Simultaneous pancreas kidney transplantation (SPK) with over 30 000 transplants performed worldwide has become the treatment of choice for patients with type I diabetes and end-stage renal failure [1▪]. Advances and refinements in graft preservation, surgical techniques and, in particular, advances in immunosuppressive drug development and treatment strategies have led to significant improved outcomes in pancreas transplantation over the past two decades. According to the Scientific Registry of Transplant Recipients (SRTR) the most common used maintenance regimen today is a combination of tacrolimus and mycophenolate mofetil (MMF) with early or delayed corticosteroid withdrawal. Additionally, more than 80% of pancreas transplant recipients received an induction therapy, with T-cell-depleting agents or anti-IL2 receptor antagonists .
These regimens lead to a significant decrease in acute cellular rejection (ACR) rates and resulted in 1-year patient survival rates of 97% and a pancreas allograft survival of 88%. Despite such short-term success, the long-term pancreas graft survival has not shown a similar rate of improvement. According to data from the United Network of Organ Sharing (UNOS) the 5-year graft survival has not changed significantly since 1987 and remains idle at 63% [1▪,3]. This stagnancy in improving the long-term outcome after pancreas transplantation is closely related to adverse effects and toxicities of the commonly used immunosuppressant agents and maintenance regimens. This clearly advocates to continue to critically analyze the results of clinical trials and to investigate drug combinations that could avoid potentiated but modifiable risk factors and toxicities.
In this review we will give an overview of the currently used protocols as well as recent and new developments with regards to both protocol design and novel immunosuppressive agents. Since a comprehensive review on this topic was published in 2008 by Singh and Stratta  in this journal we have focused on the most recent literature as well as advances and trends over the past few years.
Anti-T-cell antibody induction therapy with either polyclonal [rabbit antithymocyte globulin (rATG)] or monoclonal antibodies [anti-CD52 antibody, alemtuzumab; anti-interleukin (IL)-2 receptor antibodies, basiliximab and daclizumab] has been a cornerstone of immunosuppressive protocols used for pancreas transplantation and is currently applied in nearly 90% of all SPK recipients [5–7]. Antibody induction in SPK is used under the premise to lower the risk of early acute rejection episodes, to improve renal allograft function and perhaps even inducing tolerogenic effects . However, the type of antibody induction given to pancreas transplant recipients still varies greatly amongst individual transplant centers and there is no consensus on whether to use poly-or monoclonal preparations or depleting and nondepleting agents . Amongst all the available agents, alemtuzumab or rATG is currently the most common approach for T-cell-depleting antibody induction in pancreas transplantation.
As one of the first groups Kaufman et al.  performed a comparative study of alemtuzumab vs. rATG as induction immunosuppression in 88 SPK recipients given an early steroid elimination protocol and tacrolimus/sirolimus-based maintenance therapy. At 3 years, the overall patient, pancreas, and kidney graft survival rates showed no difference. However, the incidences of acute rejection at 12 months for rATG vs. alemtuzumab were 6.1 and 2.6%, respectively. Furthermore, the alemtuzumab group had statistically significantly lower viral infectious complications [cytomegalovirus(CMV)] and compared to rATG the cost of alemtuzumab induction was lower.
More recently, Farney et al.  reported a prospective randomized single-center study evaluating the safety and efficacy of single-dose alemtuzumab (30 mg) and rATG antibody induction in adult kidney and pancreas transplant recipients. The maintenance protocol consisted of tacrolimus, MMF, and either early steroid withdrawal or rapid steroid taper. With a median follow-up of 2 years, overall patient, kidney, and pancreas graft survival rates were 96, 89, and 90%, respectively. Early biopsy-proven acute rejection episodes occurred in 16 (14%) of the alemtuzumab patients compared with 28 (26%) in the rATG patients. However, late acute rejection episodes beyond 12 months were comparable in both groups with one (8%) in the alemtuzumab group and three (11%) in the rATG patients. Also infectious and malignant complications were similar between the two induction regimens.
