Intestinal and Multivisceral Transplantation

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198 Intestinal and Multivisceral Transplantation

Peter Abrams, Kareem Abu-Elmagd, Kathryn Felmet, Jorge Reyes, George Mazariegos

The ongoing development of intestinal and multivisceral transplantation remains a dynamic process moved forward by advances in multidisciplinary care of intestinal failure, surgical technique, innovative immunosuppressive strategies, and an improved understanding of intestinal transplantation immunology. Recognition of intestinal transplantation as an established modality for select intestinal failure patients and better outcomes over the past decade have led to an increasing number of candidates referred for intestinal transplantation each year (Figure 198-1) and allowed more patients to benefit. In the United States alone, nearly 700 patients are alive with a functioning intestinal allograft as of December 2007.¹ Although the time interval between listing and intestinal transplant has decreased over the past decade (Figure 198-2), waitlist mortality remains high, particularly for infants and adults with concomitant liver failure.² Immunosuppression for intestinal and multivisceral transplantation now commonly involves perioperative antibody induction. The inability to prevent and treat chronic rejection in isolated intestinal allografts continues to be a fundamental barrier to achieving successful long-term outcomes and is the subject of rigorous investigation. Long-term data on nutritional outcomes and transplantation morbidity will help further define the optimal timing and role of intestinal and multivisceral transplantation in patients with intestinal failure.

Figure 198-1 A, Number of candidates on the isolated intestine waiting list by age, 1999-2008. B, Number of candidates on the combined liver and intestine waiting list by age, 1999-2008.

(Adapted from Mazariegos GV, Steffick DE, Horslen S, Farmer D, Fryer J, Grant D et al. Intestine transplantation in the United States, 1999-2008. Am J Transplant 2010;10:1020-34.)

Figure 198-2 Median time to transplant for intestine waiting list registrants, 1999-2008.

(Adapted from Mazariegos GV, Steffick DE, Horslen S, Farmer D, Fryer J, Grant D et al. Intestine transplantation in the United States, 1999-2008. Am J Transplant 2010;10:1020-34.)

Management of Intestinal Failure

Intestinal failure is clinically defined as the loss of nutritional autonomy secondary to bowel dysfunction. Patients with intestinal failure are initially managed by administration of total parenteral nutrition (TPN) through central venous access. The duration of intestinal failure is variable and in certain patients unpredictable, from short-term to lifelong, and depends largely on the adaptation capacity of the remaining viable intestine. Improved long-term outcomes in TPN-dependent pediatric patients have been reported recently by single centers.^3,^4,⁵ Nonetheless, there remains a significant subset of patients who develop irreversible intestinal failure and require indefinite TPN therapy with its attendant complications. Intestinal transplantation may be lifesaving in this group of patients.⁶

Optimal management of the patient with intestinal failure is achieved after a detailed multidisciplinary evaluation.^7,⁸ Obtaining a comprehensive history is critical and must include birth and disease history, past surgical procedures, infections, number and location of previous central venous lines, presence of central venous thrombosis, a detailed nutrition history including duration of TPN, details of TPN prescriptions and maximal enteral feeding tolerance, as well as medication history and frequency/volume of stools. A careful history and physical examination by the intestine rehabilitation team is critical to the process of achieving a complete pretransplant workup. Further investigations may include upper gastrointestinal (GI) contrast study with small-bowel follow-through, contrast enema if indicated, abdominal sonogram, ultrasound exam of central venous anatomy, endoscopy with small-intestinal aspiration for quantitative microbial culture and mucosal biopsy, and liver biopsy if there is evidence of liver dysfunction or portal hypertension.

Management of the patient with intestinal failure focuses on optimization of gut adaptation and recovery of intestinal function to achieve enteral autonomy. Surgical therapies that have a role in adaptation after intestinal failure include serial transverse enteroplasty (STEP).⁹ Alternatively, if gut dysfunction is considered irreversible, management of these patients concentrates on maintaining optimal growth in children and nutritional repletion in adults to prepare them for eventual intestinal transplantation.

Small-bowel bacterial overgrowth (SBBO) is a common clinical problem in patients with intestinal failure and is treated with a variety of antibiotic regimens. To date, there are no comparative studies available to enable an evidence-based approach to treatment of SBBO. The use of metronidazole for anaerobic overgrowth, combined with trimethoprim and sulfamethoxazole or an oral aminoglycoside for gram-negative organisms, is a common theme. Metronidazole monotherapy is used if the dominant symptoms suggest predominantly anaerobic overgrowth (such as bloating, increasing diarrhea, and D-lactic acidemia). The extreme sensitivity of anaerobes to oxygen makes the use of small-bowel aspirate cultures relatively unreliable as a means of microbial surveillance or indication to treat for SBBO. Probiotics such as Lactobacillus and Saccharomyces have been used in an attempt to limit SBBO. Given the absence of randomized evidence to support the efficacy of probiotics, coupled with reasonable concerns about impurities and possible contamination with other bacteria (e.g., Leuconostoc), the use of probiotics has been discouraged in patients with intestinal failure.

