Overview of intestinal and multivisceral transplantation

INTRODUCTION — Intestinal transplantation (ITx) has evolved into an established therapeutic modality in the management of patients with irreversible intestinal failure (IF). It is performed for patients with short bowel syndrome or for patients with functional intestinal failure, with multivisceral transplantation reserved for those patients with associated end-stage liver disease or diffuse portomesenteric vein thrombosis. Primary indications for intestinal transplant include depletion of central venous access sites, multiple episodes of catheter-related sepsis, electrolyte disturbance, dehydration, and progressive cholestatic liver failure. Additional indications for intestinal and multivisceral transplant include diffuse portomesenteric thrombosis, malignancies limited to the abdominal compartment, and congenital motility and absorption disorders of the intestine.

The number of patients who undergo ITx is much lower than other forms of organ transplantation, and there are fewer centers that perform it. The Intestinal Transplant Registry (an international registry for intestinal transplant centers) reported in 2016 that 3194 patients (including 1731 children) had received an intestinal transplant [1]. The Organ Procurement and Transplantation Network reported that in the United States between 1990 and 2021, a total of 3286 ITx were performed [2]. The number of ITx in the United States was highest in 2007 (198 transplants); however, the annual number of ITx has been declining, from approximately 140 transplants annually between 2014 and 2016 to 96 transplants in 2020 [2].

This topic provides an overview of intestinal and multivisceral transplantation. The American Gastroenterological Association (AGA) guideline for short bowel syndrome and ITx [3], as well as other AGA guidelines, can be accessed through the AGA website.

INDICATIONS — Intestinal transplantation (ITx) has been performed in children with a variety of causes of short bowel syndrome (SBS) including congenital anomalies, necrotizing enterocolitis, intestinal atresia, mid-gut volvulus, gastroschisis, and motility disorders (figure 1). In adults, ITx has been performed mainly in those with SBS related to Crohn disease, mesenteric thrombosis, trauma, and desmoid tumors (figure 2) [4-6].

In both children and adults, ITx is usually considered in patients who develop serious complications related to chronic parenteral nutrition, such as when:

●More than one-half of the sites typically used for parenteral nutrition (PN; ie, jugular, subclavian, and iliac veins) become inaccessible due to thrombosis [7].

●Catheter-related sepsis has resulted in repeated episodes of disseminated infections and/or repeated bacteremia.

●Patients have developed cholestatic liver disease attributable to PN (such patients may also require liver transplantation). A large database study found that patients with PN-related liver disease who underwent combined liver and intestinal transplantation had significantly worse outcomes than patients who underwent isolated ITx [8]. This prompted a change in the organ allocation system so that donor organs from throughout the United States (rather than just organs donated within the patient's geographic region) could be offered to patients who require combined liver and intestine grafts in order to minimize their risk of death on the transplant list.

ITx is also performed in patients who do not have SBS but have other causes of intestinal failure. These include dysmotility disorders (such as generalized Hirschsprung's disease, megacystis microcolon, intestinal pseudo obstruction), genetic intestinal disorders of the mucosal cells (such as microvillus inclusion disease and tufting enteropathy), disease with a high potential for malignant degeneration (such as familial adenomatous polyposis), neoplastic tumors of the gastrointestinal tract and pancreas that are limited to the abdominal cavity (eg, neuroendocrine tumors), and radiation-induced bowel injury.

Another indication for multivisceral transplantation of the liver, stomach, pancreas, and small and large intestine is the development of diffuse porto-mesenteric venous thrombosis [9].

