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Intestinal Transplantation: An Unexpected Journey
Journal of Pediatric Surgery 49 (2014) 13–18
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Robert E. Gross Lecture
Intestinal Transplantation: An Unexpected Journey Jorge D. Reyes ⁎ Transplant Services, Seattle Children's Hospital, Seattle, WA 98105, USA
a r t i c l e
i n f o
Article history: Received 30 August 2013 Accepted 30 September 2013 Key words: Intestinal failure Intestine transplant Short gut syndrome Immunosuppression
a b s t r a c t The development of pediatric intestine transplantation has required continuous refinements in the management of intestinal failure, surgical technique, and perioperative care. The development of better immunosuppressive management (cyclosporine in 1978 and tacrolimus in 1989) and enhancements in our understanding of the relationship between recipient and host immune systems have resulted in better longterm survival. Paralleling this, advancements in the organ procurement techniques and organ preservation solutions have made possible the procurement and transplantation of various types of intestine containing grafts tailored to the needs of the various indications for which intestine transplantation is being performed. With improved outcomes, the indications for intestine transplantation have been better defined in the context of risk benefit for the most important complications of TPN, which include liver disease, life threatening infection, and loss of central venous access. The first survivors of transplantation would also go on to demonstrate the interaction (host-versus-graft and graft-versus-host) between recipient and donor immunocytes (brought with the allograft), which under the cover of immunosuppression allows varying degrees of graft acceptance. The struggle to achieve better transplantation survival outcomes came about with the development of improved strategies to better manage intestinal failure. This has been accomplished largely through the establishment of centers that incorporate a multidisciplinary team approach to medical and surgical care. Intestine transplantation represents a lifesaving therapy for many patients with intestinal failure who have significant complications of their disease. It is hoped that with the minimization of immunosuppression strategies currently used, the long-term survival of these intestine organ transplant recipients will continue improving, together with their rehabilitation and quality-of-life. © 2014 Published by Elsevier Inc.
1. Historical background The evolution of clinical transplantation has spanned over 60 years and resulted in successful engraftment of kidney, pancreas, liver, heart, lung, and more recently the intestine [1]. Each organ
⁎ Corresponding author. Seattle Children's Hospital Transplantation MB 9.420 Transplant Services 4800 Sand Point Way NE Seattle, WA 98105, United States. Tel.: 206 987 1800. E-mail address: [email protected]. 0022-3468/$ – see front matter © 2014 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jpedsurg.2013.09.022
specific trial has been able to breach the immunologic barrier using treatment strategies that seemed to be applicable to all organs. The feasibility of such management, however, is better understood in the context of shared immunologic principles. The development of these principles would begin after a series of experiments conducted between 1944 and 1960 by Medawar (Nobel Laureate, 1960) demonstrating that rejection of tissue grafts was an "immunologic event" [2]. Strategies to alter this immunologic response were described by Bellingham et al. in 1953 as "acquired tolerance" [3]; their experimental model used immunocompetent adult spleen cell injections in utero or perinatally into mice not yet able to reject them, with the consequent development of leukocyte chimerism and failure to recognize donor tissue as alien. Main and Prehn had demonstrated a similar tolerance outcome with irradiated cytoablated mice and reconstitution with donor bone marrow [4]. This strategy was later extended to clinical bone marrow transplantation inducing stable chimerism in humans by the infusion of donor bone marrow, but in the setting of a good Human Leukocyte Antigen (HLA) match [5–7]. With successful engraftment chronic immunosuppression was frequently not needed, though there would be the risk of graft-versus-host disease (GVHD). Whole organ transplantation was being accomplished through trial and error, without dependence on HLA matching, risk of GVHD, or leukocyte chimerism, but maintenance immunosuppression of the
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recipient was necessary lifelong. Total body irradiation and the use of myelotoxic drugs (6-mercaptopurine, azathioprine) had poor clinical results at first [7–9]. The development of "drug cocktails" in 1962 combined azathioprine with prednisone [10] with a success rate that allowed for further developments, which included antilymphocyte globulin, cyclosporine, and then FK506 (tacrolimus) [11,12]. These strategies controlled, to some extent, a unidirectional reaction of recipient immune cells resulting in "rejection" (the one way paradigm), which when present could be reversed with steroid therapy [13]; notable as well was the observation the maintenance immunosuppression could later be decreased over time. Intestinal transplantation did not fit the one-way paradigm described for other organs and experimentally tested in dogs by Lillehei in 1959 and Starzl in 1960 [14,15]. Though these studies served as technical centerpieces for all intra-abdominal organ transplant procedures, the predicted cellular events of rejection and GVHD were poorly understood. As a result the early experience of intestine transplantation with and without cyclosporine was largely unsuccessful [16]; until 1990, only the isolated intestine recipient of Goulet and a living related donor intestine of Deltz had survived [17,18]. The introduction of tacrolimus in 1990 significantly improved survival, though the post-operative course remained complex and the long-term outcomes were unsatisfactory [19]. Notable in these cases was that the liver seemed protective of the intestine against rejection, as had been suggested by previous combinations of liver plus other organs such as the kidney. More importantly, the first survivors of intestine transplantation would demonstrate the interaction (host-versus-graft and graft-versus-host) between recipient and donor immunocytes (brought with the allograft), the two way paradigm [20]. 2. Intestinal failure and the need for intravenous therapy or transplantation Intestinal failure (IF) describes the inability to maintain nutritional autonomy (protein/calorie, fluid, electrolyte, micronutrients) due to loss or dysfunction of the patients native intestine, with the consequent need for permanent total parenteral nutrition (TPN). The majority of these patients have short gut as a result of congenital deficiency or acquired condition. In others, the cause of IF is a functional disorder of motility or absorption, and rarely tumor or autoimmune diseases (Table 1). Transplantation for this type of organ failure came on the heels of the successful introduction of maintenance therapy with TPN by Dudrick in the late 1960's [21]. The success of TPN management, however, hinges around the patients’ ability to adapt in the absence of TPN induced complications. The complications of IF can be better appreciated as syndromic and include loss of venous access, life-threatening infections, and TPNinduced cholestatic liver disease. Patients who develop these complications have a ~ 70% 1 year mortality and thus require organ replacement therapy with intestinal transplantation.