Parenteral nutrition–associated liver disease (PNALD), also referred to as intestinal failure–associated liver disease (IFALD), remains a critical problem in this patient population, affecting infants disproportionately. The 1-year mortality of patients with PNALD exceeds 80% in the absence of TPN weaning or transplantation. Although not always feasible, the best strategy to prevent and treat PNALD involves a commitment to the advancement of enteral nutrition. Despite a conscientious approach to TPN therapy, many children and adults still develop cholestasis relatively early in their clinical course. Prevention and timely treatment of infection, minimizing SBBO, preventing overfeeding with dextrose, providing adequate amino acids, cycling TPN, providing TPN-free days when possible, and providing taurine to neonates are probably all important measures to slow the progression of PNALD.¹⁰ Stasis of bile in the non-stimulated biliary system and gallbladder can lead to sludge buildup and cholelithiasis. In the authors’ experience, cholecystectomy rarely improves liver function and is not indicated for PNALD alone. None of the components of standard parenteral nutrition solutions have been conclusively shown to cause or contribute to PNALD, but excessive glucose and improper ratios of glucose to amino acid have been associated with hepatic steatosis. Recently, interest in the manipulation of the lipid component of TPN has led some to advocate for the removal of soy-based lipid solutions or their substitution with Omegaven (a fish-oil-based, intravenous [IV] lipid solution rich in omega-3 fatty acids); however, substantive evidence that these measures retard or reverse the progression of liver disease has not yet been demonstrated.^11,^12,¹³ Many clinicians will add but not entirely substitute fish-oil-based lipids for soy-based solutions only after liver function tests demonstrate abnormalities.

In addition to PNALD, patients on long-term parenteral nutrition are also at risk of developing metabolic bone disease (MBD). Associated with an insidious onset of bone pain that can become quite severe, patients with MBD will present with normal serum calcium, phosphorus, vitamin D and parathyroid hormone, but with hypercalciuria. Nontraumatic spinal and rib fractures have been reported in these patients. To optimize bone maintenance in patients on TPN, it is important to include calcium in parenteral formulations, prevent metabolic acidosis, and minimize aluminum contamination. Symptoms of MBD tend to resolve only after stopping parenteral nutrition.

Most intestinal transplant recipients will require intensive care unit (ICU) care during the pretransplant period; in fact, more than 10 % of intestinal and multivisceral recipients are in intensive care at the time of transplantation. Sepsis and GI hemorrhage are common reasons for ICU admission in patients with intestinal failure. Blood products, though necessary in the resuscitation of GI hemorrhage, should be used judiciously in the absence of acute bleeding. Pretransplant exposure to blood products, particularly platelets, can predispose intestinal transplant recipients to developing antibody-mediated rejection. Leukoreduced blood products may be preferable in patients awaiting transplant.

Catheter-associated bloodstream infections are common in TPN-dependent patients and often necessitate removal of a tunneled central venous catheter. Smaller pediatric patients and patients with a history of thrombosis may have limited venous access, necessitating preservation of an infected line. Percutaneous lines should be placed with caution in these patients; great vessels may no longer be patent, and trauma to remaining vessels may have serious consequences. Ultrasonic evaluation of deep veins to guide percutaneous central line placement is occasionally necessary.

Nutritionally deplete patients are relatively immune suppressed and prone to a severe course with community acquired infections. Pediatric patients with intestinal failure and IFALD are at increased risk of respiratory failure even with common viral infections. Because children have a compliant chest wall, increased abdominal girth creates a mechanical disadvantage even during normal tidal volume breathing. In the setting of pulmonary infection, volume overload, or decreased cardiac output, the work of breathing can lead to fatigue.

Indications For Transplant

In October 2000, the Center for Medicare and Medicaid Services approved intestinal, combined liver-intestine, and multivisceral transplantation as a standard of care for patients with irreversible intestinal failure who could no longer be maintained with TPN. Intestinal and multivisceral transplantation are now considered for patients with irreversible intestinal failure who fail TPN therapy due to complications, who cannot tolerate quality-of-life limitations associated with TPN therapy, or who must undergo native bowel resection for potentially life-limiting indications. The myriad causes of bowel dysfunction can be subcategorized into acute and chronic pathophysiologies. Common causes of acute dysfunction include necrotizing enterocolitis, volvulus, and mesenteric thrombosis. Common causes of chronic dysfunction include Crohn’s disease and radiation enteritis. These disease processes can alternatively be classified as either surgical due to resection leading to short bowel syndrome (SBS) or nonsurgical due to congenital enterocyte disorders leading to dysmotility or malabsorption. Unlike patients with SBS, patients with nonsurgical causes of intestinal failure may have native intestine which demonstrates normal gross morphology and anatomic length. Table 198-1 lists the already well-described indications for intestinal and multivisceral transplantation.

TABLE 198-1 Indications for Intestinal and Multivisceral Transplantation

Pediatric Patients	Adult Patients
Volvulus	Superior mesenteric artery thrombosis
Gastroschisis	Crohn’s disease/irritable bowel disease (IBD)
Necrotizing enterocolitis	Desmoid tumor
Pseudo-obstruction	Volvulus
Microvillus inclusion disease	Trauma
Intestinal polyposis	Familial polyposis
Hirschsprung’s disease	Gastrinoma
Trauma	Budd-Chiari disease
	Intestinal adhesions
	Pseudo-obstruction
	Radiation enteritis

Owing to the particularly high morbidity and mortality of children with PNALD, increasing efforts have been made by the pediatric medical community to optimize timing of referral of these patients to specialized intestine-failure rehabilitation centers and transplant centers to improve overall outcomes. A recent expert consensus panel ¹⁴ recommended the following pediatric criteria for consultation or referral for small-bowel transplant assessment: (1) children with massive small-bowel resection, (2) children with severely diseased bowel and unacceptable morbidity, (3) continuing prognostic or diagnostic uncertainty, (4) microvillus inclusion disease or intestinal epithelial dysplasia, (5) persistent hyperbilirubinemia (>6 g/dL), (6) thrombosis of 2 of 4 upper body central veins, (7) the request of the patient or family.

Determining which type of allograft to use in a patient with intestinal failure involves a comprehensive evaluation of the function and anatomy of the remaining bowel along with other abdominal organs. Intestinal failure patients are considered candidates for isolated intestinal transplant, combined liver and intestine transplant, multivisceral transplant (includeing liver, stomach, duodenum, pancreas, and small-bowel), or modified multivisceral transplant which excludes the liver. Whether to perform simultaneous hepatic replacement remains a challenging decision even to experienced transplant surgeons, particularly for patients with asymptomatic portomesenteric venous thrombosis and significant liver injury. The key factors in determining whether to perform liver transplant in patients with intestinal failure are the extent of portal hypertension and the severity of parenchymal liver disease. In general, patients with mild portal hypertension should be cautiously considered for isolated intestinal transplant. It is preferable under these circumstances that venous outflow from the intestinal allograft bypass the portal circulation and be drained to the recipient systemic circulation through the inferior vena cava.