Consensus criteria — The American Society of Transplantation and the Centers for Medicare and Medicaid Services initially recommended intestinal transplantation under the following conditions [10,11]:

●Failure of home parenteral nutrition:

•Impending or overt liver failure

•Thrombosis of ≥2 central veins

•Two or more episodes per year of systemic sepsis, particularly those requiring hospitalization with shock and fungemia

•Frequent episodes of dehydration

●High risk of death

●Severe SBS (gastrotomy, duodenostomy, residual small bowel <10 cm in infants and <20 cm in adults)

●Frequent hospitalization, opioid dependency, or pseudo-obstruction

●Unwillingness to accept long-term home parenteral nutrition

The appropriateness of these criteria was confirmed in at least one study that evaluated survival based upon them [12].

A subsequent consensus paper has summarized the indications for placement on the intestine transplant waiting list (table 1) [13].

CONTRAINDICATIONS — The contraindications to ITx are similar to those for liver and other solid organ transplantation. The presence of active infection, aggressive or metastatic malignancy, multisystem organ failure, cerebral edema, and advanced human immune deficiency virus infection are absolute contraindications for ITx [14].

PRETRANSPLANT RECIPIENT EVALUATION — Most patients with intestinal failure have an extensive medical history and are either home or hospital bound when they are referred for intestinal transplantation (ITx). Any patient with intestinal failure should be referred to a tertiary care center with a specialized intestinal failure team since intestinal rehabilitation has become an important first step in the pretransplant evaluation. The intestinal failure team may use several strategies for disease management (eg, meeting nutritional requirements, optimizing use of parenteral nutrition, gut rehabilitation surgery, and, if the patients fails to respond, intestinal transplant) [15].

Transplant evaluation is then performed by a multidisciplinary team that includes a transplant clinician, hepatologist/gastroenterologist, social worker, financial coordinator, pharmacist, infectious disease specialist, cardiologist, nutritionist, and psychologist [16,17].

The past medical and surgical histories and prior endoscopic and radiologic evaluations are reviewed in detail (table 2). A liver biopsy is performed in patients with suspected liver disease, although it may be deferred in those with clinical features of advanced liver disease [18]. Ultrasound of the liver and central veins is obtained to assess the vasculature. The use of magnetic resonance venography has been proposed as a more comprehensive method to assess central venous access in pediatric patients with intestinal failure [19].

Serologic studies include testing for cytomegalovirus, Epstein-Barr virus, human immune deficiency virus (HIV), hepatitis B virus, and hepatitis C virus. Blood typing human leukocyte antigen (HLA) is performed for crossmatching purpose. Evaluation for hypercoagulability is obtained in patients with history of mesenteric vessel thrombosis.

Part of the outcome of the evaluation is to determine whether the patients should undergo ITx alone, or combined ITx and liver or multivisceral transplantation. Combined ITx and liver transplantation may be required in those with IF and end-stage liver disease, while a multivisceral transplant may be required in those with IF and the presence of neuropathy or extensive mesenteric thrombosis. Intestinal transplantation without liver transplantation may be feasible in some patients with mild to moderate portal fibrosis and liver dysfunction; improvement in liver histology following intestinal transplantation has been described in such patients [20].

WAIT LIST — In the United States, where the most intestinal transplantations are performed, the total number of patients on the ITx waiting list has been decreasing, most likely due to the advances made in intestinal rehabilitation [21]. While the number of adult patients on the waiting list has been increasing, pediatric patients still account for the majority of patients on the waiting list [21]. The number of patients who are listed for intestine transplantation alone are not significantly different from the number of patients who are listed for combined liver-intestine transplant.

The median time to transplantation among the patients on the waiting list has decreased over time. For patients listed in 2016 to 2017, median time to transplant was 5.2 months for adults and 8.2 months for pediatric recipients [22]. The pretransplant mortality rate in 2016 and 2017 was 7.9 per 100 waitlist-years for adults and 3.7 per 100 waitlist-years for children [22].  

DONOR SELECTION/OPERATION — Hemodynamically stable donors after brain death who have no intestinal pathology represent the majority of donors. Cytomegalovirus (CMV)-positive donors are preferred for CMV-positive recipients [23].

