The new england journal of medicine

review article

Current Concepts Intestinal Transplantation

Thomas M. Fishbein, M.D.

From the Georgetown Transplant Institute, he results of intestinal transplantation have improved over Georgetown University Hospital, Wash- the past decade. During this period, the number of intestinal transplant pro- ington, DC. Address reprint requests to 1 Dr. Fishbein at the Georgetown Trans- cedures performed in North America has increased by a factor of three. In plant Institute, 2 Main, Georgetown Uni- T 2008, a total of 185 intestinal transplantations were performed in the United States, versity Hospital, 3800 Reservoir Rd. NW, and 221 patients were registered on the waiting list as of June 2009 (http://optn. Washington, DC 20007, or at tmf8@gunet. georgetown.edu. transplant.hrsa.gov). Early attempts at transplantation were hindered by technical and immunologic complications that led to graft failure or death. As a result of recent N Engl J Med 2009;361:998-1008. surgical advances, control of acute cellular rejection, and a decrease in lethal infec- Copyright © 2009 Massachusetts Medical Society. tions, the rate of patient survival at 1 year now exceeds 90% at experienced centers. Although long-term follow-up data are still lacking, the role of intestinal transplan- tation in the treatment of patients with gut failure is becoming clearer. is currently the primary maintenance therapy for patients in whom intestinal absorptive function has failed. Transplantation is offered to patients with irreversible gut failure who have one of three problems: complications of par- enteral nutrition, an inability to adapt to the quality-of-life limitations posed by in- testinal failure, or a high risk of death if the native gut is not removed (as in the case of unresectable mesenteric tumors or chronic intestinal obstruction). However, there is still controversy about exactly which patients should continue to receive paren- teral nutrition and which should receive an intestinal transplant. This article explores the current indications for intestinal transplantation, the surgical procedures involved, our current understanding of the immunology of in- testinal transplantation, the detection and treatment of complications, postopera- tive outcomes, and future applications.

Intestinal Failure

Intestinal failure refers to actual or impending loss of nutritional autonomy due to gut dysfunction. The condition is initially managed by parenteral delivery of nutri- tion.2,3 Many patients, particularly those with the short-bowel syndrome, require only temporary parenteral support while the injured intestine is given time to adapt, and the support can eventually be discontinued. However, this process is unpredictable. In some patients, adaptation is rapid, whereas in others, it takes years or is never achieved. Table 1 lists the clinical factors that influence the outcome of treatment with parenteral nutrition.2,4-14 Markers of intestinal epithelial biomass, such as the level of plasma citrulline, may also predict the likelihood of nutritional rehabilitation. Patients in whom nutritional autonomy cannot be achieved have irreversible intes- tinal failure, and which of these patients ultimately undergo transplantation depends on the success or failure of their adaptation to parenteral nutrition.

Disease States Intestinal transplantations are performed in both children and adults (Table 2). The majority of children who require transplants have the short-bowel syndrome, usually