Table 1 Causes of intestinal failure in children requiring transplantation. Short Bowel Congenital disorders Necrotizing enterocolitus Intestinal Dysmotility Intestinal pseudo-obstruction Enterocyte Dysfunction Microvillus inclusion disease Crohn’s disease Tumors Familial polyposis
Volvulus Intestinal atresia
Gastroschisis Trauma
Intestinal aganglionsis
(Hirschsprung disease)
Tufting enteropathy
Autoimmune disorders
Inflammatory pseudotumor
There are only 6 readily accessible venous sites (bilateral internal jugulars, subclavians, and iliac veins) for centrally placed venous catheters. Loss of venous access occurs in the setting of recurrent catheter sepsis and thrombosis; an arbitrary assumption has been that the loss of half of these sites warrants consideration for intestinal transplantation. Life-threatening catheter sepsis can result in metastatic infectious foci in lungs, kidneys, liver, and brain, the presence of unusual pathogens, and multisystem organ failure. Cholestatic liver disease is by far the most serious complication of TPN, and may be a consequence of the toxic drug effects of TPN on hepatocytes, a disruption of bile flow and bile acid metabolism, bacterial translocation with sepsis, and endotoxin release into the portal circulation [22]. This complication varies in frequency depending on age and the etiology of the IF and is most common in neonates with extreme short gut. The effects on the liver include fatty transformation, steatohepatitis and necrosis, fibrosis, and then cholestasis. The development of jaundice and thrombocytopenia are significant risk factors for poor outcome, given the association of these changes with the presence of portal hypertensive gastroenteropathy, hypersplenism, coagulopathy, and uncontrollable bleeding [23]. 3. The Transplant Operation Intestinal grafts are usually procured from hemodynamically stable, ABO-identical brain-dead donors; as with other types of abdominal grafts, the HLA has been random and crossmatch results are usually not factored into the utilization criteria. Exclusion criteria includes a history of malignancy and intra-abdominal evidence of infection, or evidence of bowel ischemia at the time of procurement; evidence of bacterial infections is not exclusionary. Donor preparation has been limited to the administration of systemic and enteral antibiotics, and graft pretreatment using irradiation or a monoclonal antilymphocyte antibody for the prevention of GVHD has been limited to isolated centers or clinical trials; grafts have been preserved with the University of Wisconsin solution [24]. 4. Types of Intestinal Grafts The complex multivisceral grafts reported by Starzl in the first survivors of intestinal transplantation included the liver/stomach/ duodenum/pancreas/and small bowel [25]; this transitioned to a graft which included the liver and small bowel, and was reported by Grant et al. with some success under cyclosporine immunosuppression [26]. It became evident from these reports that intestine containing grafts could be modified to fit the requirements of the various clinical circumstances presented by patients who have IF, with or without the need for replacement of the liver. Thus, an intestine graft can be transplanted alone (as an isolated intestine graft), or with the liver/ duodenum/pancreas (essentially a liver–intestine graft); the inclusion of duodenum/pancreas is an expeditious way of preserving the hepatic hilus and biliary tree, thus obviating the need for biliary reconstructive procedures and facilitating both the donor and recipient operations [27]. When the recipient operation requires exenteration and replacement of all of the patient’s gastrointestinal tract (as with intestinal pseudo-obstruction or extensive Hirschprung's disease) and liver, then this replacement operation is known as a multivisceral transplant; in some occasions of preserved native liver function, the replacement graft will not include the liver. The procurement and transplant of these various types of grafts rely on the preservation of the arterial vessels of celiac and/or superior mesenteric arteries, and venous outflow of superior mesenteric vein or hepatic veins. The larger liver containing grafts retain the celiac and superior mesenteric arteries; the isolated intestine graft retains the superior mesenteric artery and vein. These grafts are dissected out in situ and then removed after cardiac arrest of the donor, with core
J.D. Reyes / Journal of Pediatric Surgery 49 (2014) 13–18
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Fig. 1. The various abdominal organs are isolated in situ, providing isolated or liver containing grafts. Separation of intestine and pancreas is feasible, with preservation of the inferior pancreaticoduodenal artery (IPDA) and vein (IPDV). The use of vascular homografts from the donor allows connections to the superior mesenteric pedicle (SMA and SMV), to aorta, inferior vena cava (IVC) or portal vein (inset). (Reproduced with permission from Abu-Elmagd K, Fung J, Bueno J, et al: Logistics and technique for procurement of intestinal, pancreatic and hepatic grafts from the same donor. Ann Surg 232:680–697, 2000).
cooling and infusion of preservation solution into the graft via the infrarenal aorta (Fig. 1). Other modifications to these grafts have also included: • The inclusion of colon in order to enhance independence from parenteral fluid support in the recipient, and also as an adjunct to reconstructive procedures of the ano-rectum; though the early experience with this segment was fraught with infectious complications the more recent clinical cases suggest otherwise. • The reduction of the liver graft (into left or right side) and variable reductions of the intestine graft have facilitated abdominal closures where a larger donor than the recipient was used, given also that the recipient may have lost his or her "abdominal domain" as a consequence to short gut [28]. • The loss of abdominal domain has also prompted important innovations in the area of transplantation of abdominal wall (a composite tissue graft) or other non-vascularized components of abdominal fascia [29,30]. • The development of living donor intestine grafts has been limited, and included the isolated intestine graft as well as the combination with left lateral liver segment (from the same donor) [31]. 5. The Recipient Operation Intestinal transplantation can be a formidable technical challenge, particularly in the setting of advanced liver failure and multiple prior operations. With isolated intestinal transplantation exposure of the infrarenal aorta and vena cava allows for placement of vascular homografts using donor iliac artery and vein. The use of the native superior mesenteric vessels is also feasible (Fig. 1).
The transplantation of a liver/intestine grafts requires the removal and replacement of the native liver and, in the case of multivisceral transplantation, complete abdominal exenteration. The infrarenal aorta is exposed for placement of an arterial conduit graft of donor thoracic aorta; the venous drainage occurs through the graft hepatic drains to recipient vena cava. Intestinal anastomosis to native proximal and distal bowel is performed leaving an enterostomy of distal allograft ileum for graft surveillance. 6. The evolution of Immunosuppression Since the early 1990's successful immunosuppression of intestinal grafts has been based on tacrolimus and corticosteroids. The therapeutic range of tacrolimus was generally nephrotoxic, rejection rates were high (in the order of N 80%), and infections with Cytomegalovirus (CMV), Epstein Barr Virus (EBV, and Post Transplant Lymphoproliferative disease [PTLD]), and other agents would result in a gradual loss of patients and grafts [19]. Subsequent protocols added drugs such as azathioprine, cyclophosphamide, mycophenolate mofetil, rapamycin, and induction with an interleukin-2 (IL-2) antibody antagonist with improvements in the incidence of rejection, yet these patients continued to require high levels of immunosuppression long term; a persistence of significant infection and toxicity continued to result in patient and graft loss. The ability to diagnose and preemptively treat CMV and EBV similarly provided an added benefit to many patients, but without significant improvements in long term survival (Fig. 2). The intestine graft was more susceptible to rejection than other abdominal organs, and similar to other tissues exposed to environmental antigens such as skin and lung. The immunogenicity of the intestine graft could be associated with the innate immunity of the enterocyte (an antigen presenting cell) and intestinal passenger
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Pediatric Population July 1990 - December 2001
Cumulative Survival (%)
100
N=87
80 60
7. The legacy of Intestinal Rehabilitation
40 20
Primary Graft Patient Survival
0 0
1
2
3
4
5
6
7
8
9 10 11 12
Time After Transplantation (year)
Fig. 2. Early Pittsburgh Pediatric Intestine Transplant patient and graft survival showing continued attrition in survival due to high immunosuppressive burden, rejection, infectious complications, and other toxicities.