Evaluation For Transplant

For both children and adults, the evaluation of intestinal and multivisceral candidates usually begins as an inpatient process. The goals of the transplant team are to determine whether the patient may benefit from transplantation, assess alternatives to transplant, evaluate any contraindications to transplantation, and provide education to the patient regarding the complex process of undergoing transplantation.

Transplantation Procedures

Brief descriptions of recipient operations are provided. The multivisceral donor procurement operation has already been well described.¹⁵

Isolated Intestinal Transplant

For isolated intestinal transplant (Figure 198-3), the donor intestinal graft (jejunum and ileum) is procured along with donor vascular conduits, including an artery (iliac and/or carotid) and a vein (iliac). The donor superior mesenteric vessels are occasionally anastomosed directly to the recipient superior mesenteric artery and vein if adequate length is achieved. More commonly, interposition vascular conduits are anastomosed to the recipient infrarenal aorta and recipient superior mesenteric vein (portal drainage) or inferior vena cava (systemic drainage) to provide sufficient length and proper orientation for the allograft.

Figure 198-3 Isolated intestinal transplant.

The intestinal reconstruction involves a proximal duodeno- or jejunojejunostomy, depending on individual recipient considerations of remnant bowel viability and anatomy. The distal length of intestinal allograft may end as a permanent end ileostomy if the recipient has no remaining viable colon or may be anastomosed to the remnant colon, leaving a short portion of allograft distal to the enterocolic anastomosis to bring out as a temporary end ileostomy that allows access to the bowel for endoscopic surveillance and mucosal biopsies. Single or multiple feeding tubes may be placed based on multiple considerations including recipient pretransplant oral intake capacity as well as donor bowel length.

Combined Small-Bowel And Liver Transplant

For combined small-bowel and liver transplant (Figure 198-4), the recipient hepatectomy is performed with preservation of the native retrohepatic inferior vena cava. The recipient foregut including stomach, native pancreas, and proximal duodenum is also preserved, and its outflow maintained with a permanent end-to-side portocaval shunt. The composite donor allograft includes the primary organs (liver and small bowel) as well as the donor duodenum and pancreas, allowing for maintenance of donor hepatobiliary continuity. Arterial inflow to the composite donor allograft is achieved using an arterial interposition conduit from the recipient infrarenal aorta. Liver venous outflow commonly involves the well-described “piggyback” technique, anastomosing donor suprahepatic inferior vena cava to the confluence of the recipient hepatic veins and cava. Intestinal reconstruction is performed in a similar fashion to an isolated intestinal transplant. Feeding tubes are placed as indicated.

Figure 198-4 Combined liver and intestinal transplant: A, Portocaval shunt draining native foregut. B, Combined liver and intestinal transplant with feeding jejunostomy.

Full Multivisceral Transplant

In the full multivisceral transplant procedure (Figure 198-5), prior to implantation, the recipient distal stomach, duodenum, pancreas, liver, and remaining small bowel are resected. The recipient inferior vena is meticulously preserved. The absence of remaining foregut or midgut precludes the need for portocaval shunt. Vascular inflow is similar to composite liver-bowel transplant but now includes celiac inflow to the stomach as well. Vascular outflow is identical to composite liver-bowel transplant. The donor spleen is removed from the composite allograft on the backtable prior to reperfusion.

Figure 198-5 Full multivisceral transplant.

Intestinal reconstruction is performed proximally with a gastrogastrostomy anastomosis, and the distal anatomosis is similar to previously described intestinal transplants. To avoid gastric outlet obstruction due to vagal denervation, a Heineke-Mikulicz pyloroplasty is routinely performed after reperfusion. Feeding tubes are placed as indicated.

A “modified” multivisceral transplant (Figure 198-6) involves transplantation of a full composite allograft without a liver. The recipient liver is preserved along with its vasculature and extrahepatic biliary system. Vascular conduits are used routinely (Figure 198-7). This procedure involves disruption of hepatobiliary continuity, commonly requiring in children a recipient-to-donor Roux-en-Y hepatojejunostomy, and in adults a choledochocholedochostomy (duct-to-duct) anastomosis, as well as vascular anastomoses to the recipient common hepatic artery and portal vein.

Figure 198-6 Modified multivisceral transplant.

Figure 198-7 Vascular conduit extensions for modified multivisceral transplant.

Immunosuppression

Although a variety of combinations of immunosuppressive drugs have been used in intestinal transplant recipients, most patients are maintained on tacrolimus (Prograf [Astellas, Tokyo, Japan]) therapy along with other adjunctive medications. Organ Procurement and Transplantation Network (OPTN) data show that 99% of intestinal transplant recipients receive tacrolimus as part of for maintenance immunosuppression at the time of posttransplant discharge. Moreover, during the first posttransplant year, only a select number of patients are taken off tacrolimus, with nearly 97% remaining on tacrolimus-based therapy. The most common regimen at 1-year post transplant is currently tacrolimus in combination with steroids, with the second most common being tacrolimus monotherapy.

Two classes of immunomodulatory drugs have recently been introduced for intestinal transplantation and have been associated with improvements in 1-year patient and graft survival. Depleting antilymphocyte antibody therapies include rabbit antithymocyte globulin (rATG, Thymoglobulin [Genzyme Corp., Cambridge, Massachusetts]) and alemtuzumab (Campath-1H [Genzyme Corp.]). The individual use of these agents by high-volume single centers has demonstrated improved short-term survival and decreased rejection rates as well as severity.^16,^17,¹⁸ Associated with similar improvements in survival and decreased incidence of acute rejection and severity, induction with nondepleting interleukin (IL)-2 receptor antagonists, daclizumab (Zenapax) and basiliximab (Simulect), has also gained increasing acceptance by many intestinal transplant programs. Immunosuppression for intestinal and multivisceral transplantation now involves perioperative antibody induction in 60% of cases.

