Intestinal Transplantation Treatment & Management

Updated: Jan 18, 2017
  • Author: Colin P Dunn, MA; Chief Editor: Mary C Mancini, MD, PhD, MMM  more...
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Treatment

Surgical Therapy

Procurement

The basic steps of the procurement of an isolated small bowel graft are as follows:

  • Although some transplant programs perform a decontamination of the donor bowel via a nasogastric tube, this is not uniformly performed
  • Immunosuppression is given to the donor by some transplant programs just before or at the time of the procurement; antithymocyte globulin, muromonab, basiliximab, and steroids are most frequently used
  • University of Wisconsin Universal Organ Preservation (UW) solution for both in situ flushing and cold storage is most frequently used
  • Obtain wide exposure to the abdominal cavity and encircle the abdominal aorta distally for subsequent insertion of the infusion cannula and proximally above the celiac axis for cross-clamping
  • Perform dissection, in situ cooling of abdominal organs, and exsanguination before removing the organs to the back table for preparation
  • Detach the small bowel from the large bowel by total colectomy
  • Mobilize and devascularize the cecum and ascending colon, with care to preserve the ileal branches of the ileocolic artery
  • Divide and close the ileum with a GIA stapler near the ileocecal valve
  • Devascularize the colon by ligating and dividing the middle colic, left colic, and inferior mesenteric arteries near their origin
  • After transection of the gastrocolic ligament and transection of the stapled sigmoid colon, remove the large bowel and greater omentum
  • Free the root of the small bowel mesentery from its retroperitoneal attachments
  • Expose the mesenteric root, abdominal aorta, and infrahepatic vena cava, including entry of the renal veins
  • Divide the highest jejunal vascular arcades
  • Preserve the vascular supply to the fourth part of the duodenum and the proximal part of the jejunum
  • Transect the proximal jejunum after mobilizing and dividing the ligament of Treitz and the inferior mesenteric vein (IMV)
  • At this stage, the intestine is attached to the donor only by the superior mesenteric pedicle, containing the superior mesenteric artery and superior mesenteric vein
  • Divide the mesenteric root distal to the level of the ligated middle colic vessel.
  • More recent studies have shown that preservation of the ileocecal valve is critical for optimal outcomes [38, 39]
  • Transaortic cooling requires UW solution (50-100 mL/kg) for pediatric donors
  • Vent venous beds via the suprahepatic vena cava
  • Avoid overperfusion of the intestine
  • Remove the small-intestine graft by dissection of the superior mesenteric artery and superior mesenteric vein below the origin of the inferior pancreaticoduodenal artery
  • Excise a large Carrel patch from the anterior aortic wall containing the celiac axis and superior mesenteric artery
  • Procure iliac and carotid arteries and veins as potential vascular grafts
  • Note: for living donors, a technique has been described for laparoscopic removal of the allograft [28]

Back-table preparation of organs

See the list below:

  • Small-intestine grafts require little revision
  • If the pedicle of the superior mesenteric artery is too short, it may be lengthened with free vascular grafts
  • Identify and tie lymphatics
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Intraoperative Details

See the list below:

  • The intestinal graft implantation begins with the takedown of adhesions, which are usually abundant in these patients secondary to previous surgeries
  • The aorta and cava are dissected in preparation for the vascular anastomosis
  • The proximal and distal ends of the remnant digestive track are dissected free
  • Venous anastomosis to the graft is usually performed to the recipient cava
  • Arterial anastomosis is performed to the abdominal aorta
  • After reperfusion of the graft and profuse hemostasis, the proximal and distal end of the intestinal graft is anastomosed to the proximal and distal ends of the remnant digestive track
  • A loop ileostomy is created for future endoscopic surveillance; see the image below
    Isolated intestinal transplant. A gastrostomy tube Isolated intestinal transplant. A gastrostomy tube, jejunostomy tube, and loop ileostomy are in place.
  • The closure of the abdominal wall can be another challenging part of the procedure, especially considering that these pediatric patients are often small
  • Do not risk the perfusion of the graft by attempting a closure under tension; if this is the case, keeping the abdominal wall open and planning for a sequential closing is preferable
  • In special situations, transplantation of the abdominal wall from the same deceased donor can relieve tension during closure [40, 41]
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Postoperative Details

Patients require intensive care unit (ICU) monitoring postoperatively.