Uemura et al.  performed a study of 28 pancreas transplants [17 SPK, 5 pancreas after kidney (PAK) and 6 pancreas transplant alone (PTA)] receiving induction therapy using a single dose of alemtuzumab induction. The maintenance immunosuppression regimen was steroid-free and tacrolimus and mycophenolate-based. Median patient follow-up was 25 months (range 9–49 months). ACR occurred in 42% of patients but most of them at 1 or 6 months post transplant. CMV and bacterial infections occurred with an incidence of 28 and 36%, respectively. The 1-year actuarial patient/graft survival was 100/100% in SPK, PAK, and PTA. Three-year actuarial patient/pancreas graft survival rates of SPK, PAK, and PTA were 100/100/100% and 100/100/83%, respectively. Despite the fact that this was an uncontrolled study with a small-sized patient cohort the authors were able to demonstrate that excellent graft survival with alemtuzumab induction and steroid free, tacrolimus and MMF-based immunosuppression can be achieved as compared with the US national average (SPK 79%, PTA 65%, PAK 65%).
A retrospective analysis of 74 SPK recipients who received either alemtuzumab induction and rapid steroid taper (n = 41) or rATG and rapid steroid taper (n = 33) was reported by Reddy et al. . Maintenance therapy in both groups consisted of tacrolimus and MMF. Steroids were limited to five doses starting on the day of transplantation. The percentages of steroid-free patients after 1 year were similar in both groups (rATG 82% vs. alemtuzumab 80%). In addition, the incidences of clinical acute rejection episodes (rATG 12% vs. alemtuzumab 15%), CMV infections, and BK virus (BKV) nephropathy, as well as graft survival rates, were not significantly different between the two study groups. Only mean HbA1C was lower at 12 months in the alemtuzumab vs. the r-ATG group (5.3 ± 0.4 and 5.6 ± 0.4, respectively; P < 0.002).
Although currently the use of T-cell-depleting antibody induction is clearly favored and continuously increasing, anti- IL-2 antibodies are considered as the prime induction agent in about 10% of all pancreas transplant cases performed [14▪].
Pascual et al.  reported a retrospective cohort study comparing alemtuzumab and basiliximab induction, in 136 SPK recipients. Maintenance immunosuppression consisted of tacrolimus, mycophenolic acid prodrugs, and prednisone. Acute cellular kidney rejection was found to be more frequent in SPK recipients induced with basiliximab (2-year 12.8 vs. 3.1%). The incidence of antibody-mediated rejection, however, was similar (2-year 18% with basiliximab vs. 13.8% with alemtuzumab) in both groups. Acute kidney rejection was associated with clinical pancreas rejection in about 70% of cases, without differences between the two study groups. Although more pancreatic grafts were lost due to acute rejection in alemtuzumab-treated patients, pancreas graft survival was similar in both groups. However, the lack of protocol biopsies in this study limits the ability to assess subclinical rejection and to assess the real incidence of acute cellular or antibody mediated rejection in the study population.
In a most recent study, Bazerbachi et al.  retrospectively analyzed their single-center series of 128 SPK with either ATG (n = 79) or basiliximab (n = 49) induction. Maintenance therapy in all patients consisted of tacrolimus, MMF, and steroids in a tapered fashion. Their follow-up was 5 years. ATG vs. basiliximab therapy was associated with decreased 3-month (6 vs. 21%) and 1-year (14 vs. 27%) acute rejection rate and resulted in identical 1-year (90 vs. 93%), 3-year (87 vs. 89%), and 5-year (87 vs. 89%) pancreatic graft survival. Similarly, no differences were observed in terms of overall complications as well as 1, 3, and 5-year kidney graft survival and kidney graft and pancreas graft function up to 5 years. It was concluded from their study that ATG vs. basiliximab induction resulted in decreased acute rejection in the first 12 months post transplant with comparable side effects. However, long-term graft function and survival are not different between the two induction modalities.
Similar favorable results with basiliximab induction were reported in a retrospective study conducted by Zhang et al. [17,18] in combination with tacrolimus, MMF, and steroid maintenance therapy in 91 SPK patients. The 5-year patient, kidney, and pancreas graft survival rates were 88, 79, and 71%, respectively. At 1, 3, 5, and 7 years, the cumulative incidences of acute rejection episodes were 24, 29, 29, and 41%, respectively.