Immunologic Monitoring

The gold standard for monitoring and diagnosing rejection in intestinal and multivisceral transplant recipients remains routine ileoscopy and proximal enteroscopy with histopathologic examination of multiple random mucosal biopsies. Significant investigation is underway toward the development of tools to guide and monitor the immunologic state of the intestinal transplant recipient. Ideally, noninvasive markers such as serologic, proteomic, or genomic markers may identify those patients who are at increased risk of rejection and, conversely, those who might benefit from decreased levels of immunosuppression.^19,²⁰ Preformed antibody and de novo antidonor-specific antibody measurement may be of assistance in determining risk of rejection.^21,²² When technically feasible, the presence of circulating donor cells in the recipient peripheral blood should be serially evaluated after transplantation by either flow cytometry or polymerase chain reaction (PCR). Monoclonal antibodies specific for donor HLA class I molecules are used for single-color immunofluorescence analysis. The presence of donor-specific antibodies in intestinal transplant recipients at the University of Pittsburgh prompts aggressive therapy with serial plasmapheresis and intravenous immunoglobulin (IVIG) until clearance of antibodies has been confirmed. For PCR analysis, primers specific for donor HLA class II alleles or else the sex-determining region of the Y chromosome (in male donor to female recipients) can be used. The use of fecal calprotectin or serum citrulline as noninvasive biochemical markers of allograft rejection does not appear to be warranted based upon currently available data.^23,²⁴

In recipients of intestinal or multivisceral transplants, surveillance endoscopy (esophagogastroduodenoscopy [EGD], ileoscopy, colonoscopy) is performed biweekly for the first 4 to 6 weeks post transplant, and then weekly for an additional 4 to 6 weeks to monitor for rejection. After the first 3 months post transplant, the frequency of surveillance endoscopies performed in recipients is based upon individual clinical assessments.

Postoperative Management

Advances in the technical aspects of intestinal and multivisceral transplantation have occurred in parallel with improvements in intraoperative monitoring and postoperative critical care management of these challenging patients.

Ventilatory Management

Extubation is commonly achieved within 48 hours of the transplant operation in adult patients. Mitigating factors which might delay extubation include graft malfunction, delayed abdominal wall closure, volume overload, sepsis, organ failure, and surgical complications such as bleeding. In children, delayed abdominal wall closure is commonly necessary and requires continued neuromuscular blockade. Given that recipients tend to be nutritionally compromised preoperatively and that intestinal and multivisceral transplant operations are relatively long in duration (8-18 hours), a careful assessment of weaning parameters prior to extubation is essential. Pleural effusions are common and due to nutritional depletion with hypoalbuminemia and intraoperative manipulation of the diaphragm; they may not be responsive to diuretics. Changes in intraabdominal pressure and abdominal girth may adversely affect respiratory mechanics, leading to rapid, shallow breathing. These problems are most common in children, in small adults who receive a large allograft, and in patients whose course is complicated by large-volume ascites.

Renal Function

It is common for intestinal transplant recipients to demonstrate some degree of renal dysfunction pretransplant, owing to multiple episodes of sepsis with hypotension, the side effects of antibiotics, and hepatic dysfunction. Although patients receive significant volumes of fluid during the long course of the transplant operation, intravascular volume depletion can be a problem in the immediate posttransplant period. Significant fluid volume may accumulate in the intestinal allograft secondary to preservation injury (peaking at 48-72 hours), and large-volume ascites production due to mesenteric lymphatic leakage may occur. Either of these processes can lead to profound and sometimes underappreciated intravascular volume depletion and can worsen the nephrotoxicity of immunosuppressive agents and antibiotics.

Maintenance of ideal volume status is challenging in these patients; interventions should be directed at optimizing cardiac output and organ perfusion. Extravascular volume overload is common and should be interpreted with caution, particularly in the immediate posttransplant period. In patients with impaired renal function or high tacrolimus drug levels, urine output may not be an accurate indicator of perfusion. Skin perfusion, mixed venous oxygen concentration, and serum lactate are useful surrogates. Because intestinal transplant recipients are nutritionally deplete, use of 5% albumin as a volume expander may be preferable to larger volumes of crystalloid solution. In patients with large-volume stoma output or ascites drainage, standing orders for fluid replacement may be necessary. Balancing adequate volume resuscitation with the avoidance of volume overload in the setting of baseline renal dysfunction can be a significant challenge that requires considerable clinical experience and meticulous attention to detail.

Infection Control

Recipients of intestinal or multivisceral transplants will routinely receive prophylactic broad-spectrum antibiotics post transplant. Any history of nosocomial infections before transplant should be addressed with the administration of appropriate specific antibiotics. Colonizing organisms growing from enterocutaneous fistula tracts should also be covered appropriately. Selective bowel decontamination with nonabsorbable oral antibiotics is performed in some intestinal transplant patients. Surveillance stool cultures are performed on a weekly basis post transplant.

Translocation of bacteria or bacterial toxins from the intestine to the bloodstream can cause sepsis or systemic inflammatory response syndrome (SIRS). A history of repeated exposure to broad-spectrum antibiotics leads to colonization with multiply resistant organisms in many intestinal transplant recipients. Empirical antibiotic therapy for sepsis should include coverage for common enteric organisms and should take into account a history of antimicrobial resistance. Episodes of translocation occur most commonly during acute rejection, when the mucosal barrier of the allograft has been compromised, but can also be demonstrated with enteritis associated with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection. In the absence of positive blood cultures to direct antibiotic therapy, organisms growing from quantitative stool cultures in significant numbers (>10⁸ colony-forming units [CFU]/mL) in a patient with sepsis or acute cellular rejection may be considered potential causes of bacteremia and may be treated with IV antibiotics. The high incidence of renal dysfunction in intestinal transplant recipients should prompt use of non-nephrotoxic antibiotics when possible and careful monitoring of antibiotic levels when necessary.