leukocytes (intraepithelial lymphocytes, mesenteric lymph nodes, Peyer's patches) known to be less tolerogenic than from other abdominal organs [32]. These represent a variety of cellular, humoral, and effector mechanisms which include γ/δ T cells, phagocytic cells, NK cells, natural antibodies, compliment system, and antimicrobial peptides. Immune recognition is provided through pathogen-associated molecular patterns (PAMP), the signal transduction of which is mediated by Toll-like receptors. Intestinal transplantation is associated with inflammatory signals as a consequence to ischemia reperfusion injury, bacterial signals, and Lipopolysaccharide (LPS) translocation, recognition by the enterocyte, and subsequent activation of the effector T cell [33]. The assumption that control of such an immunologic repertoire using the strategies previously reported would result in improved survival had not been observed. The paradox could be explained by the understanding of tolerance induction and activation-induced cell death, with the development of regulatory T cells as a consequence to signaling by Th 1 cytokines. Indeed, the heavy burden of nonspecific immunosuppression with steroids and calcineurin inhibitors has been shown to break tolerance and trigger rejection in various experimental models and the clinic [34,35]. The introduction in 2000 of recipient pretreatment using antilymphocyte antibodies and the elimination of recipient therapy with steroids envisaged ameliorat-
Pediatric Patient Survival (%) N=157
ing the ischemia reperfusion phenomenon and facilitating activation induced apoptosis (clonal deletion) [36]; this has resulted in improved transplant survival, with a significant decrease in incidence of rejection and infection, permitting the gradual decrease of immunosuppressive drug therapy within 3 months of transplant and a decline in drug toxicity events (Fig. 3).
FK/Pred N=48 Cytoxan/Zenapax N=38 Thymoglobulin N=71
100 90 80 70 60 50
The initial successes of intestinal transplantation in the early 1990's resulted in an overwhelming flow of children with intestinal failure to centers performing these procedures, and though the early survival provided the encouragement for future milestones, the failure rate of patients waiting for transplant and the clinical presentation of patients who lost their grafts followed their pretransplant cohorts. Indeed, the survival of children with IF who presented with liver disease was no greater than 30% at one year. This prompted an important development in the management of these patients both before and after transplantation, which focused the care of the patient in the center of a multidisciplinary team of gastroenterology, surgery, nutrition, specialized nursing, interventional radiology, psychiatry, and intensive care, and with the following principles of care: • • • • • • • •
Maintain nutrition and growth Optimize bowel function Prevent complications manage complications Feeding therapy Health surveillance, immunizations, development monitoring Coordination of care regarding co-morbidities Family support
This approach would eventually result in comprehensive diagnostic evaluations, nutritional support and then rehabilitation; the incorporation of restorative surgical interventions and consideration for transplantation would be done in carefully selected patients. Surprisingly, it became evident that many patients referred for transplantation were becoming independent of TPN support, and the patients transplanted were in much better clinical condition at the time of surgery. Examples of clinical and surgical milestones which contributed to the success of these efforts included the application of ethanol lock therapy, novel lipid management strategies with consequent improvement in TPN induced liver disease, and corrective surgical procedures such as STEP [37–39]. In order to better understand and share these insights in care the Pediatric Intestinal Failure Consortium was developed, with findings delineating the standards of care which have resulted in a significant decrease in the incidence of liver disease, infection, and need for transplantation (and a decrease in death on the transplant wait list) [40]. In our efforts to improve transplant outcomes, the development of intestinal rehabilitation has demonstrated that most patients can be rehabilitated without the need for transplantation. Thus Parenteral Nutrition provided by an expert center remains the preferred treatment for chronic intestinal failure. 8. Outcomes
40 30 20 10 0 0
6
12 18 24 30 36 42 48 54 60
Time After Transplantation (Mos)
Fig. 3. Comparative survival of 3 immunosuppressive protocols used for intestine transplantation, demonstrating the impact of Antithymocyte Globulin induction [33].
Intestinal transplantation is lifesaving in children with IF who have significant complications of total parenteral nutrition. Data from the International Intestinal Transplant Registry thru 2010, the OPTN/SRTR Annual Report 2012, and center-specific data reports have documented significant improvements with short- and long-term survivals for transplantations occurring principally in the last 10 years [41,42]. Over 2600 Intestinal transplants have been performed in almost 80 centers worldwide, though most cases have been done in 35 centers. Given the success of intestinal rehabilitation, however, the number of
J.D. Reyes / Journal of Pediatric Surgery 49 (2014) 13–18
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Fig. 4. OPTN/SRTR 2011 Annual Report demonstrating the decreasing numbers of patients listed and transplanted. http://srtr.transplant.hrsa.gov/annual_reports/2011/default.aspx.
patients needing transplantation has declined since 2005, with the majority of patients coming from home at the time of their transplant (illness severity has decreased), and over half of patients requiring only the isolated intestine transplant (through prevention/resolution
of TPN induced liver disease) (Fig. 4). With the immunosuppression minimization strategies currently in use there has been a significant improvement in long-term survival as well, similar to what has been observed with other organ transplants (Fig. 5). The best survival is
Fig. 5. OPTN/SRTR 2011 Annual Report demonstrating a significant decrease in graft failure, with an increased use of T-cell depleting agents. http://srtr.transplant.hrsa.gov/ annual_reports/2011/default.aspx.