The donor procurement operation is similar to other solid abdominal organ procurement procedures. A long midline or cruciate incision from suprasternal notch to pubic symphysis is made, and the gross anatomy is reviewed with particular attention given to variations in the vascular anatomy of the liver. A biopsy of the liver is performed if there is obvious fatty change.

The organs are harvested and generally preserved in either University of Wisconsin solution (UW solution) or histidine-tryptophane-ketoglutarate solution [24]. Cold ischemia time is kept to a minimum by coordinating timing of the donor operation with the recipient patient's surgery team.

The intestinal graft is prepared at the back table. The type of graft is based upon the requirements and condition of the recipient [25].

Anesthesia — The principles of anesthesia are similar to those for liver transplantation. However, as noted above, patients with intestinal failure (IF) often have limited vascular access. As a result, assistance from an interventional radiologist may be required to ensure adequate venous access. Transesophageal Doppler ultrasound can also be helpful to monitor cardiac status of the recipient if a Swan-Ganz catheter cannot be positioned or if the patient does not have adequate venous access to allow for it [24]. (See "Liver transplantation: Anesthetic management".)

General surgical principles — The recipient operation is started when the donor organs are harvested and deemed satisfactory. The incisions are planned carefully, keeping in mind the presence of the stomas and creation of new stomas. The recipient inflow and outflow vessels are dissected. If an interposition vascular graft is needed (such as aortic graft or venous mesenteric graft), it is placed in the recipient before the new graft is brought to the front table.

General surgery principles are followed for restoration of intestinal continuity, with two layer visceral anastomosis. The intestinal anastomosis is usually constructed in side-to-side fashion to minimize ischemia and overcome any size discrepancy between the graft and the recipient intestine. A feeding jejunostomy or gastrostomy is occasionally created. The distal end of the graft can be brought out as a standard end ileostomy or a loop ileostomy to allow surveillance endoscopy and monitor for rejection. Liver graft cholecystectomy is performed routinely. Nissen fundoplication and pyloroplasty are performed if the stomach is included in the multivisceral graft. There is an increased trend towards utilization of the donor colon within the allograft since there has been no observed risk of increased postoperative complications [26]. In some patients, intestinal transplantation can be performed without creation of a stoma [27].

Isolated intestinal transplantation — Isolated intestinal transplantation is performed in patients who have only isolated IF and no associated liver disease (figure 3). The arterial inflow can be from the native superior mesenteric artery, but it is usually created with an interposition graft from the recipient infra-renal aorta. Venous outflow is directed to the native superior mesenteric vein, or in patients with compromised mesenteric venous return, to the inferior vena cava (systemic drainage). The portal vein outflow is preferred due to the concept of hepatotrophic factors providing insulin-like factors for continued optimal hepatocyte function.

Liver-intestinal transplantation — Liver-intestinal transplantation (L-ITx) is considered in recipients who have irreversible IF and end-stage liver disease (ESLD) (figure 4).

In small children, the procedure may be modified to include the duodenum and a rim of pancreas to avoid the need for biliary reconstruction. Inclusion of the pancreas (total) has not increased complication rates [28].

There are some data to suggest that inclusion of the liver helps to confer immunologic tolerance to the small bowel grafts [29,30]. However, the degree of benefit (and shortage of liver grafts) does not appear to justify routine use of such an approach. As a result, a liver transplant is generally reserved for patients who have ESLD.

Multivisceral transplantation — Multivisceral transplantation (MVTx) includes the stomach, duodenum, pancreas, small intestine, large intestine, and liver (figure 5). A modified multivisceral transplant excludes the liver if the recipient's liver function is normal. Kidney transplant is occasionally included if the recipient has end-stage kidney disease. Inclusion of the spleen has been proposed as a possible means to reduce the incidence of post-transplant lymphoproliferative disorder, but data are limited [31].