Antiviral Prophylaxis

Antiviral prophylactic strategies have evolved over the past decade of intestinal transplantation. Viral infections can cause significant morbidity, especially in pediatric recipients in the early postoperative period. Common pathogens include CMV, EBV, herpes simplex virus (HSV), adenovirus, and influenza viruses. Many pediatric recipients have no prior protective exposure to these viruses, so primary infection occurs in these patients while they are highly immunosuppressed. Recent advances in prophylaxis and preemptive therapy have significantly decreased early morbidity associated with EBV, CMV, and HSV, lowering the incidence of clinically significant infection to less than 5%. Lack of definitive treatment for infection with respiratory viruses such as influenza and adenovirus in the early postoperative period can be catastrophic because of clinical sequelae including disseminated viremia, necrotizing pneumonitis, and bacterial superinfection. The currently recommended anti-CMV prophylaxis includes a 2-week course of IV ganciclovir with concomitant administration of cytomegalovirus-specific hyperimmune globulin (Cytogam). The IV dose for ganciclovir is 5 mg/kg twice daily. The dose for Cytogam is 150 mg/kg in donor CMV-positive/recipient CMV-negative mismatches, administered 2, 4, 6, and 8 weeks after transplant and 100 mg/kg/d at 12 and 16 weeks after transplant.

Nutritional Support

Immediate posttransplant nutritional support is administered using standard TPN, which is tapered gradually as enteral feeding is advanced. Tube feedings with isotonic formula are started based upon clinical determination of intestinal allograft function. In the authors’ experience, most intestinal transplant patients do not voluntarily ingest adequate amounts of nutrition in the early postoperative period. To achieve maximal nutritional repletion, tube feeding is usually required once the intestinal tract becomes functional. Resistance to oral feedings is a particular clinical challenge in younger pediatric recipients, many of whom demonstrate oral aversion.

Assessment Of Intestinal Allograft

The process of examining the anatomic and functional integrity of the intestinal allograft begins in the operating room. The normal intestinal allograft after reperfusion appears pink and nonedematous, with occasional contractions. Alterations from this appearance can be observed in the operating room and in the proximal jejunal and distal ileal segments using endoscopy postoperatively.

Surveillance for intestinal allograft rejection in the early postoperative period focuses on clinical evaluation and gross morphologic examination of the stoma and distal ileum. Frequent routine enteroscopy surveillance is the most reliable method for achieving an early diagnosis of intestinal rejection (Figure 198-8). Endoscopic evaluations are performed initially twice a week through the allograft ileostomy; upper endoscopy is reserved for occasions where clinical changes are not well explained by distal allograft evaluation and biopsy. Common changes to the normal appearance of an intestinal allograft include edema, cyanosis, congestion, and increased stomal output. These changes should prompt an immediate workup, with a differential diagnosis that includes preservation injury (Figure 198-9), sepsis, rejection, and enteritis.

Figure 198-8 Enteroscopic findings consistent with acute cellular rejection of intestinal allograft.

(Courtesy Kareem Abu-Elmagd, MD.)

Figure 198-9 Ischemia-reperfusion injury. Reperfusion injury is characterized by extensive loss of villi, followed by pronounced regenerative changes of crypt epithelium with conspicuous mitosis, capillary congestion, shortening of villi, and variable degrees of neutrophil-rich inflammatory infiltration.

The allograft stomal output is assessed for volume and consistency. Normal stomal output during the early postoperative period is characteristically clear and thin. During the first week post transplant, normal stomal output is 1 to 2 L/d and 40 to 60 mL/kg/d for adult and pediatric recipients, respectively. If these stomal volumes are exceeded in the absence of significant pathology, agents to control volume of output can be started including paregoric, loperamide, pectin, somatostatin, or oral antibiotics. The presence of blood in the stomal output is an ominous sign and implies acute rejection until proven otherwise.

Intestinal allograft absorption of nutrients and medications develops gradually and commonly requires several weeks post transplant to manifest. Abnormal absorption after approximately 1 month should prompt an aggressive search for underlying pathology, especially rejection. The ability to maintain whole-blood tacrolimus trough levels above 15 ng/mL on oral therapy alone is a good indicator of adequate absorption. In the authors’ experience, intestinal transplant recipients demonstrate evidence of sufficient absorptive function at a mean of 28 days after transplantation. Recipients of multivisceral transplants demonstrate even longer delay until intestinal allograft absorption is well established.

Management of Allograft Rejection

Allograft rejection (Figure 198-10) is strongly associated with graft loss and patient death and remains a significant obstacle to achieving successful long-term outcomes for intestinal and multivisceral transplant recipients. Historically, acute cellular rejection was reported in 70% to 90% of intestinal allografts within 90 days post transplant. In contrast, rejection rates of 30% to 40% are currently reported by large centers thanks to advances in allograft histopathologic surveillance, immunosuppression, and immunologic monitoring. Unlike liver allograft rejection, the natural history of rejection of intestinal allograft is unforgiving, making early diagnosis and treatment critical for successful reversal of the rejection process.

Figure 198-10 Acute cellular rejection of intestinal allograft: mild (A), moderate (B), and severe (C).