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achieved when the patient is at home waiting, and a liver component is added to the intestine graft. Though the long term data are not robust, there is evidence that recipients are independent of TPN, there are good growth and development in children, and the quality of life after transplantation appears equal to or better than the quality of life on TPN [43]. The most frequent associated morbidities have been dysmotility of the graft, hypertension, osteoporosis, diabetes mellitus, and renal failure [44]. The success of intestinal transplantation has fostered the development of multidisciplinary intestinal centers which have focused on intestinal rehabilitation and improving the devastating effects of TPN on the liver. Intestine transplantation has thus become a less frequent necessity, and follows the guidelines stipulated in this report, and by others. References [1] Starzl TE et al. Transplantation of multiple abdominal viscera. JAMA 261: 1449, 1989. [2] Medawar PB. The behavior and fate of skin autografts and skin homografts in rabbits. J Anat 1944;78:176. [3] Billingham R, Brent L, Medawar P. Quantitative studies on tissue transplantation immunity. III. Actively acquired tolerance. Philos Trans R Soc Lond (Biol) 1956;239:357. [4] Main JM, Prehn RT. Successful skin homografts after the administration of high dosage X radiation and homologous bone marrow. J Natl Cancer Inst 1955;15:1023. [5] Bach FH. Bone-marrow transplantation in a patient with the Wiskott–Alderich syndrome. Lancet 1968;2:1364. [6] Gatti RA, et al. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet 1968;2:1366. [7] Mathe G, et al. Haematopoietic chimera in man after allogenic (homologous) bone marrow transplantation. Br Med J 1963(1633). [8] Kuss R, et al. Homologous human kidney transplantation, experience with six patients. Postgrad Med K 1962;38:528. [9] Merrill JP, et al. Successful homotransplantation of the kidney between nonidentical twins. N Engl J Med 1960;262:1251. [10] Schwartz R, Dameshek W. The effects of 6-mercaptopurine on homograft reactions. J Clin Invest 1960;39:952. [11] Calne RY, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet I 1978;2:1033. [12] Starzl TE, et al. FK 506 for human liver, kidney, and pancreas transplantation. Lancet 1989;2:1000. [13] Starzl TE, Marchioro TL, Waddell WR. The reversal of rejection in human renal homografts with subsequent development of homograft tolerance. Surg Gynecol Obstet 1963;117:385. [14] Lillehei R, Goott B, Miller F. The physiological response of the small bowel of the dog to ischemia including prolonged in vitro preservation of the bowel with successful replacement and survival. Ann Surg 1959;150:543–61. [15] Starzl TE, Kaupp H. Mass homotransplantation of abdominal organs in dogs. Surg Forum 1960;11:28–30. [16] 15.Grant D, Wall W, Mineault R, et al. Successful small bowel/liver transplantation. Lancet 335:181-184, 1990. [17] Goulet O, Revillon Y, Brousse N, et al. Successful small bowel transplantation in an infant. Transplantation 1992;53:9940–3. [18] Deltz E, Schroeder P, Gerbhard H, et al. Successful clinical small bowel transplantation: report of a case. Clin transpl 1989;21:89–91. [19] Todo S, Reyes J, Furukawa H, et al. Outcome and analysis of 71 clinical intestinal transplantation. Ann Surg 1995;222(3):270–82.
[20] Starzl TE, et al. Cell migration, chimerism and graft acceptance. Lancet 1992;339: 1579. [21] Dudrick S. Early developments and clinical applications of total parenteral nutrition. J Parenter Enteral Nutr 2003;29:272. [22] Balisteri WF, Bove KE. Hepatobilary consequences of parental alimentation. Progressive Liver Disease 1990;9:567–601. [23] Bueno J, Ohwada S, Kochosis S, et al. Factors impacting on the survival of children with intestinal failure referred for intestinal transplantation. J Pediatr Surg 1999;34:27–33. [24] Abu-Elmagd K, Fung J, Bueno J, et al. Logistics and technique for procurement on intestinal, pancreatic, and hepatic grafts from the same donor. Ann Surg 2000;323: 680–97. [25] Starzl TE, Rowe MI, Todo S, et al. Transplantation of multiple abdominal viscera. JAMA 1989;261:1449–57. [26] Grant D, Wall W, Mimeault R, et al. Successful small-bowel/liver transplantation. Lancet 1990;335:181–4. [27] Sudan DL, Iyer KR, Deroover A, et al. A new technique for combined liver–small intestinal transplantation. Transplantation 2001;72:1846–8. [28] Reyes J, Fishbein T, Bueno J, et al. Reduced-sized orthotopic liver–intestinal allograft. Transplantation 1998;66(4):489–92. [29] Levi DM, Tzakis AG, Kato T, Madariaga J, Mittal NK, Nery J, Nishida S, Ruiz P. Transplantation of the abdominal wall. Lancet 28;361(9376):2173-6, 2003. [30] Gondolesi G, Selvaggi G, Tzakis A, et al. Use of the abdominal rectus fascia as a nonvascularized allograft for abdominal wall closure after liver, intestinal, and multivisceral transplantation. Transplantation 2009;87(12):1884–8. [31] Testa G, Holterman M, John E, et al. Combined living donor liver/small bowel transplantation. Transplantation 2005;27:1401–4. [32] Harlan DM, Karp CL, Matzinger P, et al. Immunological concerns with bioengineering approaches. Ann N Y Acad Sci 2002 Jun;961:323–30. [33] Pirenne J, Kawai M. Tolerogenic protocols for intestinal transplantation. Transpl Immunol 2004;13(2):131–7. [34] Koshiba T, Kitade H, Waer M, et al. Break of tolerance via donor-specific blood transfusion by high doses of steroids: a differential effect after intestinal transplantation and heart transplantation. Transplant Proc 2003;35(8):3153–5. [35] Lan F, Hayamizu K, Strober S. Cyclosporine facilitates chimeric and inhibits nonchimeric tolerance after post-transplant total lymphoid irradiation. Transplantation 2000;69(4):649–55. [36] Reyes J, Mazariegos GV, Abu-Elmagd K, et al. Intestinal transplantation under tacrolimus monotherapy after perioperative lymphoid depletion with rabbit anti-thymocyte globulin (Thymoglobulin®). Am J Transplant 2005;5(6): 1430–6. [37] Wales PW, Kosar C, Carricato M, et al. Ethanol lock therapy to reduce the incidence of catheter-related bloodstream infections in home parenteral nutrition patients with intestinal failure: preliminary experience. J Pediatr Surg 2011; 45(5):951–6. [38] Diamond IR, Sterescu A, Pencharz PB, et al. Changing the paradigm: omegaven for the treatment of liver failure in pediatric short bowel syndrome. Journal of Pediatic Gastroenterol Nutrition 2009;48(2):209–15. [39] Wales PW, de Silva N, Langer JC, et al. Intermediate outcomes after serial transverse enteroplasty in children with short bowel syndrome. J Pediatr Surg 2007;42(11):1804–10. [40] Squires RH, Duggen C, Teitelbaum DH et al. Natural history of pediatric intestinal failure: initial report from the Pediatric Intestinal Failure Consortium. The Journal of Pediatrics 161(4):723-8.e2, 2012. [41] .Organ Procurement and Transplantation Network: data (website) HYPERLINK http://optn.transplant.hrsa.gov/data/. [42] OPTN/SRTR 2011 annual report. US Dept. of Health and Human Services HRSA, 2011: Data (website) HYPERLINK http://srtr.transplant.hrsa.gov/annual_reports/ 2011/pdf/04_intestine_12.pdf. [43] Sudan D. Long-term outcomes and quality of life after intestine transplantation. Curr Opin Organ Transplant 2010;15(3):357–60. [44] Abu-Elmagd KM, Kosmach-Park B, Costa G, et al. Long-term survival, nutritional autonomy, and quality of life after intestinal and multivisceral transplantation. Ann Surg 2012;256(3):594–608.
