Secondary Logo

Journal Logo


Pediatric small bowel transplantation

Boluda, Esther Ramos

Author Information
Current Opinion in Organ Transplantation: October 2015 - Volume 20 - Issue 5 - p 550-556
doi: 10.1097/MOT.0000000000000231
  • Free



Intestine has been considered a nontransplantable organ due to the large amount of lymphoid tissue included in the graft. The first attempt of intestinal transplantation in animals was performed in 1901 by Carrel [1]. In the 1960s, some unsuccessful attempts were made, but it was not until the late 1980s when the first successful isolated cases of intestinal transplantation in humans were published [2,3]. When tacrolimus became available, intestinal transplantation extended, so that in the 1990s, it became a practical means of treating intestinal failure in those patients who developed serious side effects of parenteral nutrition or those who were not able to maintain a good quality of life [4–6]. Since then, more than 2880 transplants have been made according to data from the last registry [7▪▪].

Box 1
Box 1:
no caption available


The most common indication for intestinal transplantation is permanent intestinal failure related to short bowel syndrome, with 63% of pretransplant diagnoses in children, followed by motility disorders. The most common causes of loss of anatomic small bowel are gastroschisis, necrotizing enterocolitis and volvulus. Motility disorders are mainly exemplified by chronic intestinal pseudo-obstruction and extensive Hirschsprung's disease. Other malabsorption syndromes related to severe diarrhea and refractory intestinal failure are caused by congenital mucosal abnormalities such as microvillus inclusion disease and intestinal epithelial dysplasia (congenital tufting enteropathy). Figure 1 shows other conditions and their frequencies.

Indications for transplantation in children (a) and adults (b)[7▪▪].

Parenteral nutrition remains the main therapeutic resource in the management of intestinal failure. Recent advances in parenteral nutrition-dependent patient care have improved survival and quality of life, with higher rates of enteral autonomy achieved, and lower rate and later onset of complications. Therefore, the number of transplants performed per year has declined in the past years. However, 20–25% of these patients develop complications that force the child's reference to an intestinal rehabilitation unit for evaluation [8,9]. These complications are well defined and they can establish ‘indication for intestinal transplant’ [10,11]:

  • Liver disease: Intestinal failure-associated liver disease (IFALD) is the most frequent cause of considering intestinal transplant in children. The development of severe liver dysfunction confers poor results and the need of including the liver in the graft.
  • Recurring sepsis: Two or more episodes of sepsis/year (usually catheter-associated sepsis) or complicated sepsis (fungemia, septic shock, metastatic infectious foci like endocarditis, etc.).
  • Loss of central venous access: Thrombosis of two of the four standard venous channels (subclavian and jugular veins).
  • High morbidity and poor quality of life: High enteric fluid loses with severe dehydration, development of extraintestinal complications (renal impairment), severe obstruction episodes in intestinal pseudo-obstruction and so on can be a reason to receive an intestinal transplant.
  • Other indications due to underlying disease: Desmoid tumors, congenital mucosal diseases (microvillus inclusion disease, intestinal epithelial dysplasia), ultrashort bowel syndrome (<10 cm in infants without ileocecal valve or 20 cm in adults).

Contraindications are similar to other solid organ transplants.


The nomenclature used to classify types of graft in intestinal transplant has been controversial [12,13]. Traditionally, the definitions were as follows:

  1. Small intestine transplant (isolated small bowel): Intestine without liver or stomach. It can include the colon.
  2. Liver and small intestine (combined liver and small bowel): Intestine with liver, but without stomach.
  3. Modified multivisceral transplant: Stomach and intestine, without liver.
  4. Multivisceral transplant: Intestine with liver and stomach.

Pancreas is usually included in the composite grafts for technical reasons. Figure 2 shows types of grafts following traditional nomenclature.

Type of intestinal grafts[12]. (1) Inclusion of the pancreaticoduodenal complex (unshaded organs) is optional and commonly utilized for technical reasons; (2) optional or when medically indicated.

In 2007, however, at the International Small Bowel Transplant Symposium, experts from major transplant programs around the world met and tried to create an accurate nomenclature, because the term ‘multivisceral’ transplantation meant different things in different programs, so it was suggested that this terminology should be avoided and a descriptive nomenclature should be used. This description would describe whether the graft includes the liver or not and whether evisceration of the recipient foregut was performed. The term isolated small bowel transplantation can be used.

