abstract]
252. Gruessner RW 1997 Tacrolimus in pancreas transplantation: a multicenter analysis. Tacrolimus Pancreas Transplant Study Group. Clin Transplant 11:299–312[Medline]
253. Egidi MF, Trofe J, Stratta RJ, Flax SD, Gaber LW, Shokouh-Amini MH, Jones M, Vera SR, Grewal HP, Alloway RR, Gaber AO 2001 Posttransplant lymphoproliferative disorders: single center experience. Transplant Proc 33:1838–1839[CrossRef][Medline]
254. Birkeland SA, Hamilton-Dutoit S, Bendtzen K 2003 Long-term follow-up of kidney transplant patients with posttransplant lymphoproliferative disorder: duration of posttransplant lymphoproliferative disorder-induced operational graft tolerance, interleukin-18 course, and results of retransplantation. Transplantation 76:153–158[CrossRef][Medline]
255. Epstein S, Dissanayake I, Goodman G, Bowman AR, Zhou H, Ma Y, Jee WS 2001 Effect of the interaction of parathyroid hormone and cyclosporine A on bone mineral metabolism in the rat. Calcif Tissue Int 68:240–247[CrossRef][Medline]
256. Bowman A, Sass D, Dissanayake I, Ma YF, Liang H, Yuan Z, Jee WS, Epstein S 1997 The role of testosterone in cyclosporine-induced osteopenia. J Bone Miner Res 12:607–615[CrossRef][Medline]
257. Fornoni A, Cornacchia F, Howard G, Roos B, Striker G, Striker L 2001 Cyclosporin A affects extracellular matrix synthesis and degradation by mouse MC3T3–E1 osteoblasts in vitro. Nephrol Dial Transplant 16:500–505[Abstract/Free Full Text]
258. Stempfle HU, Werner C, Siebert U, Assum T, Wehr U, Rambeck WA, Meiser B, Theisen K, Gartner R 2002 The role of tacrolimus (FK506)-based immunosuppression on bone mineral density and bone turnover after cardiac transplantation: a prospective, longitudinal, randomized, double-blind trial with calcitriol. Transplantation 73:547–552[CrossRef][Medline]
259. Weber T, Quarles L 2000 Preventing bone loss after renal transplantation with bisphosphonates: we can, but should we? Kidney Int 57:735–737[CrossRef][Medline]
260. Chiu M, Sprague S, Bruce D, Woodle E, Thistlethwaite J, Josephson M 1998 Analysis of fracture prevalanece in kidney-pancreas allograft recipients. J Am Soc Nephrol 9:677–683[Abstract]
261. Smets Y, van der Pijl J, de Fijter J, Ringers J, Lemkes H, Handy N 1998 Low bone mass and high incidence of fractures after successful simultaneous pancreas-kidney transplantation. Nephrol Dial Transplant 13:1250–1255[Abstract/Free Full Text]
262. Nisbeth U, Lindh E, Ljunghall S, Backman U, Fellstrom B 1999 Increased fracture rate in diabetes mellitus and females after renal transplantation. Transplantation 67:1218–1222[CrossRef][Medline]
263. Vautour LM, Melton III LJ, Clarke BL, Achenbach SJ, Oberg AL, McCarthy JT 2004 Long-term fracture risk following renal transplantation: a population-based study. Osteoporos Int 15:160–167[CrossRef][Medline]
264. O’Shaughnessy E, Dahl D, Smith C, Kasiske B 2002 Risk factors for fractures in kidney transplantation. Transplantation 74:362–366[CrossRef][Medline]
265. Durieux S, Mercadal L, Orcel P, Dao H, Rioux C, Bernard M, Rozenberg S, Barrow B, Bourgeois P, Deray G, Bagnis CI 2002 Bone mineral density and fracture prevalence in long-term kidney graft recipients. Transplantation 74:496–500[CrossRef][Medline]
266. Jeffery JR, Leslie WD, Karpinski ME, Nickerson PW, Rush DN 2003 Prevalence and treatment of decreased bone density in renal transplant recipients: a randomized prospective trial of calcitriol versus alendronate. Transplantation 76:1498–1502[CrossRef][Medline]
267. Mack-Shipman L, O’Grady D, Erickson J, Walker CW, Moore TE, Burkman T, Lane JT, Larsen JL2004 Heel ultrasonography is not a good screening tool for bone loss in kidney and kidney-pancreas transplant recipients. Clin Transplant 18:613–618
268. Cahill BC, O’Rourke MK, Parker S, Stringham JC, Karwande SV, Knecht TP 2001 Prevention of bone loss and fracture after lung transplantation: a pilot study. Transplantation 72:1251–1255[CrossRef][Medline]
269. Mitchell MJ, Baz MA, Fulton MN, Lisor CF, Braith RW 2003 Resistance training prevents vertebral osteoporosis in lung transplant recipients. Transplantation 76:557–562[Medline]
270. Stempfle H-U, Werner C, Echtler S, Wehr U, Rambeck WA, Siebert U, Uberfuhr P, Angermann CE, Theisen K, Gartner R 1999 Prevention of osteoporosis after cardiac transplantation. Transplantation 68:523–530[CrossRef][Medline]
271. Krieg M, Seydoux C, Sandini L, Goy JJ, Berguer DG, Thiebaud D, Burckhardt P 2001 Intravenous pamidronate as treatment for osteoporosis after heart transplantation: a prospective study. Osteoporos Int 12:112–116[CrossRef][Medline]
272. Van Cleemput J, Daenen W, Geusens P, Dequeker P, Van De Werf F, VanHaecke J 1996 Prevention of bone loss in cardiac transplant recipients. A comparison of biphosphonates and vitamin D. Transplantation 61:1495–1499[CrossRef][Medline]
273. Bianda T, Linka A, Junga G, Brunner H, Steinert H, Kiowski W, Schmid C 2000 Prevention of osteoporosis in heart transplant recipients: a comparison of calcitriol with calcitonin and pamidronate. Calcif Tissue Int 67:116–121[CrossRef][Medline]
274. Nincovic M, Love S, Tom B, Bearcroft P, Alexander G, Compston J 2002 Lack of effect of intravenous pamidronate on fracture incidence and bone mineral density after orthotopic liver transplantation. J Hepatol 37:93–100[CrossRef][Medline]
275. Fan S, Almond M, Ball E, Evans K, Cunningham J 2000 Pamidronate therapy as prevention of bone loss following renal transplantation. Kidney Int 57:684–690[Medline]
276. Carreau A, Gueugnon J, Benavides J, Vige X 1997 Comparative effects of FK-506, rapamycin and cyclosporin A, on the in vitro differentiation of dorsal root ganglia explants and septal cholinergic neurons. Neuropharmacology 36:1755–1762[CrossRef][Medline]