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Robert E. Gross Lecture
Intestinal Transplantation: An Unexpected Journey Jorge D. Reyes ⁎ Transplant Services, Seattle Children's Hospital, Seattle, WA 98105, USA
a r t i c l e
i n f o
Article history: Received 30 August 2013 Accepted 30 September 2013 Key words: Intestinal failure Intestine transplant Short gut syndrome Immunosuppression
a b s t r a c t The development of pediatric intestine transplantation has required continuous refinements in the management of intestinal failure, surgical technique, and perioperative care. The development of better immunosuppressive management (cyclosporine in 1978 and tacrolimus in 1989) and enhancements in our understanding of the relationship between recipient and host immune systems have resulted in better longterm survival. Paralleling this, advancements in the organ procurement techniques and organ preservation solutions have made possible the procurement and transplantation of various types of intestine containing grafts tailored to the needs of the various indications for which intestine transplantation is being performed. With improved outcomes, the indications for intestine transplantation have been better defined in the context of risk benefit for the most important complications of TPN, which include liver disease, life threatening infection, and loss of central venous access. The first survivors of transplantation would also go on to demonstrate the interaction (host-versus-graft and graft-versus-host) between recipient and donor immunocytes (brought with the allograft), which under the cover of immunosuppression allows varying degrees of graft acceptance. The struggle to achieve better transplantation survival outcomes came about with the development of improved strategies to better manage intestinal failure. This has been accomplished largely through the establishment of centers that incorporate a multidisciplinary team approach to medical and surgical care. Intestine transplantation represents a lifesaving therapy for many patients with intestinal failure who have significant complications of their disease. It is hoped that with the minimization of immunosuppression strategies currently used, the long-term survival of these intestine organ transplant recipients will continue improving, together with their rehabilitation and quality-of-life. © 2014 Published by Elsevier Inc.
1. Historical background The evolution of clinical transplantation has spanned over 60 years and resulted in successful engraftment of kidney, pancreas, liver, heart, lung, and more recently the intestine [1]. Each organ
⁎ Corresponding author. Seattle Children's Hospital Transplantation MB 9.420 Transplant Services 4800 Sand Point Way NE Seattle, WA 98105, United States. Tel.: 206 987 1800. E-mail address: [email protected]. 0022-3468/$ – see front matter © 2014 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jpedsurg.2013.09.022
specific trial has been able to breach the immunologic barrier using treatment strategies that seemed to be applicable to all organs. The feasibility of such management, however, is better understood in the context of shared immunologic principles. The development of these principles would begin after a series of experiments conducted between 1944 and 1960 by Medawar (Nobel Laureate, 1960) demonstrating that rejection of tissue grafts was an "immunologic event" [2]. Strategies to alter this immunologic response were described by Bellingham et al. in 1953 as "acquired tolerance" [3]; their experimental model used immunocompetent adult spleen cell injections in utero or perinatally into mice not yet able to reject them, with the consequent development of leukocyte chimerism and failure to recognize donor tissue as alien. Main and Prehn had demonstrated a similar tolerance outcome with irradiated cytoablated mice and reconstitution with donor bone marrow [4]. This strategy was later extended to clinical bone marrow transplantation inducing stable chimerism in humans by the infusion of donor bone marrow, but in the setting of a good Human Leukocyte Antigen (HLA) match [5–7]. With successful engraftment chronic immunosuppression was frequently not needed, though there would be the risk of graft-versus-host disease (GVHD). Whole organ transplantation was being accomplished through trial and error, without dependence on HLA matching, risk of GVHD, or leukocyte chimerism, but maintenance immunosuppression of the
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recipient was necessary lifelong. Total body irradiation and the use of myelotoxic drugs (6-mercaptopurine, azathioprine) had poor clinical results at first [7–9]. The development of "drug cocktails" in 1962 combined azathioprine with prednisone [10] with a success rate that allowed for further developments, which included antilymphocyte globulin, cyclosporine, and then FK506 (tacrolimus) [11,12]. These strategies controlled, to some extent, a unidirectional reaction of recipient immune cells resulting in "rejection" (the one way paradigm), which when present could be reversed with steroid therapy [13]; notable as well was the observation the maintenance immunosuppression could later be decreased over time. Intestinal transplantation did not fit the one-way paradigm described for other organs and experimentally tested in dogs by Lillehei in 1959 and Starzl in 1960 [14,15]. Though these studies served as technical centerpieces for all intra-abdominal organ transplant procedures, the predicted cellular events of rejection and GVHD were poorly understood. As a result the early experience of intestine transplantation with and without cyclosporine was largely unsuccessful [16]; until 1990, only the isolated intestine recipient of Goulet and a living related donor intestine of Deltz had survived [17,18]. The introduction of tacrolimus in 1990 significantly improved survival, though the post-operative course remained complex and the long-term outcomes were unsatisfactory [19]. Notable in these cases was that the liver seemed protective of the intestine against rejection, as had been suggested by previous combinations of liver plus other organs such as the kidney. More importantly, the first survivors of intestine transplantation would demonstrate the interaction (host-versus-graft and graft-versus-host) between recipient and donor immunocytes (brought with the allograft), the two way paradigm [20]. 2. Intestinal failure and the need for intravenous therapy or transplantation Intestinal failure (IF) describes the inability to maintain nutritional autonomy (protein/calorie, fluid, electrolyte, micronutrients) due to loss or dysfunction of the patients native intestine, with the consequent need for permanent total parenteral nutrition (TPN). The majority of these patients have short gut as a result of congenital deficiency or acquired condition. In others, the cause of IF is a functional disorder of motility or absorption, and rarely tumor or autoimmune diseases (Table 1). Transplantation for this type of organ failure came on the heels of the successful introduction of maintenance therapy with TPN by Dudrick in the late 1960's [21]. The success of TPN management, however, hinges around the patients’ ability to adapt in the absence of TPN induced complications. The complications of IF can be better appreciated as syndromic and include loss of venous access, life-threatening infections, and TPNinduced cholestatic liver disease. Patients who develop these complications have a ~ 70% 1 year mortality and thus require organ replacement therapy with intestinal transplantation.
