**8. Immunosuppression**

• Cross-clamping of the supraceliac aorta is performed simultaneously with or immediately

• In situ cooling of abdominal organs, and exsanguination before removing the organs to the

• University of Wisconsin (UW) Universal Organ Preservation solution for both in situ flush-

• Retrieve iliac, brachiocephalic and/or carotid arteries and veins as potential vascular grafts.

Intestinal grafts require minimal back table; however, this depends on the retrieval technique and the extension of the allograft. Most commonly, back table involves to identify and tie the lymphatics. If the pancreas is retrieved along with a small bowel only graft, then it has to be

• Implantation begins commonly with adhesiolysis, as adhesions are usually abundant sec-

• Depending on the type of transplant, the aorta and IVC or SMA and SMV/PV are dissected

• Venous anastomosis to the graft is frequently performed to the recipient cava. However,

• After reperfusion of the graft and careful hemostasis, the proximal and distal ends of the intestinal graft are anastomosed to the proximal and distal ends of the native digestive

• Most centers bring out a temporary stoma by utilizing various techniques (e.g. Bishop Koop), for post-operative endoscopic surveillance. This stoma is usually reversed in

• Closure of the abdominal wall can be very challenging and should not be attempted under tension; if this is the case, keeping the abdominal wall open and planning for a sequential closing is preferable. Some centers are routinely performing abdominal wall transplanta-

Patients are monitored in intensive therapy unit (ITU) post-operatively. It is common practice to administer broad-spectrum intravenous antibiotics and antifungals for 5–7 days post transplantation. Blood tests are sent daily and as well as arterial/venous blood gases to check

• The proximal and distal ends of the native digestive track are identified and dissected.

• Arterial anastomosis is performed to the abdominal aorta via arterial jump graft.

when possible, venous anastomosis to the portal system is preferred.

track. In some cases, the distal end is brought out as a permanent stoma.

tion from the same deceased donor in order to achieve closure.

following venting of the IVC or atrium and cold perfusion is commenced.

back table for preparation.

**6.2. Back-table preparation of organs**

removed/sacrificed on the back table.

ondary to previous surgeries.

and mobilized for the vascular anastomosis.

**6.3. Recipient operation**

6–12 months.

**7. Postoperative considerations**

bleeding and homeostasis.

ing and cold storage is most frequently used.

298 Organ Donation and Transplantation - Current Status and Future Challenges

The intestine is the largest lymphoid organ in the body and hence, appropriate immunosuppression has been a real challenge. The lack of effective immunosuppressive agents hampered the first attempts of ITx in the 1960s. Over the years, advances in immunosuppression have transformed ITx with the intent of attenuating the intestinal allograft immunity and shifting it to a tolerogenic status [32].

Induction strategies to minimize rejection by reducing the recipient's T-cell load were implemented, initially with cyclophosphamide induction therapy, which was later replaced by daclizumab, an interleukin-2 receptor antagonist (IL2RA) [33]. Basiliximab, another IL2RA, in addition to tacrolimus and prednisone immunosuppression has also been utilized and shown to decrease the incidence of acute rejection [34, 35].

Alemtuzumab induction is becoming increasingly popular and Lauro et al. [36] reported significantly less early rejection episodes, with no sepsis implications. The use of Basiliximab monthly as part of maintenance immunosuppression has been associated with a decrease in acute rejection in liver-excluding transplants [37].

Immunosuppression regimen varies, with several protocols having been reported: Tacrolimus and steroids (35.8%) followed by tacrolimus, mycophenolate and steroids (18.7%), tacrolimus and mycophenolate without steroids in 15.4% of cases and tacrolimus alone in 13.8% of cases [38].

Most centers will endeavor to perform early, frequent endoscopies because of high prevalence of acute rejection in the early post transplantation phase [21] and then continue with

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The Oxford group, who is utilizing vascularized composite allograft (VCA) transplants from the same donor [45], is now mostly relying on the VCA as a surrogate marker for rejection and is not strictly adherent to early, intensive intestinal biopsy protocols [46]. They have reported that the VCA can provide lead time (about 7 days) before the onset of bowel dysfunction and

Rejection episodes are usually treated with pulses of methylprednisolone, and in resistant

A recent case series reported good outcomes in ITx of positive cross-match patients with only one patient developing acute rejection, with the use of intravenous immunoglobulin (IVIG) and rituximab [47]. Bortezomib, a proteasome inhibitor, has also been recently shown to be effective against donor-specific antibody (DSA)-related rejection [48]. Recently, Eculizumab, a monoclonal antibody that inhibits complement factor 5a, was shown to be effective in maintaining a 2-year rejection-free period in a highly sensitized patient [49]; however, high costs

As mentioned before, biomarkers such as citrulline have gained interest in recent years. The prospective cohort study by Hibi et al. [50] reported excellent negative predictive value (range 93–99%) for citrulline levels as exclusionary marker for all types of acute rejection (cut-off point, 20 mmol/l) and moderate or severe acute cellular rejection (cut-off point, 10 mmol/l). Another study by the Bologna group [51] showed that citrulline sensitivity and specificity in detecting acute rejection, when adjusted for chronic renal failure, almost doubled the sensitivity of citrulline as a non-invasive marker of acute rejection in ITx. In general, citrulline can act as an exclusionary tool, as high levels are unlikely to be found in intestinal allograft rejection. Recently, a large series evaluating video capsule endoscopy has shown to be potentially useful in the diagnostic management of patients with ITx [52]. Other non-invasive predictors of rejection include a recent retrospective study that revealed low insulin-like growth factor-1 and high calprotectin levels during malnutrition states post-ITx, and these findings should prompt the clinicians to investigate for acute rejection or infection [53]. Circulating apoptotic T cells following Caspase 3 activation may be a non-invasive marker for patients who are less

Chronic rejection is diagnosed histologically with the identification of an obliterative arteriopathy in medium-sized vessels in the serosal layer with diffuse concentric intimal thickening [55]. This necessitates full-thickness biopsy and makes diagnosis challenging. Chronic rejection is clinically associated with diarrhea, ulceration, focal loss of mucosal folds, mural thickening and pruning of mesenteric artery arcades [55]. Surgery in such a hostile environment may lead to unwanted enterotomies and fistulae. Re-transplantation should therefore

likely to have rejection episodes than those who have lower levels [54].

regular endoscopies as part of their surveillance protocol [44].

this could be proven as a unique prognostic tool [45].

cases, thymoglobulin [32] or alemtuzumab [46].

make this approach prohibitive for general use.

**9.2. Chronic rejection**

Target trough levels of tacrolimus vary between centers. Pittsburgh has reported target levels between 10 and 15 ng/ml in the first 3 months and thereafter 5–10 ng/ml [39]. Tacrolimus with low-dose steroids remains the most effective and durable long-term combination therapy [21] and is the most common maintenance immunosuppressive regimen [7].

Sirolimus, a rapamycin inhibitor, has been shown as a useful adjunct to tacrolimus in the presence of nephrotoxicity or rejection [40]. However, it carries the disadvantage of severe debilitating oromucosal ulceration. Azathioprine and mycophenolate mofetil have also been used as adjunctive immunosuppressive therapies [33]. Mycophenolate mofetil, however, causes symptomatic diarrhea (increased stoma output) and microscopically evident apoptosis in approximately 40% of solid organ transplant recipients, which could regrettably be mistaken for rejection [41].