The North American centers account for the 76% of the world activity. Figure 3 shows the proportion of the different intestinal transplants performed in the past year (Intestinal Transplant Registry Report). We can see that isolated small bowel transplant is increasing in frequency, with a 45.3% of intestinal transplants. However, this frequency declines when the recipients are children, falling to 36.2% [7▪▪]. The advantage of combined liver and small bowel and multivisceral graft is that no hilar dissection is needed, so biliary or vascular complications are less frequent. According to the 2013 Registry data, 1611 out of 2887 intestinal transplants performed between January 1985 and February 2013 were in pediatric recipients (<18 years). Nevertheless, in some series, the adult proportion is higher [14▪▪]. There is a trend to include a colon segment in the graft. Early series suggested that when colon was included, there was an increased risk of infection. Lately, it has been reported that inclusion of colon seems to be safe and decreases water loss in the stool, with less hydroelectrolytic disturbance, so at this moment, colon is included in more than 25% of transplants.

Proportion of different types of intestinal transplants[7▪▪]. MMVT, modified multivisceral transplant; MVT, multivisceral transplant; SB + Liv, small bowel and liver.


Intestine is the most immunogenic of the transplanted solid organs; therefore optimal immunosuppression is crucial for success. Advances in immunosuppression have resulted in better graft and patient survival rates. As previously mentioned, the appearance of tacrolimus marks a turning point, since the results of transplantation using cyclosporine were unacceptable. After some years of experience, it was found that overimmunosuppression is responsible for two of the most feared complications of transplantation: post-transplant lymphoproliferative disease (PTLD) and graft-versus-host disease (GVHD). Finding the balance between minimizing the risk of rejection and preventing the occurrence of these complications is an ongoing challenge.

In general, all immunosuppression regimens are based on induction therapy and maintenance of immunosuppressive treatment. Induction therapy involves the use of monoclonal or polyclonal antibodies in the peritransplant period. Most patients are induced with either an interleukin (IL)-2 blocker (basiliximab or daclizumab) or a depleting agent (alemtuzumab or thymoglobulin). Alemtuzumab is only used in patients older than 4 years.

Maintenance therapy is almost exclusively based on tacrolimus and frequently steroids. However, Sirolimus (rapamycin), an mTOR inhibitor, although emerging, is an alternative option, showing its efficacy and safety in an increasing number of cases. There are several outstanding issues as if all types of transplantation should receive the same immunosuppression (some studies indicate that when the graft includes the liver, it exerts a protective effect against the rejection to the intestine) [15,16] or if children should receive a different immunosuppressive therapy from adults.


After the transplant, recipients require life-long immunosuppression. Some complications are related to this fact.

Surgical complications

Advancement in surgical techniques has made these complications decreased considerably. However, surgical complications remain common. Some groups reported reoperation rates around 60% related to thrombosis, bleeding, anastomotic dehiscence or abscesses [17–19].

The first technical difficulties arise from the previous pathology. It is common to find a native duodenum damaged by previous surgeries, and it can be challenging in case of isolated intestinal transplantation, because there is a high risk of duodenal perforation. Another problem is abdominal wall closure. Recipients are often patients with multiple laparotomies, implying scars and loss of tissue, and many of them are virtually anenterics, so intestine has lost the domain space. Therefore, there is a risk of abdominal compartment syndrome, and this often requires staged abdominal closure with higher rates of infection. Some groups have included donor abdominal wall in the graft with good results [20]. Reduced graft sometimes becomes necessary when there is recipient-to-donor weight mismatch.


