Chapter 131. Intestinal and Multivisceral Transplant

Intestine transplantation is now an established treatment for irreversible intestinal failure, allowing affected children the possibility to eat and drink normally while having an improved survival with good growth, development, and quality of life.

The first ventures into intestine transplantation were experiments in animals, demonstrating the technical feasibility of this surgical innovation.1 Technical achievements aside, clinical success remained elusive, primarily because of the inability to control immunologic issues leading to rejection and infection. Even during the 1980s, in which the use of cyclosporin A was introduced, survival following intestinal transplantation was extremely rare. The introduction of tacrolimus heralded in the modern era for intestinal transplantation with improved long-term graft and patient survival.

To understand the challenges faced in achieving outcomes comparable to other forms of solid organ transplantation, it is important to recognize some fundamental differences between the gut and the more familiar transplant organs: the kidney, heart, and liver. The gastrointestinal tract is in direct and continual contact with billions of microbes in an intensely immunologically complex environment. The mass of intestinal tissue transplanted is large and carries a vast number of lymphocytes both in the lamina propria and Peyer patches as part of the gut’s mucosal immune system. The intestinal allograft is not sterile and comes with it own sizable microbial populations. Immunosuppression is critical to preventing cellular rejection and yet diminishes immunoprotective mechanisms. In the face of mucosal injury as a result of rejection, barrier functions is impaired allowing bacterial translocation at a time when immunosuppressive medication is being increased. The balancing act between too much and too little immunosuppression is a common theme in transplant medicine but for intestinal transplantation the margin for error is especially narrow.

Over the past 20 years, as the success of the procedure has improved, the number of intestine transplants has increased steadily to the current figure of about 200 intestine transplants per year worldwide. More widespread application is limited by: (1) the shortage of suitable size-matched, deceased donor organs and (2) the continued high rates of late graft and patient loss as a result of infection and rejection.2-6 The first of these factors mean that even if listed the mortality on the waiting list for intestine transplantation is the highest for any group of patients awaiting solid organ transplantation and is especially significant for the young children in need of composite intestine and liver allografts where pretransplant mortality has been reported as high as 60% of candidates. Competition for organs, especially from the larger group of patients awaiting isolated liver transplantation, as well as the size constraints for intestine and liver donors because of the small peritoneal volume in infant recipients with short gut syndrome, limits organ availability. Although reducing intestinal length and removing the right hepatic lobe can achieve reduction of allograft volume, outcome data for this procedure are limited. There are no widely available living related options but these have been successful at the University of Illinois in Chicago. In the United States, organ allocation policy has been modified in an attempt to increase access to suitable organs for these patients but it remains to be seen if waiting-list mortality declines.

Intestinal failure, the inability of the gut to support one’s nutritional requirements, may result from a significant surgical resection, such as short bowel syndrome, disorders of intestinal motility, particularly pseudo-obstructive syndromes, and severe enteric mucosal dysfunction, for example, microvillus inclusion disease. All children with irreversible intestinal failure or complications of intestinal failure should be offered the opportunity for evaluation at an experienced pediatric intestinal failure program. This assessment assures optimization of the management of intestinal failure, including attempts to limit the complications associated with long-term parenteral nutrition. Causes of intestinal failure leading to intestinal transplantation are shown in Table 131-1.

Long-term parenteral nutrition can be administered on an outpatient basis at home. This is commonly associated with good quality of life and adequate growth and development particularly for older children and adults. Therefore, uncomplicated intestinal failure is not in itself sufficient reason to contemplate intestinal transplantation.2 The fundamental indication for intestinal transplantation is irreversible intestinal failure with life-threatening complications. Such complications include progressive liver disease, recurrent severe infection, particularly fungemia, loss of central venous access sites, or uncontrollable enteral losses leading to metabolic or fluid instability.

Less frequent indications for intestine transplantation (with or without other abdominal organs) are in those instances when liver transplantation is required but cannot be achieved without concomitant intestine transplantation because of extensive portal and mesenteric venous thrombosis, or because resection of a tumor cannot be achieved without removal of the mesenteric root.

Types of organ transplants for intestinal failure are shown in Table 131-2, with general indications listed for intestine, liver, and composite transplantation.

Contraindications include active systemic infection, multisystem organ failure, severe congenital or acquired immunodeficiency, metastatic tumor, and severe cardiopulmonary or neurodevelopmental disease. Psychosocial issues such as inadequate family support, active drug abuse, or a history of noncompliance may make the transplant process untenable.

