*8.1.1. Induction therapy*

*7.3.2. Abdominal CT scan*

*7.3.3. Interventional radiology*

reliable screening technique.

**8. Immunosuppression and prophylaxis**

care to the patient.

**8.1. Immunosuppression**

quate treatment.

**7.4. Monitoring of vascular thrombosis**

In some cases, Doppler ultrasound may be technically limited (abdominal distension, obesity) or the study might need to be extended, such as in the patient with abdominal pain, fever, and/or graft dysfunction, intra-abdominal collection not accessible to ultrasound drainage, intra-abdominal collection drained by ultrasound, but without adequate clinical response. If a vascular pathology or bleeding is suspected, a contrast-enhanced CT scan is advised.

Interventional radiology may be used for diagnostic confirmation and/or treatment (throm-

Thrombosis is the most common vascular complication in the initial post-transplant (8–10 days post-transplant) period. Therefore, early diagnosis is important to establish ade-

If a first post-transplant imaging study to confirm the vascular permeability of the graft (splenic and mesenteric artery/vein) is not achieved due to bowel distention, the decision whether or not to extend the radiological procedure will be based on pancreas functionality: (1) in normal functioning graft the study is repeated in 24–48 h, (2) if dysfunctional the study is extended to a non-invasive imaging technique, such as angio-CT. Some groups advocate performing angio-CT as standard monitoring image technique due to its ability to establish a grading score for venous thrombosis [30]. In our experience, in the presence of an experienced radiologist, Doppler ultrasound, with or without contrast-enhanced ultrasound (CEUS), is a

During the first 48-h post-transplant, the patient usually stays in the intensive care unit, to be transferred later to the conventional hospital ward if there have been no adverse effects. Progressively, the oral intake is introduced and the abdominal drainage is removed. Before hospital discharge, it is important to to give a detailed description of medication and home

Advances in immunosuppression protocols during the last two decades significantely increased short- and long-term pancreas graft survival. The purpose of immunosuppression is control alloimmune response, and protocols often include a combination of different drugs to minimize the damage to the graft and the risks to the patient. They are similar in all solid organ transplants. Nonetheless, it is of particular relevance in pancreas transplant recipients due to the increased risk of acute rejection, especially in recipients of pancreas transplant alone (PTA). The greatest burden of immunosuppression is then usually administered in the recipients of a PTA.

bectomy) of a partial arterial and/or venous thrombosis of the graft.

278 Organ Donation and Transplantation - Current Status and Future Challenges

This consists of the administration of a polyclonal or monoclonal antibodies and is currently assumed as standard treatment for pancreas transplantation. These decrease the incidence of acute rejection or delay its onset, and reduce the number of steroid-resistant rejections. Depleting T-cell antibodies may be polyclonal, most widely used, such as rabbit anti-thymocyte globulin (Thymoglobulin®/ATG-Fresenius®) or monoclonal, such as the anti-CD52 alemtuzumab (Campath®); among non-depleting monoclonal antibodies, anti-IL-2 receptor (anti-CD-25; basiliximab) is the most frequently used.

There is no consensus on which is the best protocol. Depleting antibodies appear to increase graft survival by reducing acute rejection risk [8] and are the most widely used. Nonetheless, due to financial constraints and also due to an increased infection and cancer risk associated with T-cell depleting agents, some groups use monoclonal anti-IL-2 antibodies in low-immunological risk simultaneous pancreas-kidney tranplantation.

#### *8.1.2. Maintenance treatment*

As an adjunctive treatment to induction therapy, and as long-term maintenance immunosuppression, a combination of three drugs is most often used: a calcineurin inhibitor (CNI), an anti-prolipherative, and steroids.

The discovery of cyclosporine 35 years ago marked a new era in solid organ transplantation. The incidence of acute rejection was drasticly reduced, and despite an increased risk for renal calcineurin toxicity and subsequent renal failure, the patient and graft survivals observed a spetacular improvement. Tacrolimus (or FK-506), also a CNI, exhibits a better and more potent immunsoppression profile and is currently considered the drug of choice in pancreas transplantation. CNI's act by inhibiting the transduction of the first signal between antigenpresenting cells and T-cells. Several comparative studies have shown a lower incidence of acute rejection, as well as a lower severity of rejection and a better survival of the pancreatic graft in the short and long term, in those patients treated with tacrolimus.

CNI is often associated with an anti-prolipherative agent. Their action focuses on a different pathway of the T- and B-cell activation and prolipheration. Azathioprine, the first to be used, arrests cell cycle in the G2 phase, inhibiting the progress to the M phase and subsequent clonal expansion. On the other hand, antimetabolite agents (mycophenolate-mofetil or mycophenolate sodium) inhibit nucleotide syntisis, removing the substrate to DNA replication, finally achieving the same result as azathioprine—prevents cell prolipheration. Finally, the latest agent to be introduced to solid organ transplantation were mammalian target of rapamycin (mTOR)-inhibitors (sirolimus and everolimus). Both act as anti-prolipherative drugs by inactivating the mTOR pathway following the receptor CD25 activation by antigen-presenting cells.