Induction therapy is often initiated intraoperatively. The most common induction class used is T-cell depleting agents, which 61.0% of patients receive; 12.2% of patients receive interleukin 2 (IL-2) receptor antagonists, and 20% receive no induction. [17]

As of 2011, the most frequently used immunosuppressive regimen after induction was tacrolimus and steroids (35.8%) followed by tacrolimus, mycophenolate, and steroids (18.7%). Tacrolimus and mycophenolate without steroids was administered in 15.4% of cases, and tacrolimus alone was administered in 13.8% of cases. [17]

Tacrolimus, administered enterically, and intravenous steroids are typically begun immediately after the surgery and are maintained at discharge. High levels of immunosuppression are maintained early in the postoperative period (tacrolimus levels of 20-25 ng/mL).

Lauro et al found that induction therapy on day 0 and 7 with 15 mg of alemtuzumab resulted in significantly lower rates of early rejection, with no increase in sepsis. [42]

Consider the variable absorption and bioavailability of whichever immunosuppression regimen is used (ie, tacrolimus, cyclosporine microemulsion). Because the bioavailability of these drugs depends on intestinal surface area and transit time, the function of the grafts directly affects drug availability.

Prostaglandin E1 (PGE1) is occasionally intravenously administered for the first 5-10 days posttransplant because of its ability to improve the small bowel microcirculation and its potential immunosuppressive effects. A study of intestinal ischemia/reperfusion injury in rats found that intravenous PGE1 prior to intestinal ischemia resulted in lower myeloperoxidase levels, less polymorphonuclear cell invasion, and an improvement in histologic score. [43] The literature specifically examining the role of PGE1 in aiding circulation in transplant patients is sparse.

Other postoperative monitoring includes the following:

  • Administer broad-spectrum intravenous antibiotics for about 1 week after the transplant
  • Check laboratory findings regularly for evidence of bleeding
  • Monitor serum pH and lactate levels to detect any evidence of intestinal ischemia

When GI function is re-established, as indicated by decreasing gastrostomy tube returns and increasing gas and enteric contents in the ileostomy, a diet can be initiated and cautiously advanced as tolerated to provide full nutritional support. To avoid the development of chylous ascites, a consequence of the graft's severed lymphatics during the procurement, a no-fat or low-fat diet can be initially used.

Initiate appropriate antiviral prophylaxis with ganciclovir and/or cytomegalovirus (CMV) immunoglobulin (CytoGam). At regular intervals, perform the following studies:

  • CMV antigenemia assay
  • Quantitative Epstein-Barr virus (EBV) polymerase chain reaction (PCR) surveillance [44]
  • Routine cultures
  • Transplant ileostomal endoscopy and biopsy

Additionally, monitor fluid status, stool losses, and serum electrolytes.

The transplanted intestine initiates peristalsis immediately after reperfusion but in a less orderly fashion, because of the disruption of the extrinsic innervation during procurement. The dysfunctional residual native intestine, stomach, or colon in a patient with a primary dysmotility syndrome could aggravate this problem.

The carbohydrates and amino acid absorptive capacity of the transplanted intestine normalize within the first several months. Fat absorption is impaired for several months following intestinal transplantation. Absorption of dietary lipids, which are primarily composed of long-chain triglycerides, depends on lymphatic drainage. Medium-chain triglycerides can be directly absorbed into the portal circulation. For these reasons, supplementing enteral feeds with medium-chain triglycerides for several months following transplantation is necessary. Intermittently supplementing the diet with intravenous fats and fat-soluble vitamins (vitamin D, E, A, and K) may be necessary until the intestinal lymphatics are reestablished.

Once enteral nutrition is providing all nutritional requirements, total parenteral nutrition (TPN) can be discontinued.

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Follow-up

Patients should have regular follow-up for as long as they are able to maintain their grafts. At each followup visit, labs should be drawn to check for changes in the blood count, lactate levels, and kidney function. Any signs of infection, malignancy, or rejection should be worked up aggressively (see corresponding sections below).

As of 2011, the most common immunosuppressive regimens at 1 year post-transplant are tacrolimus alone (30.4%), followed by tacrolimus and steroids (28.6%) and then tacrolimus, mycophenolate, and steroids (13.4%). [17]

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Complications

Patients undergoing intestinal transplant have a higher incidence of infectious complications than other transplant recipients. This is due to the high bacterial load of the transplanted graft, and the large mucosal leukocyte population that arrives with the graft, necessitating greater immunosuppression. [45]

Infectious complications are a leading cause of death in intestinal transplantation patients, account for 48% of all deaths within 5 years of transplant. [46] An autopsy series found that even in cases in which sepsis was not the immediate cause of death, 94% of patients had a coexisting infection. Posttransplant lymphoproliferative disease (PTLD) and graft rejection can lead to breakdown of the mucosal barrier, resulting in bacteremia or fungemia. [47]

Bacterial infections

The bacteria from the intestinal graft can infect the transplanted patient via two routes. The lymphatics that were divided in the procurement are a source of leakage of intestinal lymph into the peritoneal cavity. This lymph contains bacteria and can lead to bacterial peritonitis in the immunosuppressed patient. The second route is by direct translocation into the portal circulation and subsequent dissemination to other sites.