Bone marrow infusion — Infusion of donor bone marrow has been proposed as a means to induce immunologic tolerance [4,24,32]. The approaches used include a single infusion within 12 hours of revascularization of the allograft or two to five infusions of donor cells in equally divided doses. However, long-term results have not unequivocally shown advantages in terms of decreasing rejection episodes. As a result, most centers do not use this approach.

Loss of domain/abdominal wall transplantation — The abdominal wall closure is quite difficult in some recipients of ITx due to multiple surgical operations, recurrent infections, scar tissue formation, and a contracted abdominal cavity. In difficult cases, the closure is obtained with temporary mesh or Gore-Tex grafts. In some cases plastic surgical procedures are required such as rotation flaps to secure the closure of the abdominal wall. Case series have also described abdominal wall transplantation [33]. The blood supply is based upon inferior epigastric vessels left in continuity with the donor femoral and iliac vessels. In a series of nine such patients, six patients survived with five intact abdominal walls [33]. There were two mild rejection episodes and no episodes of graft versus host disease. Non-vascularized donor rectus muscle fascia can also be utilized to help bridge the gap in the abdominal wall [34].

LIVING-RELATED TRANSPLANTATION — Intestinal transplantation from live donors has been proposed as a means to increase the pool of donor organs and thereby reduce waiting time and wait list morbidity and mortality [35,36]. In addition, living donor transplantation can be performed electively, which may provide an immunologic advantage. Forty-four such procedures have been performed in the last 20 years in the United States, with no living donor cases performed since 2017, and a similar number have been performed worldwide [37].

During procurement, the donor intestine is measured from the ligament of Treitz to the ileocecal valve. A segment of terminal ileum (200 cm for adult recipients and 150 to 180 cm for pediatric recipients) is harvested 20 cm proximal to the ileocecal valve. The donor is left with at least 60 percent of the small intestine. (See "Pathophysiology of short bowel syndrome", section on 'Ileal resection'.)

One of the largest series described 11 recipients who received 12 living-related donor intestinal transplantation [36]. Three-year patient and graft survival were 82 and 75 percent, respectively.

IMMUNOSUPPRESSION — Successful intestinal transplantation would not have been possible without significant advances in the field of immunosuppression. Due to its high antigenic potential, intestinal grafts vigorously reject if inadequate immunosuppression is given, especially during the first year after transplant. The earliest attempts (in the 1960s) failed due to lack of adequate immunosuppressive agents. Success improved dramatically after the introduction of cyclosporine in the 1980s and, most notably, tacrolimus (TAC) in the 1990s.

The most successful strategy to prevent early rejection includes the use of induction therapy. In a report by the Organ Procurement and Transplantation Network, up to 75 percent of centers are using induction therapy [38]. Most centers use an induction regimen that includes antilymphocyte (thymoglobulin or ATGAM) or anti-IL-2 receptor antibodies (Simulect), with baseline immunosuppression consisting of a combination of TAC, with or without glucocorticoids. Initially, TAC is administered intravenously and switched to an oral dose as soon as the intestine resumes normal function. The 12-hour target trough level for TAC is 15 to 20 ng/mL in the first 90 days of the transplant [17,24,39]. Induction protocols used by most transplant centers have helped to reduce TAC trough levels to 5 to 10 ng/mL after 90 days [40].

Optimal strategies to use immunosuppressive agents are being studied and are evolving. Thus, several immunosuppressant agents and regimens are being used. Other agents commonly utilized are:

●Mycophenolate mofetil, which has helped reduce dose-related toxicity of calcineurin agents such as cyclosporine and TAC [24].

●mTOR inhibitors such as sirolimus or everolimus, which have the advantage of a low incidence of nephrotoxicity [32].

●Glucocorticoids are used commonly. A bolus is given at the time of transplantation with a taper for five days to a maintenance dose. Glucocorticoids are not typically used as maintenance beyond the first three months post-transplant in patients who receive induction therapy with thymoglobulin.

