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

(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. 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 Despite the great immunosuppressive profile, side effects mandate that these are reduced or withdrawn from maintenance

280 Organ Donation and Transplantation - Current Status and Future Challenges

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

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

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

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

treatment.

long-term use.

prophylaxis.

cardiovascular risk.

the first year of transplantation.

**8.2. Prophylactic treatments**

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 secondary to diabetes.

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.

Not least important, patients should be advised to maintain a proper diet to avoid weight gain, promote physical activity, avoid sun exposure, prohibit or limit the consumption of alcohol and smoking, recommend suitable footwear to avoid chafing and periodic podiatric check-up, and, in women of childbearing age, recommend measures of contraception to avoid pregnancy during the first 1–2 years of the transplant.

Pancreas' acute rejection can be successfully treated using steroids, polyclonal antibodies, and/or plasma exchange and immunoglobulins. Nonetheless, up tp 20% of grafts may be lost

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

Type 1 diabetes is the most frequent indication for pancreas transplantation. As described in the first section of this chapter, DM1 is an autoimmune disease, characterized by autoantibodies directed to β cells. Disease relapse in pancreas graft is a well-known risk for graft failure. It has been reported in up to 7% of all transplant recipients [39]. Induction and maintenance immunosuppression are likely the reason for such a low incidence. Some factors have been associated with an increased risk for disease relapse, such as donor-recipient sharing of HLA-DR alleles, particularly HLA-DR3 [39], and the increase in autoantibodies, particularly ZnT8A, predicts the risk of disease relapse [40]. As with primary disease, no treatment is established for the management of disease relapse. Increase in baseline immunosuppression maybe attempted. If a pancreas re-transplantation is indicated, recipients must be advised of

In addition to pancreas transplantation, β cell mass transfer may be performed through islet transplantation. This procedure consists of islet cell isolation from pancreas as potential donors using both mechanical and enzymatic digestion protocol, following which islets are separated using a Ricordi chamber [41]. Isolated islets are infused into recipient's portal vein, without the need for vascular and/or enteric anastomosis, reducing the surgical risks of the

The attractiveness of a minimally invasive procedure and the possibility of multiple infusions without the surgical risks associated with whole-organ pancreas transplantation have positioned islet cell transplantation as a promising treatment for patients with diabetes. Despite these advantages, islet transplantation presents two critical drawbacks when compared to whole-organ transplant. Islets obtained from a minimum of 2–3 pancreasas are often needed in order to achieve euglycemia [41], increasing organ demand, and risk of recipients' sensitization. Additionally, islets direct engraftment into a vascularized bed exposes β cells to platelets and lymphocytes. Instant blood-mediated inflammatory reaction (IBMIR) is a well characterized event associated with innate immune reaction and coagulation and complement activation following islet transplantation, leading up to 25% of total islet cell mass loss following vena cava infusion [42]. Moreover, it may increase the risk of rejection and reduces overall

In early 2000, the Edmonton group published some promising results using an induction immunosuppression protocol [41]. By the end of 2015, over 15,000 procedures had been performed worldwide [5]. Reported 1- and 5-year insulin independence is up to 80 and 50%,

during the first year following an acute rejection [10].

**9.2. Diabetes relapse**

the risk of relapse in the new graft.

**10. Islet transplantation**

procedure.

graft survival.

respectively [5].

#### **9.1. Acute and chronic rejection**

The incidence of acute rejection is higher in pancreas transplant than those reported in kidney transplantation. The actual incidence must be individualized according to transplant modality, recipient immunological risk, induction and maintenance immunosuppression, and transplant follow-up period.

Overall 1-year rejection incidence varies between 14.7% [34] and 21% [10]. PTA and PAK are associated with significantly higher incidence of acute rejection than SPK recipients [34]. Other risk factors include pancreas re-transplantation [10], absence of induction therapy or basiliximab and induction agent [8], donor age, number of HLA donor-recipient mismatch [10], and the presence of donor-specific antibodies (DSA) [35, 36].

In SPK recipients, monitoring of renal function and/or the performance of a renal biopsy had been advocated as an indirect method to establish the diagnosis and treatment of pancreas' acute rejection, since for many years it has been considered that acute rejection was present in the majority of the cases simultaneously in both grafts. However, it is now well documented that isolated rejection of one of the two organs occurs in up to 36% of cases [37].

To diagnose pancreatic graft rejection, the only biochemical markers available are pancreatic enzymes (amylases and lipases), which are elevated in most of these episodes. Lipase increase is more specific than amylase [10]. On the other hand, in acute rejection, it is possible to observe changes in graft size and eco-structure, with an increase in the resistance index when performing a Doppler ultrasound. Both parameters allow to establish the diagnosis of suspected acute rejection, but they are not specific enough to establish confirmation. This sometimes leads to unnecessary or incomplete empirical treatments, with the consequent repercussion for the patient and the graft. In addition, pancreatic rejection, as recently observed, can also be mediated by antibodies, which requires a different and specific treatment.

Currently, pancreatic biopsy is considered the gold standard for etiologic diagnosis of graft dysfunction. In our center, pancreatic graft biopsy is performed per protocol at 3 weeks and 12months post-transplant, or indicated in the following circumstances (**Figure 1**): (1) patients in whom the existence of an acute rejection of the pancreatic graft is suspected due to biochemical parameters (increase in serum glycemia, amylases, and lipases), and/or ultrasound (increase in size, changes in the graft structure, and involvement of the graft), (2) in whom the existence of a chronic rejection is suspected due to a persistent increase in amylases or serum lipases, progressive increase in glycemia and glycosylated hemoglobin, and/or progressive decrease in C-peptide secretion, and (3) in whom the recurrence of diabetic disease is suspected due to detection or progressive increase of anti-GAD antibodies, and pathologic oral glucose tolerance test. To establish the severity of the histological lesion of acute rejection, the Banff scheme should be taken as reference [38].

Pancreas' acute rejection can be successfully treated using steroids, polyclonal antibodies, and/or plasma exchange and immunoglobulins. Nonetheless, up tp 20% of grafts may be lost during the first year following an acute rejection [10].