The purpose of a multidisciplinary transplant evaluation is to determine if transplantation is an appropriate option for a given patient and, if so, which organs should be transplanted. The diagnosis should be confirmed and all treatment options short of transplantation must be considered. Relative contraindications should be considered. Comorbidities and other potential complicating factors need to be identified. The family needs to be informed about the procedure, the relative risks and benefits, treatment alternatives, outcomes including survival, and associated financial implications.3 A psychosocial assessment is imperative to identify family dynamics, coping strategies, and other emotional stressors. The patient and family will require psychological preparation for the waiting period until transplant, the procedure, and the expected aftermath. It is also important to identify support systems and resources for the patient and family.

Following completion of all tests, consultations, and assessments the patient is discussed in detail at a multidisciplinary selection meeting where all members of the team are encouraged to provide input. A decision not to put the patient on the waiting list may be based on several considerations, including the following: the patient is stable on parenteral nutrition and does not have indications for transplantation, there is a presence of contraindications, transplantation may not be technically feasible, transplantation would be futile and would not improve survival, or alternative treatments modalities have been identified.

Following a recommendation to proceed with intestinal transplantation, the family is required to consent to their child being placed on the waiting list. Although the majority of families are fully supportive of listing their child, occasionally a family decides that transplant is not the best decision for their child and decline the offer. Given the intensity, complexity, and risk of the transplant, this decision may be an entirely appropriate course of action and is to be supported, assuming the child’s best interests have been given due consideration.

Donors are matched to recipients on the basis of blood group and size; typically, a donor smaller than the recipient is preferred, especially for recipients with short gut syndrome because of loss of peritoneal domain. Cytomegalovirus (CMV) matching is preferred, although not essential.

The donor operation routinely involves an en bloc resection, with a double arterial supply from celiac axis and superior mesenteric artery and avoiding hilum of the liver. The organ cluster includes liver, duodenum, and small intestine complete to ileocecal valve. The pancreas is retained with the cluster but can be removed if not needed, while taking care to avoid injury to superior mesenteric vein and common bile duct. An isolated small bowel graft can be procured as an organ cluster with ex vivo separation of intestine, liver, and pancreas allografts.

The transplant operation includes the removal of the failed organs and exposure of the vascular anatomy. Intra-abdominal adhesions and portal hypertension frequently complicate this step. In the case of an isolated small intestine transplant, only jejunum and ileum are transplanted. Arterial inflow is typically achieved by anastomosis of donor superior mesenteric artery to infrarenal aorta with venous drainage into the recipient portal or superior mesenteric vein. If there is evidence of portal hypertension or other concerns regarding venous outflow for the allograft, drainage directly to the inferior vena cava (IVC) is employed.

Transplant of a composite allograft including the liver is usually carried out en bloc, thus avoiding the need for a biliary anastomosis. Portal venous drainage of retained native foregut must be ensured and may be achieved by the creation of a portocaval shunt, although some surgeons prefer to connect this venous drainage into the portal system of the donor. Arterialization of the allograft is facilitated by an arterial conduit from the supraceliac or infrarenal aorta connecting to a portion of the donor aorta that includes the roots of the celiac axis and the superior mesenteric artery. Venous outflow is entirely via the hepatic veins, which may be piggybacked onto the recipient IVC, or the hepatic portion of the donor IVC may be interpositioned.

Intestinal continuity is achieved with an upper gastrointestinal anastomosis and either a terminal ileostomy if there is no functional colon, as in aganglionosis (colonic transplantation as part of a multivisceral transplant has been described but experience is limited), or with an ileocolic anastomosis. In the latter case, a loop or chimney ileostomy is created for post-operative allograft monitoring.

Abdominal closure may present further difficulties. Commonly, fascial closure without skin closure is preferred because of the high incidence of wound infection as well as the risk of compression of the allograft or its blood supply. Primary abdominal closure may not be possible without undue tension because of large organs, allograft edema, or loss of peritoneal domain and may be facilitated by a temporary patch or silo closure.