The most common infectious organisms include Escherichia coli, Klebsiella, Enterobacter, staphylococci, and Enterococcus. A recent single-center study found the most common pathogens isolated were Pseudomonas (19%), Enterococcus (15%), and E coli (13%). [23]

Primeggia et al reported a 30-day postoperative infection rate of 57.5% and mean time to first infection of 10.78 ± 8.99 days [24] . The most common sites of infection were the abdomen, followed by lungs, wounds, and urinary tract infections.

Viral infections

Cytomegalovirus (CMV) infection reportedly occurs in 15-30% of patients receiving intestinal grafts and most often involves an allograft intestine. CMV disease is one of the most serious infections that can occur after a transplant because it can lead to loss of the transplanted organ and even death. The incidence of CMV disease is highest in CMV-negative recipients who receive CMV-positive grafts. As a result, transplantation of isolated intestines from CMV-positive donors to CMV-negative recipients is often avoided.

Patients with CMV enteritis usually present with fever, increased stomal output, GI symptoms, decreased WBC count, and flulike symptoms. Infection is diagnosed by measuring CMV antigenemia and by endoscopic examination findings/biopsy. Endoscopy reveals superficial ulcers, and histopathology confirms CMV inclusion bodies.

If CMV is diagnosed, the patient should be treated with therapeutic doses of ganciclovir. Foscarnet or CMV immunoglobulin (CytoGam) should be considered in case of ganciclovir resistance. Immunosuppression should be reduced until the CMV infection is controlled but should not be discontinued, to avoid breakthrough rejection.

Epstein-Barr virus (EBV) is also a concern. The risk is higher in EBV-negative recipients who receive an EBV-positive graft. An acute EBV virus infection is typically associated with severe malaise and fever, flulike symptoms, increase of liver enzyme levels, splenomegaly, and lymphadenopathy. Relapse rates have been measured as high as 20%. [48]

Post-transplant lymphoproliferative disorder

The biggest concern is the development of post-transplant lymphoproliferative disorder (PTLD). The incidence of PTLD is higher in intestinal transplant recipients than any other solid organ transplant recipients. It occurs 2-4 times more often in children than in adults [49] , and the incidence is higher after multivisceral transplantation than after isolated intestinal transplantation. Although PTLD tends first to manifest between 2 weeks and 6 months after a transplant, it can appear at any time.

Surveillance for PTLD should begin immediately following the transplant using in situ hybridization staining for EBV and early RNA and EBV polymerase chain reaction (PCR) surveillance.

Two basic approaches are used to prevent PTLD. One is long-term prophylaxis with ganciclovir, valgancyclovir, or intravenous immunoglobulin for 3-12 months. The other involves a shorter period of prophylaxis (2–6 wk) followed by monthly surveillance and preemptive therapy should surveillance identify increased EBV replication.

A recent study examining PTLD in pediatric intestinal transplants found the highest incidence at four months post-transplant. [50] Ramos et al found no correlation between immunosuppressant regimen used and PTLD rates, but did find an increased association between EBV negative recipients receiving an EBV positive graft. [50] In their cohort, fever was the most common symptom. [50]

The diagnosis of PTLD usually requires a biopsy. Often, this is most easily obtained from an enlarged superficial lymph node or from clinically or radiologically involved tissue. If the suspected organ is the intestine graft itself, differentiating PTLD from rejection or CMV infection can be difficult. Evaluating the serum for a typical monoclonal or polyclonal immunoglobulin band, which can sometimes be present, is also useful.

Gene studies are often helpful to identify abnormal karyotypes (eg, C-myc, N-ras, p53), which can aid in diagnosis and prognosis. Determine whether the abnormal lymphocytes sites are primarily B cells or T cells. Real-time PCR can also be used to detect changes in viral DNA levels. T-cell lymphomas are less common than B-cell lymphomas in PTLDs.