Table 1 Causes of intestinal failure in children requiring transplantation. Short Bowel Congenital disorders Necrotizing enterocolitus Intestinal Dysmotility Intestinal pseudo-obstruction Enterocyte Dysfunction Microvillus inclusion disease Crohn’s disease Tumors Familial polyposis
Volvulus Intestinal atresia
Gastroschisis Trauma
Intestinal aganglionsis
(Hirschsprung disease)
Tufting enteropathy
Autoimmune disorders
Inflammatory pseudotumor
There are only 6 readily accessible venous sites (bilateral internal jugulars, subclavians, and iliac veins) for centrally placed venous catheters. Loss of venous access occurs in the setting of recurrent catheter sepsis and thrombosis; an arbitrary assumption has been that the loss of half of these sites warrants consideration for intestinal transplantation. Life-threatening catheter sepsis can result in metastatic infectious foci in lungs, kidneys, liver, and brain, the presence of unusual pathogens, and multisystem organ failure. Cholestatic liver disease is by far the most serious complication of TPN, and may be a consequence of the toxic drug effects of TPN on hepatocytes, a disruption of bile flow and bile acid metabolism, bacterial translocation with sepsis, and endotoxin release into the portal circulation [22]. This complication varies in frequency depending on age and the etiology of the IF and is most common in neonates with extreme short gut. The effects on the liver include fatty transformation, steatohepatitis and necrosis, fibrosis, and then cholestasis. The development of jaundice and thrombocytopenia are significant risk factors for poor outcome, given the association of these changes with the presence of portal hypertensive gastroenteropathy, hypersplenism, coagulopathy, and uncontrollable bleeding [23]. 3. The Transplant Operation Intestinal grafts are usually procured from hemodynamically stable, ABO-identical brain-dead donors; as with other types of abdominal grafts, the HLA has been random and crossmatch results are usually not factored into the utilization criteria. Exclusion criteria includes a history of malignancy and intra-abdominal evidence of infection, or evidence of bowel ischemia at the time of procurement; evidence of bacterial infections is not exclusionary. Donor preparation has been limited to the administration of systemic and enteral antibiotics, and graft pretreatment using irradiation or a monoclonal antilymphocyte antibody for the prevention of GVHD has been limited to isolated centers or clinical trials; grafts have been preserved with the University of Wisconsin solution [24]. 4. Types of Intestinal Grafts The complex multivisceral grafts reported by Starzl in the first survivors of intestinal transplantation included the liver/stomach/ duodenum/pancreas/and small bowel [25]; this transitioned to a graft which included the liver and small bowel, and was reported by Grant et al. with some success under cyclosporine immunosuppression [26]. It became evident from these reports that intestine containing grafts could be modified to fit the requirements of the various clinical circumstances presented by patients who have IF, with or without the need for replacement of the liver. Thus, an intestine graft can be transplanted alone (as an isolated intestine graft), or with the liver/ duodenum/pancreas (essentially a liver–intestine graft); the inclusion of duodenum/pancreas is an expeditious way of preserving the hepatic hilus and biliary tree, thus obviating the need for biliary reconstructive procedures and facilitating both the donor and recipient operations [27]. When the recipient operation requires exenteration and replacement of all of the patient’s gastrointestinal tract (as with intestinal pseudo-obstruction or extensive Hirschprung's disease) and liver, then this replacement operation is known as a multivisceral transplant; in some occasions of preserved native liver function, the replacement graft will not include the liver. The procurement and transplant of these various types of grafts rely on the preservation of the arterial vessels of celiac and/or superior mesenteric arteries, and venous outflow of superior mesenteric vein or hepatic veins. The larger liver containing grafts retain the celiac and superior mesenteric arteries; the isolated intestine graft retains the superior mesenteric artery and vein. These grafts are dissected out in situ and then removed after cardiac arrest of the donor, with core
J.D. Reyes / Journal of Pediatric Surgery 49 (2014) 13–18
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Fig. 1. The various abdominal organs are isolated in situ, providing isolated or liver containing grafts. Separation of intestine and pancreas is feasible, with preservation of the inferior pancreaticoduodenal artery (IPDA) and vein (IPDV). The use of vascular homografts from the donor allows connections to the superior mesenteric pedicle (SMA and SMV), to aorta, inferior vena cava (IVC) or portal vein (inset). (Reproduced with permission from Abu-Elmagd K, Fung J, Bueno J, et al: Logistics and technique for procurement of intestinal, pancreatic and hepatic grafts from the same donor. Ann Surg 232:680–697, 2000).
cooling and infusion of preservation solution into the graft via the infrarenal aorta (Fig. 1). Other modifications to these grafts have also included: • The inclusion of colon in order to enhance independence from parenteral fluid support in the recipient, and also as an adjunct to reconstructive procedures of the ano-rectum; though the early experience with this segment was fraught with infectious complications the more recent clinical cases suggest otherwise. • The reduction of the liver graft (into left or right side) and variable reductions of the intestine graft have facilitated abdominal closures where a larger donor than the recipient was used, given also that the recipient may have lost his or her "abdominal domain" as a consequence to short gut [28]. • The loss of abdominal domain has also prompted important innovations in the area of transplantation of abdominal wall (a composite tissue graft) or other non-vascularized components of abdominal fascia [29,30]. • The development of living donor intestine grafts has been limited, and included the isolated intestine graft as well as the combination with left lateral liver segment (from the same donor) [31]. 5. The Recipient Operation Intestinal transplantation can be a formidable technical challenge, particularly in the setting of advanced liver failure and multiple prior operations. With isolated intestinal transplantation exposure of the infrarenal aorta and vena cava allows for placement of vascular homografts using donor iliac artery and vein. The use of the native superior mesenteric vessels is also feasible (Fig. 1).
The transplantation of a liver/intestine grafts requires the removal and replacement of the native liver and, in the case of multivisceral transplantation, complete abdominal exenteration. The infrarenal aorta is exposed for placement of an arterial conduit graft of donor thoracic aorta; the venous drainage occurs through the graft hepatic drains to recipient vena cava. Intestinal anastomosis to native proximal and distal bowel is performed leaving an enterostomy of distal allograft ileum for graft surveillance. 6. The evolution of Immunosuppression Since the early 1990's successful immunosuppression of intestinal grafts has been based on tacrolimus and corticosteroids. The therapeutic range of tacrolimus was generally nephrotoxic, rejection rates were high (in the order of N 80%), and infections with Cytomegalovirus (CMV), Epstein Barr Virus (EBV, and Post Transplant Lymphoproliferative disease [PTLD]), and other agents would result in a gradual loss of patients and grafts [19]. Subsequent protocols added drugs such as azathioprine, cyclophosphamide, mycophenolate mofetil, rapamycin, and induction with an interleukin-2 (IL-2) antibody antagonist with improvements in the incidence of rejection, yet these patients continued to require high levels of immunosuppression long term; a persistence of significant infection and toxicity continued to result in patient and graft loss. The ability to diagnose and preemptively treat CMV and EBV similarly provided an added benefit to many patients, but without significant improvements in long term survival (Fig. 2). The intestine graft was more susceptible to rejection than other abdominal organs, and similar to other tissues exposed to environmental antigens such as skin and lung. The immunogenicity of the intestine graft could be associated with the innate immunity of the enterocyte (an antigen presenting cell) and intestinal passenger
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Pediatric Population July 1990 - December 2001
Cumulative Survival (%)
100
N=87
80 60
7. The legacy of Intestinal Rehabilitation
40 20
Primary Graft Patient Survival
0 0
1
2
3
4
5
6
7
8
9 10 11 12
Time After Transplantation (year)
Fig. 2. Early Pittsburgh Pediatric Intestine Transplant patient and graft survival showing continued attrition in survival due to high immunosuppressive burden, rejection, infectious complications, and other toxicities.