For maintenance therapy, most transplant centers use a regimen of TAC and mTOR inhibitors as a strategy to reduce the risk of rejection while avoiding chronic glucocorticoid use.

ASSESSMENT OF INTESTINAL FUNCTION — Intestinal function can be monitored with the d-xylose absorption test, stool testing for reducing substances, or elastase levels [41]. Impaired absorption in the early transplant period may be seen with rejection, cytomegalovirus enteritis, or renal dysfunction. Other tests of intestinal function include fecal fat determination. Intestinal function may be reflected less directly by tolerance to oral feeding, the ability to taper parenteral nutrition, and serial monitoring of serum tacrolimus levels. (See "Approach to the adult patient with suspected malabsorption".)

NUTRITION — Parenteral nutrition (PN) is continued postoperatively until intestinal motility returns to normal, as assessed by bowel sounds and stoma output [24]. Once anastomotic integrity is established, enteral feeds are initiated in the form of an elemental diet through a feeding tube. The enteral feeds are advanced gradually as tolerated to goal, and then a regular diet is introduced as tolerated. Enteral feeds are discontinued once intake by mouth meets nutritional requirements.

PN is usually tapered in four to six weeks once the intestine is able to meet full caloric needs of the recipient. Some patients lack appetite. In particular, children who have been on long-term PN may have food aversion and need speech therapy to help learn how to eat again. Many patients will also continue to require supplemental intravenous fluids and electrolytes due to stoma loss during the first post-transplant year.

In a study that included 177 surviving recipients of intestinal and multivisceral transplantations, 160 (90 percent) achieved nutritional autonomy and were able to take an unrestricted oral diet without the need for intravenous nutrition or fluid supplementation after a mean follow-up of 9.4 years [42].

POSTOPERATIVE COMPLICATIONS

Technical complications — A variety of technical complications can occur early in the postoperative period, including bleeding, thrombosis, and anastomotic leaks. Such complications can lead to serious morbidity and mortality. The rate of such complications has varied across reports, but is probably in the range of 10 to 15 percent, although much higher rates have been reported [43]. In an illustrative series, 18 of 39 patients (45 percent) required emergency surgery after intestinal transplantation (ITx) [44]. Three (8 percent) developed duodenal stump leak resulting in one death, five (13 percent) developed spontaneous small bowel perforation resulting in two deaths, and three (8 percent) needed emergency laparotomy for abdominal compartment syndrome, resulting in two deaths. In another series, technical complications, including intestinal anastomotic leak, hepatic artery thrombosis, and biliary anastomotic leak, led to graft loss in 4 of 35 recipients (11 percent) [45]. In other series, the overall incidence of technical complications is described as approximately 9 percent.

Infectious complications — Infectious complications (particularly bacterial infections) are common after ITx and remain the leading cause of death. The most common include intra-abdominal or catheter-related sepsis, or sepsis related to bacterial translocation from the graft.

Treatment is directed at the underlying cause of infection and may include, in addition to broad-spectrum antibiotics, removal of the implicated catheter, treatment for cytomegalovirus (CMV) infection, or intravenous administration of immunoglobulins if serum levels of IgG are below normal. (See "Infection in the solid organ transplant recipient".)

Prophylaxis against infection is also routinely given: trimethoprim-sulfamethoxazole for Pneumocystis jirovecii (formerly Pneumocystis carinii) infection; fluconazole for fungal prophylaxis; intravenous ganciclovir or oral valganciclovir for CMV prophylaxis. (See "Prophylaxis of infections in solid organ transplantation".)

Post-transplant lymphoproliferative disease — Post-transplant lymphoproliferative disease (PTLD) develops in approximately 15 to 20 percent of ITx recipients and is usually associated with Epstein-Barr virus [46,47]. PTLD is more common in pediatric recipients, probably due to Epstein-Barr virus negative status at time of transplant. Treatment principles include a substantial decrease in the immunosuppression regimen and antiviral therapy. Standard chemotherapeutic regimens, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or rituximab-CHOP are also widely utilized in PTLD patients after ITx. (See "Treatment and prevention of post-transplant lymphoproliferative disorders".)