Magliocca et al.  from the University of Wisconsin published a single-center retrospective review of SPK patients comparing induction therapy with alemtuzumab (n = 105) with historical controls that received basiliximab (n = 226). A standard triple drug maintenance regimen consisting of tacrolimus, MMF, and steroids was used in both groups. Patient, pancreas, or renal allograft survival, graft function, Epstein–Barr virus, and BKV infection rates, as well as the incidence of post-transplant lymphoproliferative disease (PTLD) or sepsis, did not differ between the two induction regimens. However, a significantly increased rate of CMV infection was found in the alemtuzumab-treated group (29.3 vs. 16.4%), but there was no statistically significant increase in organ-specific invasive CMV infection or other viral complications.
Other previous studies evaluating anti-IL2 receptor antibody induction mostly in combination with calcineurin inhibitors (CNIs), MMF, and steroids were reviewed comprehensively by Singh and Stratta  as well as by Heilman et al. . Results showed excellent patient and graft survival rates, and also an increased incidence of acute rejection episodes as compared to alemtuzumab or rATG induction protocols [18,20–25].
Over the past decade maintenance immunosuppression protocols for pancreas transplantation have included tacrolimus, MMF, and steroids in more than 80% of cases . However, there is a growing trend towards steroid withdrawal or avoidance, mammalian target of rapamycin (mTOR)-based maintenance strategies as well as an overall attempt to implement concepts of immunosuppression minimization after pancreas transplantation. Such developments thereby clearly follow the trends seen in other types of solid organ transplants such as kidney or liver [26–28].
Following pancreatic transplantation, patients are at risk in particular due to well known toxicity and side effects like insulin resistance caused by steroids. Therefore, limiting the use of this class of immunosuppressive agents is a prime task and of critical importance in this patient population. In this context almost 25% of all SPK recipients according to the SRTR registry are currently treated under a rapid steroid withdrawal or steroid sparing protocol [29,30].
Cantarovich was the first to perform a successful study using a steroid-free maintenance protocol using rATG in combination with cyclosporine and MMF in SPK patients . Since then, excellent short-term outcomes have been achieved in multiple studies (reviewed in detail by Heilman et al. ) using rapid steroid withdrawal in combination with antibody induction and CNI and MMF-based maintenance therapy, indicating that such an approach appears to be safe and effective in the setting of SPK [5,32–36]. However, most of the studies were uncontrolled trials and included only low-risk patients, a situation that limits the grade of evidence. Large-scale prospective studies with longer follow-up will be necessary to ultimately assess the success of steroid sparing/withdrawal attempts.
Muthusamy et al.  recently reported a study evaluating the impact of alemtuzumab induction with particular reference to steroid avoidance in the maintenance phase in a total of 100 patients receiving pancreas transplants either SPK, PAK, or PAK. Induction consisted of two 30 mg doses of alemtuzumab followed by a maintenance regimen with tacrolimus, MMF, and no steroids leading to 12-month patient, pancreas, and kidney allograft survival of 97, 89, and 94%, respectively. Overall incidence of acute rejection was as high as 25%, but 83% of patients did not require any steroids after transplant. Alemtuzumab administration resulted in side effects (1–14% of all patients) such as thrombocytopenia, pulmonary edema, and rash. Infectious complications included CMV (6.8%), BKV viruria (3.8%), fungal infections (4%), and PTLD (1%).
Rajab et al.  reported a retrospective single-center analysis of 97 pancreas transplants receiving a steroid-free maintenance protocol compared with a historical control group of 124 transplants receiving a maintenance regimen that included long-term application of steroids. The steroid-free regimen consisted of induction therapy with rATG, prednisone for the first 5 post-transplant days, and maintenance immunosuppression with sirolimus and reduced-dose cyclosporine. The regimen of the comparator group included induction therapy with basiliximab and maintenance with prednisone, cyclosporine, and MMF. The 1-year patient and pancreas graft survival rates were similar in both groups (93.8 and 94.8% in the steroid-free group, 95.2 and 87.9% in the comparator group). The incidence of acute rejection in the steroid-free and in the control group was 9.3 and 28.3%, respectively. The steroid-free group experienced no pancreas graft loss due to acute rejection though in the comparator group seven patients lost their pancreas graft for this reason. The 1-year mean serum glucose and creatinine levels were not different between the two groups.
