Update on Chronic Rejection After Intestinal Transplant: An Overview From Experimental Settings to Clinical Outcomes
Augusto Lauro,1 Ignazio R. Marino 2
Chronic rejection affects the long-term survival of solid-organ transplants, accounting for an incidence of between 5% and 10% after intestinal/multivisceral transplant. Because of unclear symptoms and signs and endoscopic findings, the diagnosis is often delayed. Presently, allograft removal represents the only available therapy due to the absence of effective pharmacologic approaches. Extensive research, through animal models, has been performed over the past 20 years to clarify the complex immune- and nonimmune-mediated mechanisms behind the development of chronic allograft enteropathy, with the aim of elucidating how to avert chronic rejection. The role of donor-specific antibodies and the way to challenge them in the clinic have gained acceptance among transplant centers as one of the main steps to prevent chronic rejection, although no common protocol exists that can be applied in a systematic fashion. The adjunct of a liver graft when retrans planting is needed in a sensitized recipient due to its protective effect against humoral immunity. Multicenter studies and clinical trials are required to better understand the pathogenesis of chronic rejection and to find the therapeutic answer to this clinical query.
Since publication of studies from the Pittsburgh group dating from the early 1990s,1-4 chronic rejection (CR) has been viewed as the major cause of late graft loss and reduced late patient survival after intestinal/multivisceral transplant (ITx). This phenomenon has not been changed by recent immunosuppressive preconditioning protocols.5 It presents as enteropathy, which has an incidence ranging from 10% to 20% in historical series,6,7 and follows an insidious, progressive course lacking early or specific clinical symptoms or mucosal findings through endoscopy. The median time to develop - ment of CR is 39 months, with a range of 22 to 67 months.7 The risk increases 2 years after transplant, achieving a nadir during posttransplant year 3. An isolated small bowel transplant appears to render the graft more susceptible to CR than liver-intestine transplant procedures (21% vs 5%).7 A consensus conference (unpublished results) held in June 2015 in Buenos Aires, Argentina during the XIV Intestinal Small Bowel Transplant Symposium (ISBTS; now named Congress of Intestinal Rehabilitation and Transplantation Association) proposed several criteria to identify CR: recipients can present with abdominal pain, mass, or distension with chronic diarrhea, bowel obstruction, enterocutaneous fistulas, intolerance to feeding with recurrent emesis, weight loss, enteropathy with protein loss, failure to thrive, or complications of ostomy site. Similar to acute cellular rejection (ACR), reliable fecal and serum markers are not available. The conference proposed decreased citrullin (concomitant loss of graft mass and function) and elevated C-reactive protein/lipopolysaccharide-binding protein (mucosal translocation) as surrogate CR markers.
Computed tomography and magnetic resonance imaging may support diagnosis by showing thickening of mesentery and/or intestinal wall and rarity of mesenteric vessels. Close endoscopic monitoring is mandatory for all ITx recipients: the common endoscopic presentation of CR is persistent, non-healing, focal mucosal ulceration, which is often preceded by repeated episodes of ACR.8 Later, mucosal folds become effaced with pseudo - membranes, and the bowel appears firm and fibrotic. Biopsy specimens may show mild ischemic changes, low-grade apoptosis, crypt loss, and often mild fibrosis of the lamina propria.8 Mucosal biopsies are often noncontributory, even in front of refractory intestinal dysfunction. In biopsies with fibrosis, the cause may be unclear because fibrosis may be secondary to other causes, such as previous episodes of rejection, ischemic injury, prior infections, medication-associated chronic injury, and prior biopsy site irritation.8 Thus, clinical and endoscopic diagnoses of CR are difficult.
Chronic rejection is characterized by an arterio - pathy with blunting of villi, concentric vasculopathy, luminal occlusion, leukocyte infiltration, and a marked fibrotic change.6 The marked intimal hyperplasia associated with fibrosis leads to impaired vascular perfusion of the graft.8 Unfortunately, this finding is seen in submucosal or mesenteric arteries, which are not normally sampled on an endoscopic biopsy.
There is much discussion among transplant centers on “when” to perform graft explants in cases of irreversible chronic allograft enteropathy (that is, prior or during retransplant), and many pro and con arguments were debated during the already quoted ISBTS 2015 meeting (unpublished results). Nevertheless, diagnosis of CR is usually confirmed only in full-thickness biopsies through explanted failed grafts that show the associated obliterative vasculopathy.8 Studies and discussion on this issue continue. Therefore, it is worthwhile to review the experimental findings and clinical series on this topic to get a wider picture, to clarify the updated knowledge, and to increase the relative awareness in the medical community.
Read also: Chronic Rejection After Intestinal Transplant - Digestive Diseases and Sciences - Springer (2018)