leukocytes (intraepithelial lymphocytes, mesenteric lymph nodes, Peyer's patches) known to be less tolerogenic than from other abdominal organs [32]. These represent a variety of cellular, humoral, and effector mechanisms which include γ/δ T cells, phagocytic cells, NK cells, natural antibodies, compliment system, and antimicrobial peptides. Immune recognition is provided through pathogen-associated molecular patterns (PAMP), the signal transduction of which is mediated by Toll-like receptors. Intestinal transplantation is associated with inflammatory signals as a consequence to ischemia reperfusion injury, bacterial signals, and Lipopolysaccharide (LPS) translocation, recognition by the enterocyte, and subsequent activation of the effector T cell [33]. The assumption that control of such an immunologic repertoire using the strategies previously reported would result in improved survival had not been observed. The paradox could be explained by the understanding of tolerance induction and activation-induced cell death, with the development of regulatory T cells as a consequence to signaling by Th 1 cytokines. Indeed, the heavy burden of nonspecific immunosuppression with steroids and calcineurin inhibitors has been shown to break tolerance and trigger rejection in various experimental models and the clinic [34,35]. The introduction in 2000 of recipient pretreatment using antilymphocyte antibodies and the elimination of recipient therapy with steroids envisaged ameliorat-
Pediatric Patient Survival (%) N=157
ing the ischemia reperfusion phenomenon and facilitating activation induced apoptosis (clonal deletion) [36]; this has resulted in improved transplant survival, with a significant decrease in incidence of rejection and infection, permitting the gradual decrease of immunosuppressive drug therapy within 3 months of transplant and a decline in drug toxicity events (Fig. 3).
FK/Pred N=48 Cytoxan/Zenapax N=38 Thymoglobulin N=71
100 90 80 70 60 50
The initial successes of intestinal transplantation in the early 1990's resulted in an overwhelming flow of children with intestinal failure to centers performing these procedures, and though the early survival provided the encouragement for future milestones, the failure rate of patients waiting for transplant and the clinical presentation of patients who lost their grafts followed their pretransplant cohorts. Indeed, the survival of children with IF who presented with liver disease was no greater than 30% at one year. This prompted an important development in the management of these patients both before and after transplantation, which focused the care of the patient in the center of a multidisciplinary team of gastroenterology, surgery, nutrition, specialized nursing, interventional radiology, psychiatry, and intensive care, and with the following principles of care: • • • • • • • •
Maintain nutrition and growth Optimize bowel function Prevent complications manage complications Feeding therapy Health surveillance, immunizations, development monitoring Coordination of care regarding co-morbidities Family support
This approach would eventually result in comprehensive diagnostic evaluations, nutritional support and then rehabilitation; the incorporation of restorative surgical interventions and consideration for transplantation would be done in carefully selected patients. Surprisingly, it became evident that many patients referred for transplantation were becoming independent of TPN support, and the patients transplanted were in much better clinical condition at the time of surgery. Examples of clinical and surgical milestones which contributed to the success of these efforts included the application of ethanol lock therapy, novel lipid management strategies with consequent improvement in TPN induced liver disease, and corrective surgical procedures such as STEP [37–39]. In order to better understand and share these insights in care the Pediatric Intestinal Failure Consortium was developed, with findings delineating the standards of care which have resulted in a significant decrease in the incidence of liver disease, infection, and need for transplantation (and a decrease in death on the transplant wait list) [40]. In our efforts to improve transplant outcomes, the development of intestinal rehabilitation has demonstrated that most patients can be rehabilitated without the need for transplantation. Thus Parenteral Nutrition provided by an expert center remains the preferred treatment for chronic intestinal failure. 8. Outcomes
40 30 20 10 0 0
6
12 18 24 30 36 42 48 54 60
Time After Transplantation (Mos)
Fig. 3. Comparative survival of 3 immunosuppressive protocols used for intestine transplantation, demonstrating the impact of Antithymocyte Globulin induction [33].
Intestinal transplantation is lifesaving in children with IF who have significant complications of total parenteral nutrition. Data from the International Intestinal Transplant Registry thru 2010, the OPTN/SRTR Annual Report 2012, and center-specific data reports have documented significant improvements with short- and long-term survivals for transplantations occurring principally in the last 10 years [41,42]. Over 2600 Intestinal transplants have been performed in almost 80 centers worldwide, though most cases have been done in 35 centers. Given the success of intestinal rehabilitation, however, the number of
J.D. Reyes / Journal of Pediatric Surgery 49 (2014) 13–18
17
Fig. 4. OPTN/SRTR 2011 Annual Report demonstrating the decreasing numbers of patients listed and transplanted. http://srtr.transplant.hrsa.gov/annual_reports/2011/default.aspx.
patients needing transplantation has declined since 2005, with the majority of patients coming from home at the time of their transplant (illness severity has decreased), and over half of patients requiring only the isolated intestine transplant (through prevention/resolution
of TPN induced liver disease) (Fig. 4). With the immunosuppression minimization strategies currently in use there has been a significant improvement in long-term survival as well, similar to what has been observed with other organ transplants (Fig. 5). The best survival is
Fig. 5. OPTN/SRTR 2011 Annual Report demonstrating a significant decrease in graft failure, with an increased use of T-cell depleting agents. http://srtr.transplant.hrsa.gov/ annual_reports/2011/default.aspx.