A, Mild acute rejection is characterized by a generally mild and localized inflammatory infiltrate, which tends to be concentrated around small venules in the lamina propria. Mucosa is intact, but crypt epithelium displays evidence of injury: mucin depletion, cytoplasmic basophilia, decreased cell height, nuclear enlargement with hyperchromasia, and inflammatory infiltration. Crypt epithelial apoptosis is increased, usually with more than 6 apoptotic bodies/10 crypts. If sampled by biopsy specimen, preexisting lymphoid aggregates (Peyer’s patches) demonstrate an intense accumulation of activated lymphocytes. Villi are variably shortened, and architecture may be slightly distorted owing to expansion of lamina propria by inflammatory infiltration.

B, In moderate acute rejection, inflammatory infiltrate is widely dispersed within the lamina propria. Crypt injury and cryptitis are distributed more diffusely than in mild acute rejection, and villi tend to have a greater degree of flattening. Number of apoptotic bodies is greater than in mild acute rejection, usually with focal “confluent apoptosis.” Mild to moderate intimal arteritis may be seen. Mucosa remains intact without ulceration, although focal superficial erosions can be present.

C, Severe acute rejection is distinguished by a marked degree of crypt damage and mucosal ulceration, with lymphocytic infiltration extending deep into allograft wall and involving nerves and ganglia. As a consequence of mucosal destruction, luminal contents gain access to submucosa, prompting a neutrophil-rich infiltrate and an overlying fibropurulent (pseudomembranous) exudate with widespread mucosal sloughing as the final result. Adjacent viable epithelium usually shows rejection-associated changes such as crypt epithelial damage and abundant apoptosis. Severe intimal arteritis or transmural arteritis may be seen.

Until proven otherwise by culture and allograft biopsy, each episode of allograft dysfunction should prompt an expeditious evaluation for acute rejection. There are currently no laboratory tests available to warn of allograft dysfunction or rejection for intestinal transplantation. Clinical features of intestinal allograft rejection include nonspecific signs and symptoms such as diarrhea and abdominal pain. Infectious enteritis and medication-related loose bowel movements are common etiologies of allograft dysfunction that present with a similar clinical picture to allograft rejection. The stoma may become edematous, erythematous, and friable. Endoscopy may demonstrate normal mucosa despite mild to moderate grades of ongoing acute cellular rejection. Moderate to severe rejection of the intestinal allograft usually leads to mucosal inflammation beginning with erythema and friability, progressing to mucosal slough and exudates overlying ulcers, with eventual loss of the mucosal layer. Histologically, there is variable presence of edema in the lamina propria and villous blunting. However, mononuclear cell infiltrates and intestinal crypt apoptosis with regeneration are the hallmark signs of intestinal allograft rejection that establish the diagnosis.

Treatment of intestinal acute cellular rejection initially involves steroids. At the University of Pittsburgh, a total dose of approximately 30 mg/kg of methylprednisolone is usually given, either by 3 boluses of 10 mg/kg/d over 3 days or by a cycle of tapering doses over a more extended duration. Antilymphocyte antibodies for steroid-resistant rejection include muromonab CD3 (OKT3, a murine monoclonal anti-CD3 antibody) and antithymocyte globulin (rATG [rabbit-derived], Thymoglobulin). Adverse immune-mediated drug reactions to immunomodulatory antibodies can be life threatening. These agents are usually administered to patients with cardiopulmonary monitoring following premedication with steroids, antipyretics, and histamine blockers. In many cases, it is appropriate to initiate therapy in an ICU setting. During and after the treatment of acute rejection, tacrolimus whole-blood levels are maintained around 18 to 20 ng/mL in intestinal and multivisceral allograft recipients. Maintenance steroid therapy usually consists of 1 to 2 mg/kg/d of oral prednisone, tapered over several weeks to months based on individual clinical assessments. Addition of a third agent such as mycophenolate mofetil (MMF; CellCept [Roche]) or sirolimus (Rapamune) may be indicated if rejection is refractory or recurrent.

A fundamental principle which guides treatment of allograft rejection is the preservation of as much intestinal function as possible. Each episode of rejection shortens intestinal graft functional longevity, so the diagnosis of steroid-resistant rejection in intestinal allografts must be made in a more timely fashion than in a regenerating organ such as the liver. Antilymphocyte therapy in response to a diagnosis of steroid resistance will rapidly reduce the overall number of immunocompetent cells and is usually highly effective treatment for steroid-resistant rejection. Antilymphocyte therapy must be used cautiously in refractory rejection, after sequential biopsies separated by reasonable time intervals allow objective confirmation of steroid treatment failure. In an isolated intestine recipient with preexisting immune debilitation or a predisposition to a life-threatening illness such as posttransplant lymphoproliferative disorder (PTLD), allograft enterectomy may be safer than escalation of immune suppression and be potentially life saving.

Antibody-mediated rejection (AMR) of the intestinal allograft (Figure 198-11) is characterized by intestinal dysfunction, diffuse C4d staining on allograft biopsy, and usually identification of donor-specific antibodies. Treatment of AMR consists of plasmapheresis in combination with IVIG and steroids. Rituximab or bortezomib can be used in select recipients.

Figure 198-11 Antibody-mediated rejection of intestinal allograft. Humoral rejection is characterized by a grossly cyanotic small-intestine allograft. Histologic findings include severe congestion, neutrophilic margination, and fibrin-platelet thrombi within the lamina propria microvasculature, along with focal hemorrhage. Immunohistochemical staining to C4d confirms the diagnosis of antibody-mediated rejection with heavy and diffuse staining of the lamina propria capillaries.

Chronic rejection (Figure 198-12) is observed in 10% to 15% of pediatric and adult intestinal allografts, occurring more commonly in isolated intestinal allografts. In adult recipients at the University of Pittsburgh, multivisceral transplants including a liver allograft demonstrated a significantly better chronic rejection-free survival compared with the liver-free intestinal and other multivisceral transplant recipients.²⁵ Risk factors for chronic rejection include type of allograft and retransplantation. The clinical presentation of chronic rejection may include weight loss, chronic diarrhea, intermittent fevers, distal intestinal allograft obstruction, or GI bleeding. Histologically, chronic rejection is characterized by villous blunting, focal ulcerations, epithelial metaplasia, and scant cellular infiltrates on endoscopic mucosal biopsies. Full-thickness biopsies of intestinal allograft with chronic rejection demonstrate obliterative thickening of intestinal arterioles.