277. Brenckmann C, Papioannou A 2001 Bisphosphonates for osteoporosis in people with cystic fibrosis. Cochrane Database Syst Rev 4:CD002010
278. Arlen DJ, Lambert K, Ioannidis G, Adachi JD 2001 Treatment of established bone loss after renal transplantation with etidronate. Transplantation 71:669–673[CrossRef][Medline]
279. Kovac D, Lindic J, Kandus A, Bren A 2000 Prevention of bone loss with alendronate in kidney transplant recipients. Transplantation 70:1542–1543[Medline]
280. Henderson K, Eisman J, Keogh A, MacDonald P, Glanville A, Spratt P, Sambrook P 2001 Protective effect of short-term calcitriol or cyclical etidronate on bone loss after cardiac or lung transplantation. J Bone Miner Res 16:565–571[CrossRef][Medline]
281. Cruz D, Brickel H, Wysolmerski J, Gundberg CG, Simpson CA, Kliger AS, Lorber MI, Basadonna GP, Friedman AL, Insogna KL, Bia MJ 2002 Treatment of osteoporosis and osteopenia in long-term renal transplant patients with alendronate. Am J Transplant 2:62–67[CrossRef][Medline]
282. Giannini S, Dangel A, Carraro G, Nobile M, Rigotti P, Bonfante L, Marchini F, Zaninotto M, Dalle’Carbonare L, Sartori L, Crepaldi G 2001 Alendronate prevents further bone loss in renal transplant recipients. J Bone Miner Res 16:2111–2117[CrossRef][Medline]
283. Shane E, Addesso V, Namerow PB, Mcmahon DJ, Lo SH, Staron RB, Zucker M, Pardi S, Maybaum S, Mancini D 2004 Alendronate versus calcitriol for the prevention of bone loss after cardiac transplantation. N Engl J Med 350:767–776[Abstract/Free Full Text]
284. Schwarz C, Mitterbauer C, Heinze G, Woloszczuk W, Haas M, Oberbauer R 2004 Nonsustained effect of short-term bisphosphonate therapy on bone turnover three years after renal transplantation. Kidney Int 65:304–309[CrossRef][Medline]
285. Guichelaar MM, Malinchoc M, Sibonga JD, Clarke BL, Hay JE 2003 Bone histomorphometric changes after liver transplantation for chronic cholestatic liver disease. J Bone Miner Res 18:2190–2199[CrossRef][Medline]
286. Hay JE, Malinchoc M, Dickson ER 2001 A controlled trial of calcitonin therapy for the prevention of post-liver transplantation atraumatic fractures in patients with primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol 34:292–298[CrossRef][Medline]
287. Handelsman DJ, Ralec VL, Tiller DJ, Horvath JS, Turtle JR 1981 Testicular function after renal transplantation. Clin Endocrinol (Oxf) 14:527–538[Medline]
288. Lim VS, Fang VS 1975 Gonadal dysfunction in uremic men. A study of the hypothalamo-pituitary-testicular axis before and after renal transplantation. Am J Med 58:655–662[CrossRef][Medline]
289. Smith CR, Butler J, Iggo N, Norman MR 1989 Serum prolactin in uraemia: correlations between bioactivity and activity in two immunoassays. Acta Endocrinol (Copenh) 120:295–300[Abstract/Free Full Text]
290. Prem AR, Punekar SV, Kalpana M, Kelkar AR, Acharya VN 1996 Male reproductive function in uraemia: efficacy of haemodialysis and renal transplantation. Br J Urol 78:635–638[CrossRef][Medline]
291. Saha MT, Saha HH, Niskanen LK, Salmela KT, Pasternack AI 2002 Time course of serum prolactin and sex hormones following successful renal transplantation. Nephron 92:735–737[CrossRef][Medline]
292. Handelsman DJ, Dong Q 1993 Hypothalamo-pituitary gonadal axis in chronic renal failure. Endocrinol Metab Clin North Am 22:145–161[Medline]
293. Haberman J, Karwa G, Greenstein SM, Soberman R, Glicklich D, Tellis V, Melman A 1991 Male fertility in cyclosporine-treated renal transplant patients. J Urol 145:294–296[Medline]
294. Bererhi L, Flamant M, Martinez F, Karras A, Thervet E, Legendre C 2003 Rapamycin-induced oligospermia. Transplantation 76: 1885–886
295. Mack-Shipman LR, Ratanasuwan T, Leone JP, Miller SA, Lyden ER, Erickson JM, Larsen JL 2000 Reproductive hormones after pancreas transplantation. Transplantation 70:1180–1183[CrossRef][Medline]
296. Kim JH, Chun CJ, Kang CM, Kwak JY 1998 Kidney transplantation and menstrual changes. Transplant Proc 30:3057–3059[CrossRef][Medline]
297. Sawamura M, Takao M, Asano T, Odajima K, Nagakura K, Murai M, Nakamura H 1992 Female gonadal function after renal transplantation. Transplant Proc 24:1573–1575[Medline]
298. Koutsikos D, Sarandakou A, Agroyannis B, Tzanatos H, Tsoutsos D, Konstadinidou I, Phocas I 1990 The effect of successful renal transplantation on hormonal status of female recipients. Ren Fail 12:125–132[Medline]
299. Castaneda S, Carmona L, Carvajal I, Arranz R, Diaz A, Garcia-Vadillo A 1997 Reduction of bone mass in women after bone marrow transplantation. Calcif Tissue Int 60:343–347[CrossRef][Medline]
300. Hart LK, Milde FK, Zehr PS, Cox DM, Tarara DT, Fearing MO 1997 Survey of sexual concerns among organ transplant recipients. J Transpl Coord 7:82–87[Medline]
301. Armenti VT, Radomski JS, Moritz MJ, Gaughan WJ, Philips LZ, McGrory CH, Coscia LA, National Transplantation Pregnancy Registry 2002 Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transpl 121–130
302. Barrou BM, Gruessner AC, Sutherland DE, Gruessner RW 1998 Pregnancy after pancreas transplantation in the cyclosporine era: report from the International Pancreas Transplant Registry. Transplantation 65:524–527[CrossRef][Medline]
303. Armenti V, Radomski J, Moritz M, Philips L, McGrory C, Coscia L 2000 Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. In: Tersaki CA, ed. Clinical transplants 2000. Los Angeles: UCLA Immunogenetics Center; 123–134
304. Armenti VT, Ahlswede KM, Ahlswede BA, Jarrell BE, Moritz MJ, Burke JF 1994 National Transplantation Pregnancy Registry-outcomes of 154 pregnancies in cyclosporine-treated female kidney transplant recipients. Transplantation 57:502–506[Medline]
305. Burton PB, Yacoub MH, Barton PJ 1998 Rapamycin (sirolimus) inhibits heart cell growth in vitro. Pediatr Cardiol 19:468–470[CrossRef][Medline]