In another retrospective review, Tanchanco et al.  reported on 87 pancreas transplant recipients, who received induction therapy with thymoglobulin and maintenance immunosuppression with tacrolimus and MMF. The authors compared one group on a steroid-free regimen (n = 25) with another on a steroid-based regimen. At 6 months they found no significant difference between the two study groups in patient survival (100 vs. 96.8%), pancreatic graft survival (96.0 vs. 93.5%), acute rejection (4.0 vs. 11.3%), hospitalization due to infection, or other causes and incidence of BKV viremia. However, there were more cases of CMV viremia in the steroid-treated group (17.7 vs. 0%) and the estimated GFR at 6 months was higher in the steroid-free group (74.8 vs. 55.7 ml/min/1.73 m2).
Malheiro et al.  reviewed 77 cases of SPK with thymoglobulin induction and tacrolimus, MMF-based maintenance immunosuppression, and late steroid withdrawal (between 6 and 12 months post-transplant). The 1-year patient, kidney graft, and pancreas graft survival were as high as 93, 91, and 86%, respectively. Complete steroid withdrawal by the end of the first year was accomplished in 77.8% of patients and no subsequent acute rejection episodes occured. At present, 72 patients have a functioning kidney graft, and 65 patients also have a functioning pancreas graft. Overall the patients had a low prevalence of hypertension, hyperlipidemia, and obesity.
MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR-BASED MAINTENANCE STRATEGIES
Although the combination of tacrolimus, MMF, and steroids as the standard regimen for SPK has proven effective, more and more centers are currently considering adding or switching to mTOR inhibitors, in particular in case of documented side effects related to conventional protocols. However, as shown in several studies for both renal and pancreas transplantation, combination of sirolimus with CNIs was associated with synergistic nephrotoxicity and might have potential negative metabolic consequences [4,5].
Most recently, Ciancio et al.  performed a head to head comparison to study the long-term effect of sirolimus vs. MMF in SPK patients in a randomized, prospective, long-term, single-center trial. All 170 enrolled patients received dual induction therapy with thymoglobulin and daclizumab and low-dose maintenance tacrolimus and corticosteroids. The authors found that compared to MMF, rates of biopsy-proven acute kidney and pancreas allograft rejection were significantly reduced during the first 12 months post-transplant in rapamycin-treated patients. There was no significant difference in patient and allograft survival, creatinine, proteinuria, c-peptide, viral infections, rates of PTLD, or post-transplant diabetes. The authors concluded that in this 10-year SPK study, rapamycin in combination with tacrolimus was better tolerated and more effective than MMF.
Girman et al.  compared retrospectively the incidence of severe complications among 123 consecutive SPK recipients randomized for treatment either with tacrolimus and MMF or tacrolimus and sirolimus following rATG induction. There were no differences with regard to patient or graft survival as well the rate of serious complications (defined as the need for operative revision or prolonged hospital stay) between the two groups.
In a nonrandomized, single-center, sequential study, Knight et al.  assessed the safety and efficacy of a sirolimus-based both steroid and CNI-free immunosuppressive protocol for immunological low-risk SPK patients to a historical group treated with sirolimus, reduced doses of cyclosporin A (CsA), and prednisone. The 2-year patient, kidney graft, and pancreatic graft survival for the minimization group were 100, 100, and 91% vs. 100, 95, and 95% for the sirolimus/CsA group. After withdrawal of CsA at 6 months, the minimization group showed an increase in mean estimated glomerular filtration rate and significant improved renal function as compared with the sirolimus/CsA group. Mean fasting blood glucose levels were equivalent between the two study groups at all time points.