Figure 198-12 Chronic rejection of intestinal allograft. Histologic findings in mucosal biopsies are obliterative arteriopathy, lymphoid depletion, and mesenteric sclerosis. Mucosa shows loss of villous architecture, chronic ulcers with exudate and granulation tissue, widespread loss of the crypts of Lieberkühn, crypts of Lieberkühn with pyloric gland metaplasia, and mucosal fibrosis.

Management of Complications

Postoperative Hemorrhage

Recipients of intestinal and multivisceral transplants commonly will demonstrate varying degrees of liver dysfunction, qualitative and quantitative platelet abnormalities, and fibrinolysis which can lead to profound intraoperative coagulopathy. Intraoperative bleeding can also develop from lysis of vascularized adhesions due to previous surgeries and portal hypertension. Transient graft reperfusion coagulopathy mediated by plasminogen activators from the graft may also occur. Every effort is made to address these factors in the operating room, and usually whatever coagulopathy persists postoperatively is mild. Postoperative hemorrhage is most often a technical problem arising from vascular anastomoses or extensive raw peritoneal surfaces. Even mild coagulopathy should be completely corrected if bleeding is suspected in the posttransplant recipient. Any bleeding that causes hemodynamic alteration should be managed by early reexploration.

Vascular Complications

Superior mesenteric artery thrombosis is a catastrophic complication that leads to rapid and massive necrosis of the intestinal allograft. Elevation of hepatic enzymes (with liver allografts) and pallor of the intestinal stoma is accompanied by clinical deterioration, usually fulminant sepsis, and hepatic coma (with liver allografts). Isolated small-bowel allografts can be explanted with a reasonable expectation of patient survival; but in patients with composite allografts, removal for arterial thrombosis leads to almost certain death in the absence of immediate retransplant. Clinical suspicion of arterial thrombosis should be definitively evaluated in the operating room and not delayed by performance of Doppler ultrasound examination.

Acute venous thrombosis also leads to loss of the intestinal allograft without timely surgical intervention. Clinical signs of venous thrombosis include acute massive ascites and stomal congestion. Mesenteric infarction is the ultimate outcome of unresolved venous thrombosis, necessitating explant of the intestinal allograft.

Incomplete obstruction of major inflow or outflow vessels may be suspected on allograft biopsy or based on clinical and laboratory signs of graft dysfunction. Contrast vascular radiographic studies are confirmatory, and the correction is either surgical or endovascular based upon individual assessments and available clinical expertise.

Gastrointestinal Complications

Gastrointestinal bleeding after intestinal transplantation is an ominous sign that requires timely evaluation. Acute rejection or infectious enteritis are the most likely etiologies and should be diagnosed or excluded based upon endoscopic biopsy results. The diagnosis of rejection relies not only on histologic evidence but also on the endoscopic appearance of the mucosa. Bleeding from ulcerated EBV- or CMV-induced lesions can be routinely differentiated by gross endoscopic examination. Empirical therapy for rejection of intestinal allografts is not indicated under any circumstances.

Anastomotic leak may occur in all intestinal transplant recipients, but it is more common in pediatric patients than adults. Clinical presentation commonly involves florid sepsis, and confirmation is achieved with oral contrast imaging. Owing to immunosuppression, all bowel leaks require surgical revision, evacuation of any peritoneal contamination, and often second-look laparotomy to confirm resolution. Diagnostic laparotomy is indicated in the setting of sepsis and equivocal imaging studies.

The progression of motility patterns in the denervated intestinal allograft is still not fully understood. Hypermotility of the allograft occurs early after transplant, and in the absence of infection or rejection, it can be regulated with agents such as paregoric, loperamide, or pectin.

Renal Complications

Deterioration of renal function in intestinal transplant recipients remains a significant clinical challenge. Pretransplant renal dysfunction is exacerbated by higher target levels of immunosuppression, repeated exposure to nephrotoxic antibiotics, and episodes of dehydration with intestinal allograft dysfunction. The incidence of chronic renal failure for intestinal transplant recipients at 5 years post transplant exceeds 20%.²⁶ Overall, a review of Scientific Registry of Transplant Recipients (SRTR) data shows that patients without severe pretransplant renal dysfunction who do not receive a kidney as part of the composite allograft will generally demonstrate a 50% increase in serum creatinine at 5-year follow-up.

Posttransplant Lymphoproliferative Disorder

The development of PTLD is almost always associated with EBV infection. Posttransplant infection with EBV results in a spectrum of diseases, from mononucleosis syndromes and plasma cell hyperplasia to neoplastic PTLD (Figure 198-13). In a series of 500 intestinal and multivisceral transplants at the University of Pittsburgh, all but 2 of 57 recipients with PTLD developed the disorder as a consequence of confirmed EBV infection. Early studies found that primary tacrolimus use in pediatric patients was associated with a 15% long-term risk of PTLD, with almost 80% of these cases occurring within the first 2 years after transplant. Achieving an optimal immunosuppression steady state and avoiding excessive therapy intervals appear to be keys to minimizing EBV/PTLD complications. Cumulative PTLD-free survival for intestinal transplant recipients undergoing induction immunosuppression has improved to nearly 90%, possibly attributable to a lower incidence of acute rejection (and thus decreased need for escalation of immunosuppression) as well as improved EBV viral load monitoring.