Antimicrobial prophylaxis: infection remains one of the main causes of morbidity and mortality after pancreas transplantation. That is why it is usual to use a wider prophylaxis in these patients. At transplantation and during a variable period of time, broad-spectrum antibiotics to cover Gram negative, Gram positive, and anaerobic are recommended. They are used for 3–5 days and several associations are possible, usually cephalosporin + ampicillin or vancomycin or carbapenem + vancomycin depending on local post-transplant epidemiology. Antifungal prophylaxis with fluconazole is also often performed. Currently, some prophylactic guidelines have replaced fluconazole with a new drug, micafungin, with the advantage of avoiding interaction with tacrolimus. Since most patients receive induction treatment with polyclonal antibodies, which is well known to increase the risk of infections, especially viral infections, antiviral prophylaxis with valgancyclovir for CMV is also advisable. Finally, prophylaxis to pneumocystis jirovecii with trimetropin-sulfamethoxazole for 6 months is the

Pancreas Transplantation

281

http://dx.doi.org/10.5772/intechopen.76667

Pancreas transplant outcomes have increased in the last decades, with a median graft survival using current protocols up to 15 years. In order to achieve these outcomes, close ambulatory controls must be perfomed during the first year, with increasing the time between outpatient visits if follow-up is unremarkable. It is usual to perform a weekly control during the first 3 months post-Tx, biweekly until 6 months, and between 6 and 12 months on a monthly basis. They focus primarily on functional graft monitoring, immunosuppression, and complications

To assess pancreatic graft functionalism, baseline glycemia, glycosylated hemoglobin (HbA1c), as well as serum amylases and lipases is determined in each outpatient follow-up. In the post-transplant period, after hospital discharge and again 1 year after transplant, it is convenient to perform an oral glucose tolerance test (OGTT). Subsequently, and as a followup guideline, the intervals between these analyses varies according to the teams. It is also advisable to perform a C-peptide determination to monitor insulin secretion throughout the follow-up, as well as the determination of anti-glutamic acid decarboxylase (GAD), in order to detect a possible recurrence of diabetic disease. Both should be checked at least once a year.

During patient follow-up, it is important to control secondary complications of diabetes. Despite having a functioning pancreas graft, recipients should continue to monitor secondary complications present prior to pancreas transplantation, such as diabetic retinopathy or macrovascular complications. Some patients experience an improvement of complications present prior to transplantation, particularly in neuropathic symptoms. As to macro- and microvascular complications, most lesions tend to stabilize [33]. Therefore, it is advisable to perform an annual ophthalmological examination, regularly assess neuropathy of both peripheral and autonomic nervous system, as well as having a special surveillance to the complications related to the vasculopathy, appearance of precordial pain, or peripheral ischemic lesions.

treatment method, as used in kidney transplantation.

**9. Long-term outcomes and complications**

secondary to diabetes.

Steroids are perhaps the most widely used immunosuppressive durgs for organ transplantation. Steroids present a pleotropic effect, with an action on both innate and adaptive immune responses. Steroids reduce antigen-presenting cells' cytokine transcription and secretion, reducing the ability of innate immune system to further recruit polynuclear cells. It also inhibits activation of mononuclear cells, such as T- and B-cells. Despite the great immunosuppressive profile, side effects mandate that these are reduced or withdrawn from maintenance treatment.

Triple therapy using one agent from each category has achieved excellent results. The most widely used combination is steroid, tacrolimus, and mycophenolate. An mTOR-inhibitor may be used instead of mycophenolate, but careful management of side effects should be undertaken. Although the results obtained with this association seem to be superimposable, as far as patient and graft survival is concerned [31], the incidence of complications attributable to rapamycin in the immediate post-transplant is greater, so this combination is not as widely used in the initial period of the transplant. However, it is a good option for long-term use.

Several studies have suggested that steroids can be suppressed as maintenance therapy, especially in patients receiving a calcineurin inhibitor associated with an antimetabolite or an mTOR-inhibitor, without affecting the survival of the grafts. However, there is no consensus regarding this topic [32], due to some reported increased risk of rejection following withdrawal. It seems reasonable that the decision to suppress steroids is focused for the moment on those patients with low-immunological risk, and it should be attempted during the first year of transplantation.

#### **8.2. Prophylactic treatments**

In pancreas transplantation, prophylactic treatments are usualy wider than those used in kidney transplantation. As previously stated, pancreas low blood flow, complex vascular anastomosis, the duodenal enteric anastomosis, and the increased infection risk due to persistent hyperglycemia prior to transplantation increase the need for thrombotic and infectious prophylaxis.

Antithrombotic prophylaxis: graft thrombosis is one of the most frequent early complications in pancreas transplantation. Therefore, most transplant centers perform prophylaxis. There is no standard protocol among different centers, but the most frequent is the use of heparin and/or aspirin. Some centers use low doses of intravenous heparin, unlike others who use subcutaneous low-molecular-weight heparin. In both cases, it is important to monitor coagulation parameters and adjust dose to renal function due to uremia-induced anticoagulation and/or anticoagulation used during dialysis sessions. Heparin is often associated with low-dose aspirin, which could be continued in the long term to reduce global cardiovascular risk.

Antimicrobial prophylaxis: infection remains one of the main causes of morbidity and mortality after pancreas transplantation. That is why it is usual to use a wider prophylaxis in these patients. At transplantation and during a variable period of time, broad-spectrum antibiotics to cover Gram negative, Gram positive, and anaerobic are recommended. They are used for 3–5 days and several associations are possible, usually cephalosporin + ampicillin or vancomycin or carbapenem + vancomycin depending on local post-transplant epidemiology. Antifungal prophylaxis with fluconazole is also often performed. Currently, some prophylactic guidelines have replaced fluconazole with a new drug, micafungin, with the advantage of avoiding interaction with tacrolimus. Since most patients receive induction treatment with polyclonal antibodies, which is well known to increase the risk of infections, especially viral infections, antiviral prophylaxis with valgancyclovir for CMV is also advisable. Finally, prophylaxis to pneumocystis jirovecii with trimetropin-sulfamethoxazole for 6 months is the treatment method, as used in kidney transplantation.