It is the most common cause of graft loss. Neither clinical symptoms (increasing in stoma output, fever, bloody diarrhea, etc.) nor biochemical markers are reliable. A majority of the episodes occurs during the first 90 days after transplant. Data of the OPTN/SRTR annual report show that the incidence in pediatric intestinal transplant recipients is nearly 40% at 1 year and 45% at 2 years for isolated small bowel transplant, and 35 and 38%, respectively, for combined graft (Fig. 4). The transplanted organ has a big amount of lymphoid tissue, and it is generally accepted that antigen-presenting cells (APCs) from donor play a major role in the development of immune response. On one hand, a cellular rejection can be caused by cytotoxic T lymphocytes, with the development of an acute cellular rejection (ACR). Moreover, activation of B cells by T cells can lead to the production of specific antibodies against human leukocyte antigen (HLA) donor antigens (DSAs) appearing humoral rejection. Diagnosis must be made with both endoscopy and examination of biopsy specimens. ACR is characterized by a variable combination of apoptosis of deep crypt cells, a mixed infiltrate and epithelial cryptic damage. Although apoptosis is considered the key finding in the rejection, it is not specific and it can be seen in other situations such as preservation damage, ischemia or infection. Some attempts have been made to develop noninvasive biomarkers of ACR like serum citrulline or fecal calprotectin, but these tests have low specificity and they cannot discriminate between infectious enteritis and ACR. Recently, new tests like Cylex Immune Cell Function Assay – a noninvasive measure of cell-mediated immunity – has been proposed to be useful not only for tailoring immunosuppression but also for diagnosis of early ACR (first year post-transplant). However, it seems to have a poor sensibility and a wide interpatient variability, so more studies are needed [21]. Mild ACR is associated with favorable clinical outcomes, but severe acute rejection has a poor prognosis and removal of graft is often needed. Antibody-mediated rejection (AMR) has also gained increased attention. Data are still scarce, but some authors have reported small series of humoral rejection cases [22,23]. Diagnosis is based on clinical signs, DSA detection and histological findings consisting of mucosal congestion, neutrophilic infiltrate and fibrin and platelet microthrombi with vascular graft injury. Staining for C4d of donor endothelial cells has been proposed for diagnosis, but it has been shown to be rather unspecific [22,24,25]. Preformed DSAs can cause a hyperacute rejection in the immediate post-transplant period, so pretransplant HLA ab monitoring has a great significance in order to initiate an early treatment. De-novo DSA can also be developed, so periodic monitoring is needed. Treatment is similar to that used in other solid transplanted organs and is based on steroids, plasmapheresis, intravenous immunoglobulin, rituximab and/or bortezomib. Inclusion of liver in the graft seems to have a protective effect, so multivisceral transplant recipients have a reduced risk of AMR development [23]. Refractory AMR may progress to chronic rejection – one of the principal causes of late graft loss. Characteristic histological findings are a concentric intimal thickening of small and large arteries, hypertrophy of smooth muscle cells and fibrosis in the adventitium. Because these findings are developed in large vessels, it can rarely be seen in mucosal biopsies. Sclerosing peritonitis is often the final stage of this entity with severe graft dysfunction. Prognosis is poor because it is often unresponsive to treatment.

Incidence of first acute rejection among intestine transplant recipients[14▪▪].

Post-transplant lymphoproliferative disorder

Post-transplant lymphoproliferative disorder is a frequent and serious complication after intestinal transplantation. This high incidence is likely to be related to the amount of lymphoid tissue of the transplanted organ and the intensity of immunosuppression used. This complication is related to Epstein–Barr virus (EBV) infection, so the incidence is higher in pretransplant EBV-negative patients [26]. This condition is more frequent among pediatric patients. Type of graft and immunosuppressive protocol are proposed risk factors. The incidence varies depending on the type of graft, and it is higher after pediatric intestinal transplantation (2003 Report of the Intestinal Transplant Registry): 19% multivisceral, 11% isolated small bowel and 10% liver–intestine [27]. Among immunosuppressive drugs, anti-T-cell antibodies (thymoglobulin), equine anti-thymocyte globulin and OKT3 (muromonab-CD3) have been considered as a risk factor. Neither induction with alemtuzumab nor IL-2 receptor antagonists has been found to be associated with PTLD [28]. Regarding calcineurin inhibitors, early reports suggested a higher incidence of PTLD with tacrolimus compared with cyclosporine [29,30], but with the increasing experience in using tacrolimus and the lower targeted levels, these results have not been proven in later studies [31]. It seems that the risk of PTLD is low with the use of mTOR inhibitors, sirolimus and everolimus, but studies are contradictory [32,33].

Graft-versus-host disease

It is not surprising that the frequency of this complication is higher in intestinal transplantation than in other solid organs, given the large lymphoid population of this graft. The estimated incidence is approximately 5% of intestinal transplants, being slightly more common in children than in adults [34]. It also appears to be more frequent in the case in isolated intestinal transplants than in multivisceral grafts [35]. Skin, bone marrow, liver and native gastrointestinal tract are the most frequently affected organs. Some series show receptor's splenectomy as a risk factor for developing this complication as the spleen acts as a filter to the donor lymphocytes [34–36].

Other complications

Infection is the most common cause of death after intestinal transplant. Bacterial bloodstream due to intestinal bacterial translocation and viral infection (basically cytomegalovirus) are the most frequent agents. Hematological disorders and autoimmune cytopenia is a rare but severe complication after solid organ transplantation [37]. The immunosuppressive therapies used, associated with other concomitant factors such as viral infections, lymphoproliferative disorders, GVHD or passenger lymphocyte syndrome, play an important role in the development of autoimmune processes after intestinal transplantation. Inflammatory bowel disease like renal failure and multiple food allergies are other problems associated with intestinal transplant.