Figure 198-13 Epstein-Barr virus posttransplant lymphoproliferative disorder (EBV/PTLD). At the early phase of EBV infection, tissue is expanded by scattered EBV encapsulated RNA (EBER)-positive lymphocytes. With disease progression, the number of positive cells increases, lymphocytes become activated and transformed, and ultimately, tissue architecture is effaced by a malignant lymphoproliferative process.

Patients presenting with PTLD complain of sporadic fever, lethargy, and malaise. Weight loss, diarrhea, and GI complaints are common, as are signs of graft dysfunction. Standard laboratory evaluation may demonstrate neutropenia, atypical lymphocytosis, anemia, and thrombocytopenia. Further evaluation of PTLD is guided by findings on contrast-enhanced computed tomography (CT) scanning of the head, neck, chest, abdomen, and pelvis, with or without endoscopy, based on results of noninvasive imaging. Histologic examination of the tissue is optimal, and specimens should be promptly submitted for fresh staining with the EBER-1 probe by experienced pathologists. An evaluation for CD20 staining should also be performed.

Treatment of PTLD involves stopping immunosuppression completely. PTLD that is unresponsive to discontinuation of immunosuppression should be treated with monoclonal antibody, usually rituximab, if shown to be CD20 positive by biopsy. Complete remission rates of 60% to 70% have been reported in children. The antibody therapy is relatively well tolerated, and for the 20% of patients who have recurrence, retreatment with rituximab can be curative. For PTLD refractory to monoclonal antibody, low-dose cytotoxic chemotherapy and steroids have been used effectively.

Graft-Versus-Host Disease

Acute graft-versus-host disease (GVHD) results from immunocompetent donor T cells causing damage to recipient tissues after transplantation. The incidence of GVHD (Figure 198-14) after intestinal transplantation ranges between 5% and 10% and usually occurs within the first 6 months post transplant.²⁷ The major targets of GVHD are epithelial cells of skin, intestine, and liver. Cardiac muscle involvement is not common but has been described. A recipient with GVHD commonly presents with fever and a maculopapular rash on the upper torso, neck, or palms of hands and feet, which may coalesce to form blisters or more diffuse erythema. Other clinical signs and symptoms include oral lesions, diarrhea, intestinal mucosal ulceration, native liver dysfunction, lymphadenopathy,²⁸ and bone marrow suppression with pancytopenia. The variability of GVHD focality and severity leads to a wide spectrum of disease, from mild GVHD presenting with fevers and self-limiting rash to more severe forms leading to end-organ damage.

Figure 198-14 Intestinal allograft graft-versus-host disease (GVHD). Mucosal biopsy of native small intestine showing crypt epithelial apoptosis and lamina propria inflammation.

The diagnosis of GVHD is based on the clinical presentation and by histologic confirmation when possible. Corticosteroids are the first-line therapy to control epithelial damage caused by GVHD and are effective in around 50% of cases overall. If unresponsive to steroids, GVHD can usually be controlled by reduction of calcineurin-based immunosuppression. Other forms of refractory GVHD have been treated successfully using antilymphocytic therapy (e.g., Thymoglobulin and OKT3), as well using anti-interleukin therapy (e.g., Zenapax and Simulect) as well as anti-TNF (tumor necrosis factor) antibody therapy (e.g., Remicade).

Outcomes

Patient And Graft Survival

A significant improvement in early patient and graft survival after intestinal transplantation has been achieved over the past decade, with 1-year patient and graft survival (Figure 198-15) reaching 89.3% and 78.9% for intestine-only recipients and 71.5% and 69.0% for liver-intestine recipients, respectively. In 1998, the 1-year adjusted graft and patient survival after intestinal transplantation were only 52% and 69%, respectively. Updated outcomes for intestinal transplant recipients are now comparable to outcomes following pancreas, lung, and liver transplantation. Contributing factors to this marked improvement in outcomes after intestinal transplantation include increased experience among intestinal transplant teams, improvements in critical care, advances in immunosuppression, and advances in the detection and treatment of rejection. The hospitalization status of the recipient at the time of transplantation also remains a strongly predictive factor for patient survival, with an unadjusted 1-year survival rate of 83% for recipients not waiting in the hospital, 73% for recipients waiting in the hospital, and only 50% for recipients waiting in the ICU. In 1999, almost one-third of intestinal and multivisceral recipients were in intensive care at the time of transplantation, whereas in 2008, 70% were not in the hospital, and only 12% were in intensive care.

Figure 198-15 Unadjusted patient and graft survival for isolated intestine and combined liver and intestine recipients.

(Adapted from Mazariegos GV, Steffick DE, Horslen S, Farmer D, Fryer J, Grant D et al. Intestine transplantation in the United States, 1999-2008. Am J Transplant 2010;10:1020-34.)

In contrast to recent achievements in short-term outcomes, long-term survival after isolated intestinal transplantation has not significantly improved. Ten-year patient and graft survival remain 46% and 29% for isolated intestinal transplantation and 42% and 39% for intestine-with-liver grafts, respectively. These results are similar to those reported for lung and combined heart-lung transplantation but compare unfavorably to kidney, liver, and heart transplantation, where 10-year patient and graft survival exceed 50%.

Long-Term Rehabilitation And Quality Of Life

Long-term functional outcomes after intestinal transplantation have not been fully characterized. A small preliminary study ²⁹ in pediatric recipients with functioning intestinal allografts more than 1-year post transplant found that quality of life was perceived by recipients to be comparable to that of their peers, while parental proxy assessments compared less favorably in terms of physical functioning, general health, and family activities. Younger recipients (5-10 years of age) demonstrated significantly worse outcomes than older recipients (11-18 years of age) in terms of global health assessments, general health perception, and family activities. There have been reports demonstrating significant improvement in certain aspects of psychiatric health after transition from parenteral nutrition to posttransplant TPN independence.³⁰ In these reports, long-term physical and psychiatric rehabilitation were achieved in over 80% of intestinal transplant recipients who survived beyond the sixth postoperative month.