Intensive care admission is required following intestine transplant.1 Fluid balance requires careful control and must account for abdominal drainage and open wounds, and later by high stomal losses once postoperative ileus resolves. The recipients of composite allografts tend to require more intensive care than those receiving an intestinal graft alone because of a more debilitated state prior to transplantation, longer duration of surgery, greater blood loss/replacement intraoperatively, and a larger allograft often requiring delayed abdominal closure. In one large transplant program ICU stays were a median of 5 days for isolated intestine transplant recipients and 17 days for composite intestinal allograft.

Intensive care admission is required following intestine transplant. Recipients of composite allografts tend to require more prolonged intensive care than those only undergoing intestinal transplant.

Immunosuppression

The same immunosuppressive regimens are used for isolated and composite intestine transplantation, although these regimens vary between centers. The common immunosuppressive regimens employed currently include an induction agent, either an anti-IL2 receptor antibody (basiliximab or daclizumab) or a lympholytic preparation (thymoglobulin or alemtuzimab), and maintenance therapy with tacrolimus with or without the routine use of steroids. Sirolimus may also be used as maintenance therapy in certain centers, but its use should be delayed until wound healing is assured.

Infection Prevention and Surveillance

Infection is common following intestine transplantation because of the combined influences of extensive abdominal surgery with inherent risks of perforation, wound infection and intra-abdominal abscess formation, indwelling central venous catheters, and immunosuppression and is the leading cause of death in intestinal transplant recipients. Bacterial and fungal infections are the greatest risk in the first 4 to 6 weeks. Viral pathogens typically cause problems later post transplant. Routine surveillance for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) is common practice as seen in other transplant and immunosuppressed populations.

Postsurgical bacterial and fungal prophylaxis for the first 7 to 14 days is used. Long-term prophylactic regimens vary among transplant centers but universally include coverage for pneumocystis (carinii) jiroveci and cytomegalovirus.4

Fluid, Electrolyte and Nutritional Management

Fluid and electrolyte management after intestinal transplant must address large postoperative fluid shifts and the need to maintain hemodynamic stability and perfusion of the graft. Immediately postoperatively, intravenous fluids are administered at or below calculated maintenance requirements depending on the hydration status and renal function. Additional fluid replacement is usually required to compensate for losses from gastric and abdominal drainage and wound losses. Following resolution of allograft ileus in the first week, secretory diarrhea usually occurs. Stomal losses of greater than 35ml/kg/day are replaced with intravenous saline (0.45–0.9%), often with additional bicarbonate to avoid dehydration and electrolyte imbalances. Once full feeds are tolerated, excessive stool losses can usually be managed with enteral replacement fluids.

Monitoring Allograft Function

Clinical monitoring includes assessing the appearance and perfusion of the stoma and daily stool volumes. Allograft function is monitored early in the postoperative period by Doppler ultrasound of the abdomen to assess vascular patency, and in some programs by bedside Doppler assessment of stomal perfusion. Noninvasive tests of mucosal function such as fecal calprotectin and plasma citrulline concentrations are being evaluated and, although promising, the place for these tests in the routine care is yet to be defined. The mainstay of graft monitoring is endoscopy and mucosal biopsy. The intestinal allograft is examined by ileoscopy at least once a week in the early posttransplant weeks. In addition to routine surveillance the allograft is examined and biopsied whenever there is an unexplained change in intestinal function, primarily to rule out rejection. In the stable postintestinal transplant patient the frequency of endoscopic surveillance decreases. By the time closure of the ileal stoma is being contemplated, endoscopy may only take place when there are other clinical or biochemical indications for concern.

Surgical Complications

A high incidence of surgical complications can be seen following intestine transplantation due to the complexity and duration of the procedure, the history of previous abdominal operations, and advanced liver disease and suboptimal nutritional status. Complications include, but are not limited to, intestinal perforation or obstruction, intra-abdominal bleeding or abscess, wound dehiscence or infection, vascular thromboses, and stomal prolapse. Allograft volvulus and internal hernia are important causes of graft obstruction and carry a high risk for graft loss resulting from ischemia. Reoperation in intestine transplant recipients ranges from 60% to 90% of cases.

Infection

Infection is not only the leading cause of death in intestine transplant recipients, but is also the primary diagnosis for readmission during all periods post transplant. Bacteremia or fungemia often has its source either intra-abdominally or in relation to long-term vascular access. In addition to appropriate antimicrobial therapy management should include the drainage of intra-abdominal collections, or removal of infected catheters.