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achieved when the patient is at home waiting, and a liver component is added to the intestine graft. Though the long term data are not robust, there is evidence that recipients are independent of TPN, there are good growth and development in children, and the quality of life after transplantation appears equal to or better than the quality of life on TPN [43]. The most frequent associated morbidities have been dysmotility of the graft, hypertension, osteoporosis, diabetes mellitus, and renal failure [44]. The success of intestinal transplantation has fostered the development of multidisciplinary intestinal centers which have focused on intestinal rehabilitation and improving the devastating effects of TPN on the liver. Intestine transplantation has thus become a less frequent necessity, and follows the guidelines stipulated in this report, and by others. References [1] Starzl TE et al. Transplantation of multiple abdominal viscera. JAMA 261: 1449, 1989. [2] Medawar PB. The behavior and fate of skin autografts and skin homografts in rabbits. J Anat 1944;78:176. [3] Billingham R, Brent L, Medawar P. Quantitative studies on tissue transplantation immunity. III. Actively acquired tolerance. Philos Trans R Soc Lond (Biol) 1956;239:357. [4] Main JM, Prehn RT. Successful skin homografts after the administration of high dosage X radiation and homologous bone marrow. J Natl Cancer Inst 1955;15:1023. [5] Bach FH. Bone-marrow transplantation in a patient with the Wiskott–Alderich syndrome. Lancet 1968;2:1364. [6] Gatti RA, et al. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet 1968;2:1366. [7] Mathe G, et al. Haematopoietic chimera in man after allogenic (homologous) bone marrow transplantation. Br Med J 1963(1633). [8] Kuss R, et al. Homologous human kidney transplantation, experience with six patients. Postgrad Med K 1962;38:528. [9] Merrill JP, et al. Successful homotransplantation of the kidney between nonidentical twins. N Engl J Med 1960;262:1251. [10] Schwartz R, Dameshek W. The effects of 6-mercaptopurine on homograft reactions. J Clin Invest 1960;39:952. [11] Calne RY, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet I 1978;2:1033. [12] Starzl TE, et al. FK 506 for human liver, kidney, and pancreas transplantation. Lancet 1989;2:1000. [13] Starzl TE, Marchioro TL, Waddell WR. The reversal of rejection in human renal homografts with subsequent development of homograft tolerance. Surg Gynecol Obstet 1963;117:385. [14] Lillehei R, Goott B, Miller F. The physiological response of the small bowel of the dog to ischemia including prolonged in vitro preservation of the bowel with successful replacement and survival. Ann Surg 1959;150:543–61. [15] Starzl TE, Kaupp H. Mass homotransplantation of abdominal organs in dogs. Surg Forum 1960;11:28–30. [16] 15.Grant D, Wall W, Mineault R, et al. Successful small bowel/liver transplantation. Lancet 335:181-184, 1990. [17] Goulet O, Revillon Y, Brousse N, et al. Successful small bowel transplantation in an infant. Transplantation 1992;53:9940–3. [18] Deltz E, Schroeder P, Gerbhard H, et al. Successful clinical small bowel transplantation: report of a case. Clin transpl 1989;21:89–91. [19] Todo S, Reyes J, Furukawa H, et al. Outcome and analysis of 71 clinical intestinal transplantation. Ann Surg 1995;222(3):270–82.
[20] Starzl TE, et al. Cell migration, chimerism and graft acceptance. Lancet 1992;339: 1579. [21] Dudrick S. Early developments and clinical applications of total parenteral nutrition. J Parenter Enteral Nutr 2003;29:272. [22] Balisteri WF, Bove KE. Hepatobilary consequences of parental alimentation. Progressive Liver Disease 1990;9:567–601. [23] Bueno J, Ohwada S, Kochosis S, et al. Factors impacting on the survival of children with intestinal failure referred for intestinal transplantation. J Pediatr Surg 1999;34:27–33. [24] Abu-Elmagd K, Fung J, Bueno J, et al. Logistics and technique for procurement on intestinal, pancreatic, and hepatic grafts from the same donor. Ann Surg 2000;323: 680–97. [25] Starzl TE, Rowe MI, Todo S, et al. Transplantation of multiple abdominal viscera. JAMA 1989;261:1449–57. [26] Grant D, Wall W, Mimeault R, et al. Successful small-bowel/liver transplantation. Lancet 1990;335:181–4. [27] Sudan DL, Iyer KR, Deroover A, et al. A new technique for combined liver–small intestinal transplantation. Transplantation 2001;72:1846–8. [28] Reyes J, Fishbein T, Bueno J, et al. Reduced-sized orthotopic liver–intestinal allograft. Transplantation 1998;66(4):489–92. [29] Levi DM, Tzakis AG, Kato T, Madariaga J, Mittal NK, Nery J, Nishida S, Ruiz P. Transplantation of the abdominal wall. Lancet 28;361(9376):2173-6, 2003. [30] Gondolesi G, Selvaggi G, Tzakis A, et al. Use of the abdominal rectus fascia as a nonvascularized allograft for abdominal wall closure after liver, intestinal, and multivisceral transplantation. Transplantation 2009;87(12):1884–8. [31] Testa G, Holterman M, John E, et al. Combined living donor liver/small bowel transplantation. Transplantation 2005;27:1401–4. [32] Harlan DM, Karp CL, Matzinger P, et al. Immunological concerns with bioengineering approaches. Ann N Y Acad Sci 2002 Jun;961:323–30. [33] Pirenne J, Kawai M. Tolerogenic protocols for intestinal transplantation. Transpl Immunol 2004;13(2):131–7. [34] Koshiba T, Kitade H, Waer M, et al. Break of tolerance via donor-specific blood transfusion by high doses of steroids: a differential effect after intestinal transplantation and heart transplantation. Transplant Proc 2003;35(8):3153–5. [35] Lan F, Hayamizu K, Strober S. Cyclosporine facilitates chimeric and inhibits nonchimeric tolerance after post-transplant total lymphoid irradiation. Transplantation 2000;69(4):649–55. [36] Reyes J, Mazariegos GV, Abu-Elmagd K, et al. Intestinal transplantation under tacrolimus monotherapy after perioperative lymphoid depletion with rabbit anti-thymocyte globulin (Thymoglobulin®). Am J Transplant 2005;5(6): 1430–6. [37] Wales PW, Kosar C, Carricato M, et al. Ethanol lock therapy to reduce the incidence of catheter-related bloodstream infections in home parenteral nutrition patients with intestinal failure: preliminary experience. J Pediatr Surg 2011; 45(5):951–6. [38] Diamond IR, Sterescu A, Pencharz PB, et al. Changing the paradigm: omegaven for the treatment of liver failure in pediatric short bowel syndrome. Journal of Pediatic Gastroenterol Nutrition 2009;48(2):209–15. [39] Wales PW, de Silva N, Langer JC, et al. Intermediate outcomes after serial transverse enteroplasty in children with short bowel syndrome. J Pediatr Surg 2007;42(11):1804–10. [40] Squires RH, Duggen C, Teitelbaum DH et al. Natural history of pediatric intestinal failure: initial report from the Pediatric Intestinal Failure Consortium. The Journal of Pediatrics 161(4):723-8.e2, 2012. [41] .Organ Procurement and Transplantation Network: data (website) HYPERLINK http://optn.transplant.hrsa.gov/data/. [42] OPTN/SRTR 2011 annual report. US Dept. of Health and Human Services HRSA, 2011: Data (website) HYPERLINK http://srtr.transplant.hrsa.gov/annual_reports/ 2011/pdf/04_intestine_12.pdf. [43] Sudan D. Long-term outcomes and quality of life after intestine transplantation. Curr Opin Organ Transplant 2010;15(3):357–60. [44] Abu-Elmagd KM, Kosmach-Park B, Costa G, et al. Long-term survival, nutritional autonomy, and quality of life after intestinal and multivisceral transplantation. Ann Surg 2012;256(3):594–608.