This article has been cited by other articles:

				M.-C. Vantyghem, J. Kerr-Conte, L. Arnalsteen, G. Sergent, F. Defrance, V. Gmyr, N. Declerck, V. Raverdy, B. Vandewalle, P. Pigny, et al. Primary Graft Function, Metabolic Control, and Graft Survival After Islet Transplantation Diabetes Care, August 1, 2009; 32(8): 1473 - 1478. [Abstract] [Full Text] [PDF]

				J. Frystyk, R. A. Ritzel, J. Maubach, M. Busing, R. Luck, J. Klempnauer, W. Schmiegel, and M. A. Nauck Comparison of Pancreas-Transplanted Type 1 Diabetic Patients with Portal-Venous Versus Systemic-Venous Graft Drainage: Impact on Glucose Regulatory Hormones and the Growth Hormone/Insulin-Like Growth Factor-I Axis J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1758 - 1766. [Abstract] [Full Text] [PDF]

				C. D Dieterle, H. Arbogast, W.-D. Illner, S. Schmauss, and R. Landgraf Metabolic follow-up after long-term pancreas graft survival Eur. J. Endocrinol., May 1, 2007; 156(5): 603 - 610. [Abstract] [Full Text] [PDF]

				I. Cozar-Castellano and A. F. Stewart Molecular engineering human hepatocytes into pancreatic beta cells for diabetes therapy PNAS, May 31, 2005; 102(22): 7781 - 7782. [Full Text] [PDF]

This Article Abstract Full Text (PDF) A correction has been published Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Larsen, J. L. Search for Related Content PubMed PubMed Citation Articles by Larsen, J. L.