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The purpose of pancreas transplantation is to ameliorate type I diabetes and produce complete insulin independence. The first successful.
Table of contents

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 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. Ideally, pancreas-after-kidney transplant should be performed when the kidney graft is stable.

In , 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. 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 , Frequent, severe, hypoglycemic events are the most common indication for this procedure.

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. Even with careful patient selection, kidney function may still deteriorate over time. Yet, by 10 yr after solitary pancreas transplant, the pathological changes of diabetes can reverse Drainage of the exocrine duct into the urinary bladder was first described by Sollinger et al.

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 Oral sodium bicarbonate therapy is required in almost all and minimizes these complications in most.

The alternative to BD is ED of the exocrine duct. Roux-en-Y was used predominantly in early ED procedures, but most centers no longer prefer a Roux-en-Y connection 2. There is less need for monitoring the pancreas graft, overall, because immunosuppression has improved and frequency of rejection episodes has decreased after pancreas transplant of all types.

Indications for enteric conversion surgery are frequent episodes of severe extracellular volume depletion, severe metabolic acidosis, urological complications, or problems with the duodenal segment. The hospitalization generally lasts 6—30 d mean 12 d , with ED leak being the most common complication. In pancreas-after-kidney and pancreas-alone transplants, 1-yr pancreas graft survival is better with BD than ED 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 — 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 , 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 — were analyzed, recipients of PVD or ED had greater patient mortality 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 However, when a randomized prospective study compared the two procedures, pancreas graft survival was the same Total fasting lipid concentrations are not different between individuals receiving PVD and SVD 58 , 59 , but lipoprotein composition may be. Hughes et al. 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.

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 , 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 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 Gruessner and Sutherland 17 have recently reviewed the current immunosuppression protocols being used for pancreas transplant as reported to UNOS.

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. 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 , The choice and type of antibody induction therapy being used are even more variable 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.

The most important outcome of a new or established procedure is its impact on patient survival.


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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 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 — 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 , 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 No gender or ethnic differences in patient mortality have been reported, but duration of diabetes also increases risk 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 , 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 , 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 , 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 yr patient survival as simultaneous pancreas-kidney transplant 73 , 75 , 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 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 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. Pancreas transplant alone was also reported to cause greater patient mortality than that observed in a matched cohort waiting for this procedure 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. 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 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.

Pancreas transplantation

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. Glucose concentration and A1C normalize in most recipients immediately after successful pancreas transplant 49 — 51 , 80 , 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. 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.

Kidney and Pancreas Transplant Program

Antiinsulin antibodies can persist after transplant and can increase total insulin concentrations as well Only studies in whole-organ pancreas transplant recipients will be reviewed. Fasting insulin concentrations are two to three times greater than normal after pancreas transplant performed with SVD, but decrease over the first 12—24 months with decreasing immunosuppressant doses. Glucose- and arginine-stimulated insulin concentrations are also increased, but these peak, stimulated concentrations do not decrease considerably over time 49 — 51 , 61 , 80 , 81 , Two groups most clearly demonstrated that the hyperinsulinemia with SVD results from a delay in first-pass hepatic extraction 50 , In contrast, only mild elevations in insulin concentration are observed with PVD, similar to nondiabetic kidney transplant patients treated with corticosteroids 52 , 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.

I. Introduction

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 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 However, another group suggested that although frequency was unchanged, pulsation amplitude was increased compared with controls 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 , 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 , 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 , Several 83 , 94 — 96 , although not all 80 , 90 , investigators reported that proinsulin was increased after pancreas transplant.

Proinsulin to insulin and proinsulin to C peptide ratios are also similar to those reported in kidney transplant recipients 94 , 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 — Oral glucose suppresses glucagon secretion in pancreas transplant recipients more than controls, but is similar to that of nondiabetic kidney transplant recipients 81 , 99 , Most importantly, glucagon secretion in response to hypoglycemia recovers after transplant, returning to normal in some studies , or less than normal, but improved in others, compared with type 1 diabetic controls 90 , 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. 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.

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 , By 3 months after pancreas transplant, glucagon secretion and hepatic glucose production in response to hypoglycemia also return to normal , Although epinephrine and GH responses to hypoglycemia improve after pancreas transplant, these do not return to normal , Most importantly, hypoglycemia symptom score also returns to normal after pancreas transplant Episodic hypoglycemia was reported in a minority of recipients in the early months after pancreas transplant 82 , — 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 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 Glucose concentration after a 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 A recent case of hypoglycemia after pancreas transplant was reported to have nesidiodysplasia, another potential cause of hypoglycemia 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 , Thus, islet transplantation, commonly performed for treatment of hypoglycemia, may not be as effective a treatment for this indication.

chapter and author info

Risk of microvascular complications of diabetes is linked to glucose concentration 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 — 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 , 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.

Pancreas transplantation: review

Most pancreas transplant candidates have had laser surgery for retinopathy before transplant , This damage cannot be reversed. 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 , , , , , 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 — , , 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.

Mean A1C of the pancreas transplant group was 6. 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 Thus, patients with advanced retinopathy may or may not benefit from pancreas transplant, and normoglycemia is likely required for a benefit to be observed.

Introduction

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 However, cataracts can worsen after pancreas transplant and may be the most common long-term eye disease identified after transplant 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.

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. 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 , — In fact, continued improvement in sensory and motor neuropathies can be observed as late as 10 yr after transplant 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 However, if the pancreas fails, nerve conduction velocity can worsen again to pretransplant levels within 2 yr 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 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 Diabetic autonomic neuropathies take longer to develop, are more variable from person to person, and can be much more difficult to quantitate.

Having autonomic neuropathy already marks an individual at higher risk for mortality as discussed above 74 , 76 , 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 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 Whether or how much pancreas transplant alters the course of autonomic neuropathies is still controversial.