Patients with end-stage liver disease will die if transplant is not performed. Mortality in waiting list is high due to the scarcity of pediatric donors. Median time in waiting list is 710 months [14▪▪], so it is crucial for patient survival to be listed as soon as complications of parenteral nutrition appear.

Patient and graft survival has improved considerably in the past decade. The use of monoclonal antibodies in the induction, the inclusion of a liver graft, the use of rapamycin in maintenance and the absence of DSAs has been associated with an improved survival rates. Surveillance of opportunistic infections has also contributed to improved results. Survival rates for patients transplanted since 2000 are 77, 58 and 48% at 1, 5 and 10 years, respectively, and graft survival rates 71, 50 and 41% [7▪▪] (Fig. 5). Patient survival is higher in isolated intestinal transplant, but graft rates are better in combined grafts.

Graft and patient survival by transplant type (Intestinal Transplant Registry Report 2013).

Most patients are weaned from parenteral nutrition, but almost half of the children require tube feedings due to oral aversion. Among the pediatric recipients, 23% present growth failure, but most of them show a normal linear growth velocity [38]; retransplantation rate is 8%.


Intestinal transplant has become a reasonable therapeutic option in those patients with intestinal failure who develop complications related to parenteral nutrition. The use of induction therapy has improved patient and graft survival. Current survival rates of intestinal transplantation are similar to other solid organ transplants. However, there are some challenging issues like causes and therapeutic options in chronic rejection or early noninvasive detection of acute rejection that require future investigations.


No funding has been received for this work from any organization.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest


1. Carrel A. La technique operatoire des anastomoses vasculaires et la transplantation des visceres. Lyon MEO 1902; 98:859–864.
2. Deltz E, Schroeder P, Gebhardt H, et al. First successful clinical small intestine transplantation. Tactics and surgical technic. Chirurg 1989; 60:235–239.
3. Williams JW, Sankary HN, Foster PF, et al. Splanchnic transplantation. An approach to the infant dependent on parenteral nutrition who develops irreversible liver disease. J Am Med Assoc 1989; 261:1458–1462.
4. Goulet O, Revillon Y, Brousse N, et al. Successful small bowel transplantation in an infant. Transplantation 1992; 53:940–943.
5. Todo S, Tzakis AG, Abu-Elmagd K, et al. Cadaveric small bowel and small bowel-liver transplantation in humans. Transplantation 1992; 53:369–376.
6. Abu-Elmagd K, Reyes J, Bond G, et al. Clinical intestinal transplantation: a decade of experience at a single center. Ann Surg 2001; 234:404–416.[discussion 416–417].
7▪▪. Grant D, Abu-Elmagd K, Mazariegos G, et al. Intestinal transplant registry report: global activity and trends. Am J Transplant 2015; 15:210–219.

Report of the activity of most of the international intestinal transplant programs around the world with trends, survival data and outstanding issues.

8. Squires RH, Duggan C, Teitelbaum DH, et al. Natural history of pediatric intestinal failure: initial report from the Pediatric Intestinal Failure Consortium. J Pediatr 2012; 161:723–728.e2.
9. Pironi L, Joly F, Forbes A, et al. Long-term follow-up of patients on home parenteral nutrition in Europe: implications for intestinal transplantation. Gut 2011; 60:17–25.
10. Kaufman SS, Atkinson JB, Bianchi A, et al. Indications for pediatric intestinal transplantation: a position paper of the American Society of Transplantation. Pediatr Transplant 2001; 5:80–87.
11. American Gastroenterological Association. American Gastroenterological Association medical position statement: short bowel syndrome and intestinal transplantation. Gastroenterology 2003; 124:1105–1110.
12. Abu-Elmagd KM. The small bowel contained allografts: existing and proposed nomenclature. Am J Transplant 2011; 11:184–185.
13. Mazariegos GV, Steffick DE, Horslen S, et al. Intestine transplantation in the United States, 1999–2008. Am J Transplant 2010; 10 (4 Pt 2):1020–1034.
14▪▪. Smith JM, Skeans MA, Horslen SP, et al. OPTN/SRTR 2013 Annual Data Report: intestine. Am J Transplant 2015; 15 (Suppl 2):1–16.