Graft-versus-host disease — Graft-versus-host disease (GVHD) has been reported with all types of organ transplantation. Transplantation of the small bowel is considered to be particularly vulnerable to GVHD since the small intestine contains a large reservoir of donor lymphocytes, including the Peyer's patches, lamina propria, and large number of mesenteric lymph nodes. The incidence of GVHD after intestinal transplant is approximately 10 percent, which is higher than reported rates of GVHD with other solid organ transplants [48,49]. GVHD can lead to significant morbidity and mortality, usually from infections due to marrow aplasia. Mortality rates from published series vary and range from 14 percent to 78 percent [45,49,50].

The main targets of GVHD are skin, liver, lung, bone marrow, and gastrointestinal tract. The presentation is usually with a skin rash, mouth or tongue lesions, diarrhea, gastrointestinal ulcerations, liver dysfunction, and bone marrow suppression [50]. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)

Treatment of post-intestinal transplant GVHD includes glucocorticoids, increasing immunosuppression, and for more severe cases, infusion of anti-lymphocyte agents [49,51].

ACUTE REJECTION — The incidence of severe acute cellular rejection (ACR) is high in intestinal transplantation (ITx) compared with other organs, although progress has been made. The incidence of any type of rejection was about 85 percent during the 1990 to 1994 period and 67 percent during the 1995 to 2001 period [23,32]. In a subsequent report from the Scientific Registry of Transplant Recipients, rates of ACR during the first year ranged from 35 to 41 percent [38]. Mortality associated with severe rejection is approximately 25 to 45 percent at six months [31]. Graft loss occurs in most patients with severe rejection despite aggressive immunosuppressive therapy [31,52,53].

Clinical manifestations — Patients with acute rejection usually present with increased stoma output, fever, abdominal pain, distension, and ileus. Acute rejection also predisposes to sepsis from bacterial translocation and fungal infections.

Diagnosis — The diagnosis of acute rejection is typically made by histologic evaluation of intestinal biopsies obtained during endoscopy. The histologic features of small intestine rejection include a mixed but mostly mononuclear infiltrate with activated lymphocytes, crypt injury, inflammation, and increased crypt cell apoptosis [54]. The rejection is graded as follows: no rejection (Grade 0), indeterminate (Grade IND), mild (Grade 1), moderate (Grade 2), or severe (Grade 3) depending upon the extent of the mucosal injury and the degree of inflammatory infiltrate and apoptosis (picture 1A-C) [52].

The ability to diagnose rejection in its earliest stages provides the opportunity to intervene before irreversible complications develop. In the early postoperative period, serial endoscopies with intestinal biopsies may be performed through the stoma for graft surveillance, since the highest number of rejections is observed within the first three months posttransplant. After the ileostomy is closed, endoscopies may be performed only if indicated by clinical signs or symptoms. However, the frequency and need for surveillance endoscopy has decreased over time because rates of ACR have been declining. Thus, many centers are advocating for endoscopy and biopsy only as needed for symptoms, even during the first several months after transplant.

A less invasive approach that can facilitate the diagnosis of ACR is zoom magnification endoscopy (up to 100-fold magnification), which may reveal suggestive early mucosal changes that may not be visible with standard endoscopy. These endoscopic findings include erythema, villous congestion, and blunted and shortened villi [55-57]. In one series of adults with clinical features suggestive of acute rejection, the sensitivity and specificity of these findings compared with histology were 45 and 98 percent, respectively [56]. Similar test characteristics were described in children included in the study.

