**9.1. Acute rejection**

Allograft rejection has always been one of the most significant challenges to long-term graft and patient survival and can occur either as acute (commonly in the early phase, though can occur late) or chronic (typically taking months to years). Rejection can occur at any time but is most common in the first year, particularly the first 6 months. It affects 45% of ITx patients within the first post-transplant year, with implications on graft survival [7] and is mostly characterized by T-cell response to donor antigens.

Acute rejection should be suspected in all cases of bowel dysfunction (increased stoma output) and symptoms include fever, vomiting, abdominal pain and distension. Diagnosing acute rejection is always challenging and requires a combination of clinical, endoscopic and histopathological investigations. Intestinal allograft endoscopy and biopsies is the gold standard. However, diagnosis can be difficult to establish because of the patchy nature of rejection. Not to mention, that it is not always easy to differentiate between rejection and infection.

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

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

Rejection episodes are usually treated with pulses of methylprednisolone, and in resistant cases, thymoglobulin [32] or alemtuzumab [46].

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 make this approach prohibitive for general use.

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