The significant improvements in the results of kidney and pancreas transplantation have been due in large part to advances in immunosuppression [30]. The impact of newer immunosuppressive agents has been most notable in PAK and PTA transplants. The basic approach to immunosuppression for kidney and pancreas transplant recipients is similar to that for kidney transplant recipients. The incidence of acute rejection for patients receiving a pancreas transplants (Table 33.2) is significantly higher than a kidney transplant alone. The 1-year incidence of acute rejection is 17 % for SPK transplants, 20 % for PAK transplants, and 24 % for PTA transplants [3]. This is approximately double the rates of rejection seen in kidney transplants. With cyclosporine-, azathioprine-, and prednisone-based immunosuppression, the 1-year incidence of rejection in SPK and PAK recipients was as high as 80 %. The increased immunogenicity of the pancreas transplant has resulted in more intensive induction and maintenance immunosuppression being used for pancreas transplantation. The early and generally vigorous acute rejection associated with pancreas transplantation under conventional immunosuppression resulted in the nearly universal application of antibody-based induction therapy. With the introduction of tacrolimus and mycophenolate mofetil in the mid-1990s, the 1-year incidence of acute rejection in pancreas transplant recipients was reduced to approximately 30 %. Current agents available for induction include the polyclonal T-cell-depleting antibodies, such as Thymoglobulin or Campath. Interleukin-2 receptor blockade such as basiliximab is less commonly used for pancreas transplantation. Maintenance immunosuppression is generally based on the calcineurin inhibitors, tacrolimus, or cyclosporine. These are commonly used in conjunction with mycophenolate mofetil or mycophenolic acid. Corticosteroids are commonly used as a third agent in maintenance immunosuppression. Corticosteroid avoidance or withdrawal protocols have been successful and have been increasingly employed [31, 32]. Registry data now suggests that up to 40 % of transplant patients are not maintained on corticosteroids [3].

Most kidney and pancreas transplant programs currently use a quadruple induction protocol. Immunosuppression is achieved by induction with rabbit antithymocyte globulin and alemtuzumab which have been reported to provide equivalent results [31, 33]. These agents are generally infused for 7 days beginning on the first postoperative day for antithymocyte globulin or intraoperatively in the case of alemtuzumab. The response to antithymocyte globulin is monitored by measuring CD3-positive lymphocytes and adjusting the dose of the induction agent accordingly. Since the mid-1990s, the majority of pancreas transplant programs have used tacrolimus as the basis of immunosuppression. This is begun immediately post-transplant unless there is delayed graft function of the kidney. Tacrolimus levels are generally targeted to the 8–12 ng/mL range in the early stages of transplantation and are generally tapered to lower levels over the first few months. Mycophenolate preparations are a commonly used additional agent. This is commonly begun with a dose in the range of 1,000 mg twice a day of mycophenolate mofetil or the equivalent dose of mycophenolic acid. This dose is generally maintained unless reduction for bone marrow suppression or gastrointestinal side effects is required.

Infection prophylaxis generally is similar to that employed in kidney transplantation with oral antifungal medication for prevention of thrush, antibiotic prophylaxis for urinary tract infection, and antiviral prophylaxis with valganciclovir to prevent reactivation of cytomegalovirus. Additionally pancreas transplant recipients have been reported to develop BK virus infections either in the transplanted kidney or in the native kidney in the case of PTA recipients [34–36] and screening for evidence of polyomavirus reactivation with serum PCR or urine cytology is recommended.

There are a variety of new approaches to immunosuppression in kidney and pancreas transplant recipients that are being evaluated such as the use of calcineurin-free or minimization regimens with sirolimus [37]. Giancio et al. [38] have reported improved rejection rates and equivalent patient and allograft survival rates with the combination of tacrolimus and sirolimus and steroids compared to tacrolimus with mycophenolate mofetil and steroids. The role of co-stimulatory blockade with agents such as belatacept remains to be defined.

An accurate and timely diagnosis of acute rejection has historically been one of the most difficult clinical problems in transplantation. This has been a limiting factor in the clinical success of pancreas transplantation, especially in PAK or PTA transplants. SPK transplantation has had the distinct advantage of allowing the assessment of renal function to be a surrogate marker for pancreas rejection, since in the large majority of such cases, acute rejection occurs simultaneously in both the kidney and pancreas allograft. Isolated pancreas allograft rejection has been reported to occur in probably less than 10 % of rejections in kidney and pancreas transplant recipients [39]. Assessment of the kidney for rejection using a simple needle biopsy in most cases allowed the accurate and relatively timely diagnosis of acute rejection of the pancreas. Rejection in the kidney can be identified in some cases even if the serum creatinine is unchanged from baseline values. This approach could not be applied to solitary pancreas transplantation, and this limitation was felt to be one of the major reasons for the inferior success of solitary pancreas transplantation.

Pancreas allograft function is generally monitored through serial measurements of serum amylase and lipase. Other serum and urinary markers for the diagnosis of rejection have not proven to be superior to serum amylase and lipase values. In the occasionally encountered bladder-drained pancreas transplants, the urinary amylase can be monitored to assess pancreas function. In this situation, acute rejection is associated with a decrease in urine amylase. Serum levels of amylase and lipase are significantly increased in acute rejection; however, occasional cases of histologically proven pancreas rejection have been seen in patients with no abnormalities of serum amylase or lipase. Serum enzymes are, however, nonspecific for the diagnosis of pancreas rejection. Serum amylase is considered to have an approximate 90 % sensitivity and a significantly lower specificity for the diagnosis of acute rejection.