Serum citrulline and fecal calprotectin have emerged as additional, non-invasive markers when acute rejection is suspected [58-60]. Serum citrulline level is a marker of acute rejection and correlates with the severity of acute rejection after a minimum of three months following pediatric intestinal/multivisceral transplants. Citrulline levels are inversely proportional to the severity of acute rejection. For example, a citrulline threshold level of >20 micromol/L (for any type of ACR) and threshold of >10 micromol/L (for moderate or severe ACR) were associated with negative predictive values of 95 to 99 percent, respectively [58]. Acute rejection has been associated with high stool calprotectin levels. In a study analyzing stool calprotectin measurements from 68 patients, calprotectin levels were higher in patients with acute rejection compared with patients with viral enteritis or normal small bowel biopsies (198 mg/kg versus 7 and 19 mg/kg, respectively) [59].

Treatment — The mainstay of treatment for mild rejection typically involves bolus doses of glucocorticoids and intensification of the baseline immunosuppressive regimen. Anti T-cell antibodies may be used in glucocorticoid-resistant rejection.

Moderate and severe rejection episodes are treated with anti-lymphocyte antibodies (thymoglobulin, alemtuzumab or Atgam), as well as supplemental immunotherapy treatments such as vedolizumab, eculizumab, and bortezomib [61,62]. Unfortunately, more intensive immunosuppression increases the risk of opportunistic infections, including cytomegalovirus and Epstein-Barr virus (which increases the risk of post-transplant lymphoproliferative disorder).

Prevention — There have been efforts to reduce rates of rejection by irradiating donor grafts (ex vivo), infusing donor bone marrow, or by leukocyte depletion prior to transplant. In one report, for example, 15 ITx grafts were irradiated ex vivo and recipients also received a single bone marrow infusion [63]. Outcomes were compared with five recipients who served as controls. The incidence of rejection was much lower in the irradiated group (7 versus 80 percent). However, this approach is not used routinely because of the risk of radiation-induced small bowel injury. (See 'Bone marrow infusion' above.)

Most anti-rejection protocols include induction immunosuppression with antilymphocyte agents such as thymoglobulin, given in the peri-operative period, in conjunction with a short course of glucocorticoids, and calcineurin inhibitors plus mTOR inhibitors as maintenance therapy.

The inclusion of a liver may help to protect from rejection of the intestinal graft. (See 'Liver-intestinal transplantation' above.)

Antibody-mediated rejection — The development of donor-specific antibodies (DSA) in recipients of intestinal grafts can lead to antibody-mediated rejection (AMR). AMR is associated with significant acute rejection and with chronic rejection [64,65]. DSA levels can be monitored, and they may correlate with biopsy findings to confirm antibody-mediated rejection [66].

CHRONIC REJECTION AND GRAFT FAILURE — Chronic rejection is observed in approximately 8 percent of patients undergoing intestinal transplantation (ITx). Factors associated with chronic rejection include isolated ITx compared with small bowel-liver grafts, acute rejection within the first month, increased number and higher grade of acute rejection episodes, and older recipient age [32,67,68].

Patients usually present with poor oral intake and lack of appetite, chronic diarrhea, or intestinal obstruction due to strictures that are caused by thickening of the intestinal wall brought upon by the process of chronic rejection. The diagnosis cannot easily be established by intestinal mucosal biopsy since the chronic rejection process often involves the submucosa and muscularis mucosa of the bowel wall. Imaging with small bowel series or magnetic resonance enterography can show strictures when obstruction is the presenting symptom. Intestinal function tests (eg, d-Xylose absorption test) can suggest the diagnosis even before it becomes clinically evident and may be performed as part of a surveillance program [24]. A definitive diagnosis is made with full-thickness biopsy of the allograft, usually after allograft removal. Characteristic findings include obliteration of submucosal vessels and fibrosis of the allograft. (See "Approach to the adult patient with suspected malabsorption", section on 'Other infrequently performed tests'.)