If the diagnosis of PTLD is made, immunosuppression should be reduced to approximately half of what it had been. [51] In approximately one third of cases, this results in a remission of the PTLD. If improvement is not evident after 2 weeks, all immunosuppression should be discontinued and serious consideration should be given to additional therapeutic measures, including chemotherapy using R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or adoptive immunotherapy. [51] Radiotherapy is considered a second-line intervention against PTLD in both pediatric and adult patients. [49]

If necessary, an intestine-only graft can also be removed. However, in many cases PTLD is detected after it has spread to multiple sites, and not all cases arise within the graft itself.

Rejection

Rejection can occur at any time but is most common in the first year, particularly the first 6 months. Early diagnosis of allograft rejection, a major contributor to both the high morbidity and the high mortality associated with small-intestine transplantation, is essential. Intestinal graft rejection manifests clinically as fever, abdominal pain, increased output from the ostomy, abdominal distention, and acidosis. Malabsorption and electrolyte abnormalities occur in some patients. It can also be asymptomatic.

To detect rejection, surveillance via endoscopy (especially zoom videoendoscopy) and intestinal biopsy through the ileostomy are used. A rise in the plasma citrulline level may also be indicative of rejection (see other tests above). Diagnosis can be difficult because of the patchy nature of rejection and the presence of bleeding. Therefore, the endoscopy should include as much of the small bowel as possible, and biopsies from numerous sites should be obtained.

O'Keefe et al found sensitivity and specificity for rejection actually fell when patients were symptomatic. [52] Sensitivity was only 50% in asymptomatic patients undergoing surveillance, and it further fell to 43% in symptomatic patients. [52] Specificity was 90% in asymptomatic patients, and 67% in symptomatic patients. The authors concluded that endoscopy should effectively rule out rejection in asymptomatic patients, but ruling-in, or any studies in symptomatic patients requires biopsy for further workup.

Histologic evidence of allograft rejection includes mucosal necrosis and loss of villous architecture with transmural cellular infiltrate. Histopathology reveals crypt cell apoptosis, cryptitis or crypt loss, necrosis, and endotheliitis.

One potential marker of rejection is serum albumin levels. Although non-specific, serum albumin may be useful to monitor the progress of recovery from exfoliative rejection. [53]

David et al reported that serum citrulline levels <13 micromoles/L indicate the presence of serious rejection or infection in a previously stable intestinal recipient. Levels of 13 micromoles/L or higher practically rule out moderate or severe rejection. [54]

Rejection may be treated by an intravenous bolus of methylprednisolone (10 mg/kg), followed by steroid recycle and optimization of the tacrolimus level. Antithymocyte globulin may be used to treat steroid-resistant rejection.

In the event of detection of donor-specific anti-HLA antibodies, Gerlach et al report success using first plasmapharesis and IVIG, followed by rituximab and bortezomib if the rejection was initially refractory. [55] Donor-specific antibody values decreased upon antirejection therapy in eight of the 10 patients. [55]

Some centers have reported that combined liver-intestine transplantation provides a greater protective benefit (ie, lower incidence and severity of acute rejection) than isolated intestinal transplantation.

Graft versus host disease

The small intestine is an immunocompetent organ; its population of lymphoid cells can mount an immunologic response to the host (ie, a graft versus host disease [GVHD]) reaction. GVHD occurs in 7-9% of intestinal transplants. [56] It is more common in intestinal transplants due to the large volume of lymphatic tissue accompanying the graft. GVHD may be subclinically manifested and diagnosed only histologically. Patients with acute GVHD usually present 1-8 weeks after transplantation with fever, leukopenia, diarrhea, and rash. Other symptoms may include malaise, anorexia, arthralgia, and abdominal pain.

Diagnosis should be confirmed by biopsy of the skin or bowel. A study by Crowell et al supported the practice of performing a sigmoidoscopy only to rule in or out graft versus host disease. [57] In their study, any signs of GVHD present above the sigmoid were present at the level of the sigmoid as well. [57]

Once diagnosis is confirmed, promptly institute treatment with high-dose steroids and antithrombocyte globulin or with OKT3. Although most cases should be responsive, an alternative technique may be to use intra-arterial catheter – guided steroid administration. [58] This technique has been successful in studies of GVHD after bone marrow transplantation.