Infectious enteritis may occur in almost 40% of intestinal transplant recipients; two thirds of the cases being attributable to viral agents. Adenovirus infections are common and caliciviruses can also be significant pathogens in this population. Viral pathogens may cause prolonged but ultimately self-limiting gastroenteritis but can also cause severe allograft dysfunction post intestinal transplant. Epstein Barr virus (EBV) is an important cause of viral illness presenting either as acute infection or as EBV-induced posttransplant lymphoproliferative disease (PTLD) occurs in about 10% of patients. Treatment for PTLD in intestinal transplant recipients follows the general steps outlined in other solid organ transplant recipients; however, the reduction in immunosuppression has to be done cautiously and with close allograft monitoring as devastating rejection, even in the face of active EBV, may occur.

Graft Dysfunction

Causes of acute graft dysfunction include acute cellular rejection, systemic or abdominal sepsis, infective enteritis, PTLD, and surgical complications such as intestinal perforation and obstruction. Clinical manifestations of graft dysfunction include irritability, fever, vomiting, abdominal distension, and changes in the appearance of the stoma. Stomal output may be increased, decreased, or bloody depending on the cause and severity of graft injury. Blood and stool cultures, viral studies, endoscopy with mucosal biopsy, and radiologic studies may all be required for exclusion of other causes for symptoms. Differentiation between viral enteritits and mild acute cellular rejection may be difficult and experienced pathological interpretation of the biopsy specimens is essential (see http://tpis.upmc.com). Viral culture, immunohistochemisty, and in situ PCR may assist with the diagnosis. A lack of precision with the diagnosis of graft dysfunction can lead to inappropriate changes in immunosuppression potentially exacerbating graft injury.

Acute Rejection

A standardized system for grading the histologic changes associated with acute rejection of an intestinal allograft has gained wide acceptance.5 Changes seen in mild rejection include multiple apoptic crypt epithelial cells with lymphocytic infiltration. More severe grades include increased inflammatory cell infiltration, crypt damage, mucosal architectural alteration, and, ultimately mucosal loss. The treatment of acute rejection is with intravenous methylprednisolone boluses (10–20 mg/kg/day) usually for 3 days and an increase in the background immunosuppression either by increasing the goal serum levels of tacrolimus or by the addition of another immunosuppression agent. Endoscopy and biopsy are repeated frequently to ensure adequate treatment and to document histological improvement. Antilymphocyte preparations are reserved for severe or steroid resistant rejection. Severe rejection with loss of mucosa may necessitate graft enterectomy, particularly if no regeneration is seen following adequate immunosuppression or if infection ensues.

Chronic Rejection

The pathological lesion of chronic rejection is an obliterative arteriopathy of medium-sized vessels within the transplant mesentery and deeper layers of the deeper layers of the bowel wall. Mucosal changes, if present, are nonspecific. Diagnosis requires full thickness biopsy that is usually available only after enterectomy, when graft failure is established. Clinical signs of chronic rejection may include gradually deteriorating allograft mucosal function with increased ileal or stool outputs or allograft stricture with extensive submucosal fibrosis. Currently there are no markers of the early stages of this disease process, and once established, chronic intestinal allograft rejection does not respond to increased immunosuppression.

Survival

Short-term survival has improved most dramatically with a number of larger centers reporting 1-year survival approaching 90% in their most recent cohorts.7 Late graft loss, however, results in 5-year survival of 50% to 60%, according to the international Intestinal Transplant Registry (ITR). Factors identified by multivariate analysis as having a significant influence on survival include era of transplantation, experience of the transplant program, pretransplant status (home versus hospital), retransplantation, and induction immunotherapy.1,8 In the ITR data there is no difference in survival for isolated intestine allografts versus composite grafts although single center data has suggested better outcomes for the recipients of isolated intestines.

In patients surviving more than 6 months, greater than 70% have excellent graft function and ultimately 90% of surviving recipients. After intestinal transplantation, patients are generally able to achieve linear growth, maintain adequate muscle and fat stores and transition to an oral diet. Many children are able to achieve positive growth velocity, although catch-up growth sufficient to compensate for significant pretransplant stunting is uncommon.

Quality of Life

Quality of life is considered to be good for survivors of intestine transplantation with the large majority returning to normal daily activities however formal assessments of quality of life in children have only recently been published. A study of long-terms survivors of intestine transplantation in childhood showed that children perceived their physical and psychosocial functioning to be equivalent to the normal control population, although their parents rated their children’s general health somewhat below that of other children.9