OUTCOMES

Quality of life — There are limited data assessing quality of life in recipients of intestinal transplants. In a study of 29 pediatric patients, quality of life scores were similar to age-matched controls one year after transplant [69]. However, the assessment of quality of life differed when reported by parents. Parents more frequently reported decreased general health and physical functioning in intestinal transplant recipients. In other studies, quality of life after ITx appeared to be better than or equal to quality of life on PN [70].

In a study that included 76 adult recipients of intestinal and multivisceral transplantations, there was improvement in many psychosocial and emotional quality of life domains following transplantation, including anxiety, cognitive/emotional ability, coping skills, sleep pattern, impulsiveness/control, social support, and leisure/recreation [42]. On the other hand, depression and financial obligations were worse after transplantation.

Graft and patient survival — The outcomes in patients undergoing ITx have improved significantly compared with early efforts, with improvements in immunosuppression and early detection and treatment of rejection. Graft survival for adult and pediatric patients is similar. In the 2020 Annual Report by the Organ Procurement and Transplantation Network, one-year graft survival for recipients of an isolated intestinal graft (for the period of 2016 to 2017) was approximately 93 percent compared with 68 percent in 2009. Patients who received a liver-intestine transplant in 2019 had a one-year graft survival of approximately 53 percent. However, five-year graft survival for recipients of any type of intestine transplant (with or without liver) was 45 percent in adults and 61 percent in pediatric patients for cases performed between 2013 and 2015. [38] .

Patient survival depends on the type of graft: it was lowest for adult recipients of combined liver-intestine and highest for isolated intestine pediatric recipients [38]. Similarly, in an earlier report from the largest series of intestinal transplants, one- and five-year patient survival rates were 92 and 70 percent, respectively [71]. However, overall patient survival at 10 and 15 years was only 42 and 35 percent, respectively. Thus, short- and medium-term graft and patient survival were encouraging, but the long-term results have not significantly improved over the past 10 years.

Various predictors of graft and patient survival have been proposed. Graft and patient survival were related to the type of immunosuppression, whereas graft survival was lower with retransplantation and varied across centers [72]. However, the most important predictor appeared to be the recipients' status: Homebound recipients had a 68 percent survival, whereas hospitalized patients had a 42 percent survival at two years. These measures undoubtedly reflected the severity of underlying disease and comorbidities.

FUTURE DEVELOPMENTS — The future of intestinal transplantation (ITx) is promising despite its obvious challenges. The surgical technique has been standardized, and the immunosuppression regimens are improving. Efforts are focusing on improving immunosuppression protocols including methods to promote tolerance.

As more patients survive beyond the first several years after transplant, future challenges focus on the recognition and prevention of both short-term complications (eg, acute rejection) and long-term complications (eg, chronic renal failure, post-transplant lymphoproliferative disease, chronic rejection). Early recognition and treatment of acute rejection to prevent graft loss and associated complications of opportunistic infections and post-transplant lymphoproliferative disease remain a priority. Development of a clinical noninvasive marker for detection of acute rejection in ITx has been challenging.

The shortage of appropriate deceased donors contributes to significant wait list mortality, which needs to be overcome, possibly with the increased use of live donors. (See 'Living-related transplantation' above.)

SUMMARY AND RECOMMENDATIONS

●Background – Intestinal transplantation (ITx) has established itself as a therapeutic modality for patients with irreversible intestinal failure. (See 'Indications' above.)

●ITx is performed mainly in patients with short-bowel syndrome who have developed serious complications from parenteral nutrition (PN).

●Pretransplant evaluation – Potential candidates should be referred to a multidisciplinary team specializing in intestine rehabilitation and, if needed, transplantation. (See 'Pretransplant recipient evaluation' above.)

●Outcomes – Long-term outcomes have improved but remain worse than for other forms of solid-organ transplantation. (See 'Graft and patient survival' above.)

Quality of life after ITx appears to be better than or equal to quality of life on long-term PN. (See 'Quality of life' above.)