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Outcome and Prognosis

In 2012, the graft failure rate for 90 days was 15.7%. Information from the prior year indicated a 1 year graft failure rate of 26.4%. The number of patients who are alive with an intestinal graft has increased since the year 1998, to 1004 in 2012. The most recent death rate from 2010 per 1000 person-years was 193.5. [17]

Table 1: One-year and 5-year Graft survival in the year 2007, stratified by type of graft received

Table. (Open Table in a new window)

Graft Type Number of Years Survival % Surviving
Intestine only 1 year 74.6
5 years 48.0
Intestine and liver 1 year 68.6
5 years 53.7

 

Table 2: One-year and 5-year graft survival in the year 2007, stratified by patient age younger or older than 18 years

Table. (Open Table in a new window)

Age Number of Years Survival % Surviving
< 18 years 1 year 69.2
5 years 53.8
>18 years 1 year 74.2
5 years 48.3

 

Acute rejections (< 90 days) occurred in 68% of children and 40% of adults in 2012.

Long-term rejection rates from 2006-2010 were that 39% of patients had a first rejection episode in the 12 months following transplantation; 44% of patients had a first rejection episode in the 24 months afterward.

Rehospitalization rates were as follows:

  • 86.1% of patients rehospitalized by 6 months after transplantation
  • >90% of patients rehospitalized after 1 year

Although children may report improved quality of life after intestinal transplantation, such improvement is not guaranteed. Nor does intestinal transplantation necessarily lead to a quality of life comparable to other transplant recipients (eg, liver) or the general population. [30, 31, 59]

Other morbidity is as follows:

  • Cytomegalovirus (CMV) infection [60] : 16%-24%; relapse rate 86%
  • Graft versus host disease: 9%
  • Post-transplant lymphoproliferative disease (PTLD): 11%
  • De novo malignancy: non-skin cancer, 4%; nonmelanotic skin cancer, 5%

Mortality causes within 5 years of receiving the graft are as follows [46] :

  • Graft versus host disease: 8%
  • Graft dysfunction: 16%
  • Atherosclerosis: 55%
  • Substance abuse/suicide/lack of support: 3%
  • Graft thrombosis: 10%
  • PTLD: 19%
  • Rejection: 80%
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Future and Controversies

The number of intestinal transplants performed grew consistently for many years and is expected to increase again. From 1997-2006, the number of isolated intestinal transplants increased 171%. During the same period, the number of multiorgan transplants increased 187%; organ combinations that included the intestine were the second most common after liver-kidney transplants. At the same time, survival rates are improving.

Still, major issues remain, such as the extremely high mortality in patients on the waiting list and the organ shortage. Another issue is the difficult balance between appropriate immunosuppression in order to avoid rejection and overimmunosuppression with its devastating complications. This issue makes the development of additional markers to detect early rejection imperative. [61] . Equally important is development of more accurate staging systems to estimate mortality of patients on the waiting list for an intestinal transplant.

Multivisceral organ transplantation may have a role in the treatment of slow-growing abdominal cancers that are deemed “non-resectable”. Only recently have any reports arisen describing success rates for this indication. [62]

Another advancement that may soon reach clinical practice is the placement of mesenchymal stem cells close to the bowel anastomosis in order to limit the degree of fibrosis and stricture development. [63]

Another challenge for the future will be to better understand the physiology of the transplanted small bowel, such as its altered microflora and altered motility. New research has suggested that the flora composition within the graft may be a risk factor for acute rejection when more immunogenic species predominate. [64]

Animal studies and recent human data have suggested the use of glucagon-like peptide 2 in inducing intestinal adaptation after transplant. This adaptation includes increasing the length of villi, the depth of crypts, the overall diameter of the graft, and hyperplasia of individual enterocytes [65] . Another potential future method of inducing regain of function in short bowel syndrome is epidermal growth factor. [66]

Lastly, new research is shedding light on dysfunctional motility, which is frequently seen in grafts after transplant. A study by Raphael et al suggests that additional inflammation after transplantation may be responsible for a divergence of outcomes. [67] The drug cisapride may be useful in attenuating this inflammatory response and speeding growth of a new enteric nervous system. [67]

Many efforts have been placed on techniques to induce a state of microchimerism and tolerance by transplanting bone marrow along with the intestinal allograft. This would allow for sufficient immunosuppression with lower doses of immunosuppressants. This ongoing research may change the future of transplantation of the small bowel and other organs.

Further reading

Interested readers are directed to the following literature:

  • For further reading on operative techniques for multivisceral procurement and transplantatation, see Nickkholgh et al, 2013 [38]
  • For a discussion of the role of tissue expanders and abdominal wall transplantation in successful abdominal closure, see Watson et al, 2013, and Berli et al, 2013 [40, 41]
  • For a general discussion of gastrointestinal infections after solid organ transplantation, see Danziger-Isakov, 2014 [68]
  • For a more in-depth discussion of intestinal physiology after transplantation, see Walther et al, 2013 [69]
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