Minimization protocols after pancreas transplantation are becoming the focus of more and more studies to reduce/avoid toxic effects of immunosuppressive therapy and improve long-term outcomes. In this regard, induction therapy with rATG followed by sirolimus and reduced dose CNI combined with steroid avoidance or withdrawal regimen have demonstrated encouraging results as outlined above.
On the basis of favorable outcomes in liver, kidney, and islet transplantation with daclizumab maintenance therapy and minimization or avoidance of CNI, Kirchner et al.  recently reported on 25 pancreas transplant patients presenting with progressive CNI toxicity. These patients were switched to a daclizumab-based maintenance regimen in combination with MMF or sirolimus. In this retrospective study the daclizumab group was compared with matched control individuals (1 : 1) by transplant type and number, age, year of transplant, and duct management. Their results showed that the daclizumab group had improved graft survival rates and decreased immunologic graft loss rates at 1, 3, and 5 years compared with the control group.
T-cell depletion with alemtuzumab followed by tacrolimus monotherapy has been demonstrated to be effective for liver, kidney, lung, and even small bowel transplantation . Although possible in some patients after pancreas transplantation as reported by Thai et al.  single-drug minimization therapy seems not to be applicable to the majority of them due to increased rejection rates and immunological complications resulting in impaired long-term graft function . Higher rates of acute rejection episodes and immunological graft loss were also found using alemtuzumab induction in combination with CNI and corticosteroid avoidance and MMF monotherapy maintenance as compared to conventional therapy .
Infusion of donor bone marrow cells to create mixed or microchimerism represents another approach that is continued to be tested in clinical solid organ transplant protocols with the intention to reduce the overall amount of immunosuppressive medication or to induce donor-antigen-specific immune tolerance. Such a concept has been pioneered by the centers at the University of Pittsburgh and Miami which initiated clinical trials of donor bone marrow cell infusion also in SPK and PTA . Both groups reported that the use of donor bone marrow was associated with immunoregulatory properties, no signs of graft-versus-host disease, and a protective effect on pancreatic grafts . However, these studies were not randomized and had a relatively short follow-up. In this context, more prospective randomized trials are needed for a valid assessment of the impact of donor bone marrow cell therapy and hematopoietic chimerism in pancreas transplantation.
Due to the fact that the pancreas graft represents a composite organ including the duodenum, lymphatic, exocrine, and endocrine tissues, it is considered more immunogenic and antigenic than other solid organ transplants requiring relatively high levels of immunosuppression. Therefore, any attempts with immunosuppression minimization protocols need to be very cautiously approached and testing the feasibility of such concepts remains up to larger prospective randomized studies in all forms of pancreatic transplantation.
Significant improvements have been made over the past decade to the immunosuppressive armamentarium in solid organ transplantation. In particular, several novel small molecules, biologic agents and monoclonal antibodies are currently in clinical development, mainly tested in kidney transplantation, and may enable to more specifically and targeted regulate an alloimmune response. Such concepts may further allow to favorably change the side effect profiles by enabling CNI and corticosteroid minimization or avoidance in the future.
Whether promising novel agents such as the protein kinase C inhibitor – sotrastaurin , the JAK 3 inhibitor – tofacitinib , the proteasome inhibitor – bortezomib , the CD28-CD80/CD86 costimulatory pathway blocker – belatacept , or the C5 binding humanized monoclonal IgG antibody – eculizumab  prove beneficial for immunosuppressive regimens and also hold true for pancreas transplantation, however, require further investigation.
Given the high success rates and excellent outcomes that have been achieved after pancreas transplantation over the past decades, any novel designed immunosuppressive agent or newly designed protocol needs to be tested in prospective randomized trials. Prerequisite for clinical introduction, however, is at least a similar safety and efficacy profile compared to already existing substances and regimens. For now while we still await the results of such ongoing trials, the main task at hand remains to tailor and combine the available and established conventional agents for induction and maintenance therapy to further improve metabolic and cardiovascular profiles and optimize graft function, immunological side effects and long-term outcomes after pancreas transplantation.
Conflicts of interest
The authors declare no conflict of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 123–124).
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