Annual data of activity of American Programs of intestinal transplant.

15. Pirenne J, Kawai M. The protective effect of the liver: does it apply to the bowel too? Transplantation 2006; 81:978–979.
16. Goulet O, Damotte D, Sarnacki S. Liver-induced immune tolerance in recipients of combined liver-intestine transplants. Transplant Proc 2005; 37:1689–1690.
17. Kato T, Tzakis AG, Selvaggi G, et al. Intestinal and multivisceral transplantation in children. Ann Surg 2006; 243:756–764.[discussion 764-6].
18. Goulet O, Sauvat F, Ruemmele F, et al. Results of the Paris program: ten years of pediatric intestinal transplantation. Transplant Proc 2005; 37:1667–1670.
19. Gupte GL, Haghighi KS, Sharif K, et al. Surgical complications after intestinal transplantation in infants and children--UK experience. J Pediatr Surg 2010; 45:1473–1478.
20. Levi DM, Tzakis AG, Kato T, et al. Transplantation of the abdominal wall. Lancet 2003; 361:2173–2176.
21. Wozniak LJ, Venick RS, Gordon Burroughs S, et al. Utility of an immune cell function assay to differentiate rejection from infectious enteritis in pediatric intestinal transplant recipients. Clin Transplant 2014; 28:229–235.
22. Dick AA, Horslen S. Antibody-mediated rejection after intestinal transplantation. Curr Opin Organ Transplant 2012; 17:250–257.
23. Abu-Elmagd KM, Wu G, Costa G, et al. Preformed and de novo donor specific antibodies in visceral transplantation: long-term outcome with special reference to the liver. Am J Transplant 2012; 12:3047–3060.
24. Troxell ML, Higgins JP, Kambham N. Evaluation of C4d staining in liver and small intestine allografts. Arch Pathol Lab Med 2006; 130:1489–1496.
25. de Serre NP, Canioni D, Lacaille F, et al. Evaluation of C4d deposition and circulating antibody in small bowel transplantation. Am J Transplant 2008; 8:1290–1296.
26. Ramos E, Hernandez F, Andres A, et al. Posttransplant lymphoproliferative disorders and other malignancies after pediatric intestinal transplantation: Incidence, clinical features and outcome. Pediatr Transplant 2013; 17:472–478.
27. Grant D, Abu-Elmagd K, Reyes J, et al. 2003 Report of the Intestine Transplant Registry: a new era has dawned. Ann Surg 2005; 241:607–613.
28. Kirk AD, Cherikh WS, Ring M, et al. Dissociation of depletional induction and posttransplant lymphoproliferative disease in kidney recipients treated with alemtuzumab. Am J Transplant 2007; 7:2619–2625.
29. Nalesnik MA, Jaffe R, Starzl TE, et al. The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression. Am J Pathol 1988; 133:173–192.
30. Cockfield SM. Identifying the patient at risk for posttransplant lymphoproliferative disorder. Transpl Infect Dis 2001; 3:70–78.
31. Dharnidharka VR, Ho PL, Stablein DM, et al. Mycophenolate, tacrolimus and posttransplant lymphoproliferative disorder: a report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant 2002; 6:396–399.
32. Kauffman HM, Cherikh WS, Cheng Y, et al. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation 2005; 80:883–889.
33. Nassif S, Kaufman S, Vahdat S, et al. Clinicopathologic features of posttransplant lymphoproliferative disorders arising after pediatric small bowel transplant. Pediatr Transplant 2013; 17:765–773.
34. Wu G, Selvaggi G, Nishida S, et al. Graft-versus-host disease after intestinal and multivisceral transplantation. Transplantation 2011; 91:219–224.
35. Mazariegos GV, Abu-Elmagd K, Jaffe R, et al. Graft versus host disease in intestinal transplantation. Am J Transplant 2004; 4:1459–1465.
36. Michallet M, Corront B, Bosson JL, et al. Role of splenectomy in incidence and severity of acute graft-versus-host disease: a multicenter study of 157 patients. Bone Marrow Transplant 1991; 8:13–17.
37. Botija G, Ybarra M, Ramos E, et al. Autoimmune cytopaenia after paediatric intestinal transplantation: a case series. Transpl Int 2010; 23:1033–1037.
38. Lacaille F, Vass N, Sauvat F, et al. Long-term outcome, growth and digestive function in children 2 to 18 years after intestinal transplantation. Gut 2008; 57:455–461.

intestinal failure; intestinal transplantation; multivisceral transplantation

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.