Pancreas allograft rejection is difficult to diagnose by clinical findings. In most cases of pancreas allograft rejection, the clinical symptoms are nonexistent. In 5–20 % of patients with pancreas allograft rejection, there is associated abdominal pain and discomfort. This is likely related to peritoneal irritation from an acutely inflamed allograft. Fever may occasionally be present, but is not uniform. Inflammation of the surrounding bowel may result in an ileus and symptoms of abdominal obstruction. It is important to note that hyperglycemia is a very late finding in acute allograft rejection due to the large beta cell reserve inherent in the pancreas allograft. Patients presenting with hyperglycemia related to rejection represent advanced aggressive rejection and generally have a poor outcome with respect to reversal of the acute rejection episode.

In the pancreas allograft as in other solid organ transplants, histologic assessment of rejection is the gold standard by which the diagnosis of rejection is made. Most programs have adopted percutaneous pancreas allograft biopsy as the procedure of choice for the diagnosis of pancreas allograft rejection. This technique is very similar to that employed in kidney allograft biopsies. The pancreas is localized within the abdomen using real-time ultrasonography. The major vascular structures are identified, and a core needle biopsy using an 18-gauge automated biopsy needle is obtained for histologic assessment. This technique has a complication rate similar to that of kidney allograft biopsies. The most common complication is bleeding from the allograft. This occurs in less than 5 % of cases. In cases where there is bowel overlying the pancreas allograft, a CT-guided percutaneous biopsy can sometimes be successfully employed or, failing this, a laparoscopic biopsy can be obtained.

A standard histologic grading scheme for pancreas allograft biopsies has been developed [40]. This grading scheme has been shown to correlate with outcome following treatment of identified acute rejection episodes. Core needle biopsies have also been utilized to diagnose post-transplant lymphoma presenting in the pancreas allograft, CMV pancreatitis, and islet cell toxicity associated with calcineurin inhibitors. Pancreas biopsies also allow the assessment of chronic rejection within the pancreas allograft. This is manifested by allograft fibrosis and vascular changes similar to that seen in other solid organs. An approach to histologic grading of chronic rejection has also been described [41] and this, too, correlates with the clinical outcome of the graft. Chronically rejecting pancreas allografts with advancing fibrosis gradually decrease in size and may sometimes be difficult to identify either by ultrasound or by CT scan. A patient presenting with significant hyperglycemia, a normal serum amylase and lipase, and an unidentifiable pancreas allograft almost invariably has end-stage chronic pancreas allograft rejection and will need to resume exogenous insulin. Confusion resulting form the development of type 2 diabetes can usually be resolved by checking the serum c-peptide level. The c-peptide level is low in a chronically rejected pancreas allograft but is elevated in type 2 diabetes.

Pancreas allografts are subject to antibody-mediated rejection. The histologic criteria for diagnosis of antibody-mediated rejection have been defined by Drachenberg et al. [42] as part of the Banff transplant pathology process. Successful treatment of acute antibody-mediated pancreas allograft rejection using plasmapheresis and intravenous immunoglobulin has been reported [43]. The significance of donor-specific antibodies in the outcomes of pancreas transplantation has not been well defined. Early development of donor-specific antibody has been observed in approximately 15–20 % of pancreas transplant recipients with no impact on early outcomes in a small study [44]. Longer follow-up of donor-specific antibody-positive pancreas transplant recipients has suggested a negative impact on graft survival [45].

Acute cellular rejection is generally treated with agents similar to those used for acute kidney allograft rejection. Traditionally, pancreas allograft rejection has been felt to be poorly responsive to pulse steroids. Anti-T-cell antibody therapy is the mainstay of pancreas allograft rejection therapy. In recent years, however, the use of more potent maintenance immunosuppressive agents and the use of biopsy to diagnose acute rejection at earlier clinical stages have allowed corticosteroids to be used more successfully for the treatment of pancreas rejection. Treatment with a daily dose of 500 mg of methylprednisolone for 3 days followed by tapering doses over 2 weeks is commonly the first-line therapy and is effective in the majority of cases. Initial treatment of severe rejection or rejection resistant to therapy with corticosteroids requires the use of antilymphocyte antibody therapy. Polyclonal antilymphocyte globulin is the most commonly used preparation. This is usually given for up to 7 days. The dose is adjusted to maintain low levels of CD3-positive lymphocytes. These antilymphocyte antibody therapies are highly effective and result in reversal of the pancreas allograft rejection in over 90 % of cases.

One of the most debilitating secondary complications of diabetes is hypoglycemic unawareness. Patients with long-standing diabetes become desensitized to the symptoms of hypoglycemia that would normally serve as a warning to dangerously low levels of glucose. The normal defense mechanism includes secretion of both glucagon and epinephrine. Both of these responses may be impaired in some diabetics. Successful pancreas transplantation is able to largely abrogate this problem. Hypoglycemic clamp studies in pancreas transplant recipients have shown that both glucagon and epinephrine responses are substantially improved, although they may remain somewhat less than matched control subjects [46–48]. This freedom from hypoglycemic unawareness is one of the major benefits of successful pancreas transplantation for many recipients.

It has been more difficult to document a significant effect of pancreas transplantation on diabetic retinopathy [49–53]. The majority of patients studied have had advanced retinopathy at the time of transplantation. Although retinopathy may be stabilized, it may require longer-term follow-up to document significant benefits on progression of retinopathy.

There is evidence that diabetic nephropathy may be stabilized and even improved following successful pancreas transplantation [54–56]. Most studies involving this issue have been relatively small, and long-term follow-up of up to 10 years has been required to demonstrate a positive benefit. Shorter-term studies have shown no benefit [57]. Studies have shown that patients receiving a pancreas transplant may have improvements in glomerular basement membrane thickness and mesangial volume and glomerular structure when long-term follow-up is available. This benefit has been observed in the native kidneys of patients who have received a solitary pancreas transplant, as well as in the transplanted kidney in patients receiving both kidney and pancreas transplants.