998 n engl j med 361;10 nejm.org september 3, 2009 current concepts after surgical resection; a smaller proportion has association with clinical features, patient charac- congenital enterocyte disorders that cause infan- teristics, or complications of parenteral therapy in tile diarrhea, disturbances of motility, or malab- intestinal failure might be helpful for the future. sorption due to polyposis.15 Most adult candidates for transplantation also Candidates for Transplantation have the short-bowel syndrome, and in the ma- The complications of parenteral nutrition summa- jority of cases the cause is Crohn’s disease, mes- rized above account for the majority of indications enteric vascular accidents, trauma, volvulus, or for intestinal transplantation accepted by the Cen- surgical complications. Complications of ters for Medicare and Medicaid Services (Table 3). for obesity are increasingly being encountered. Specifically, patients should be considered for a Sometimes the only treatment option for locally transplant if they have recurrent episodes of sep- advanced benign mesenteric tumors is exentera- sis, two or more episodes of loss of central venous tion and intestinal transplantation. Multivisceral access, early cholestatic disease, evidence of transplants have also been used to treat complica- , or repeated episodes of de- tions of portal hypertension when splanchnic ve- hydration.21,27 As the outcomes of transplantation nous thrombosis precludes improve, these indications may be broadened.28 alone.16 Our increasing ability to predict the failure of par- enteral nutrition allows earlier transplantation Unsuccessful Parenteral Nutrition (with patients admitted directly from home, before The 1-year rate of survival for patients treated with they require hospitalization for complications), parenteral nutrition is approximately 90% in ex- which is associated with improved survival.15 Oth- perienced centers, which is similar to the rate er characteristics associated with an increased risk achieved with intestinal transplantation.3,7 How- of death during parenteral nutrition therapy in- ever, long-term therapy is often associated with clude specific disease states (primary motility dis- complications. The rates of survival at 3 years and orders, extremely short bowel [defined as less than at 5 years remain 70% and 63%, respectively, in 50 cm of jejunoileum], chronic obstruction, or ra- various series.3,4,6,9,10,17,18 Liver disease is widely diation injury), end-jejunostomy without colon, recognized as the most deadly complication of and abdominal-wall defects in older adults and in parenteral nutrition. It eventually develops in half children (Table 1).29 In such patients referral for the adults and children who receive continuous a transplant is much less controversial. The high therapy13,19,20; if detected early, this complication sometimes responds to cycling of the infusion, a reduction in the lipid or dextrose load, oral ad- Table 1. Factors Adversely Influencing the Outcome of Long-Term Parenteral ministration of ursodiol, alteration of the lipid Nutrition Therapy.* emulsion, or the addition of antibiotics.21,22 A new Factor Source of Data lipid preparation not yet approved for use in the Affecting survival United States shows promise as a way of decreas- Age >60 yr at institution of therapy Messing et al.4 ing the incidence of this complication, if the ini- 4 5 tial data are borne out by further study.23 How- Jejunoileal length <50 cm Messing et al., Chan et al. ever, liver disease currently leads to death within Dysmotility Scolapio et al.6 a year of its onset in the majority of patients in Radiation enteritis Howard and Malone7 5,24,25 whom it persists. More severe obstruction Messing et al.4 Thrombosis at the site of central inser- Longer treatment Howard and Malone7 tion, recurrent episodes of catheter-related sepsis, dehydration, formation of renal calculi, and elec- Affecting rehabilitation trolyte disorders are other common complica- Jejunoileal length <50 cm Wilmore et al.2 tions.26 Unfortunately, randomized or case–control Absence of ileocecal valve Wilmore et al.2 studies comparing outcomes of transplantation Mucosal disease Wilmore et al.2 with those of parenteral nutrition in similar pa- Dysmotility Scolapio et al.6 tient populations are not available, so there is Abdominal-wall defect in children Thakur et al.8 considerable controversy about which patients should be referred for transplantation. Studies * Data are from the Intestinal Transplant Registry (www.intestinaltransplant.org). evaluating the relative risk of a poor outcome in

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Types of Transplants Table 2. Distribution of Disease States among Recipients of Intestinal Transplants.* The defining component of any intestinal trans- plant is the (jejunoileum). When Adults Children this part of the gut is transplanted alone, it is Disease State (N = 1031) (N = 733) referred to as an isolated intestinal transplant (Fig. percent 1A). Commonly, however, other organs are trans- planted simultaneously from the same donor. Volvulus 17 7 When advanced liver disease is present, the liver Gastroschisis 21 1 is replaced as well (Fig. 1B). This can be accom- plished with a composite allograft or with organs Trauma 2 8 implanted separately from the same donor. The Necrotizing enterocolitis 13 1 and duodenum are often included along Ischemia 1 25 with these organs to facilitate en bloc engraftment Crohn’s disease 0 12 and to obviate biliary reconstruction, particularly 31 Intestinal atresia 8 0 in small children. The exact extent of liver dis- Other 2 8 ease associated wit h parenteral nut rit ion t hat wou ld indicate the need for a liver transplant remains a (mucosal defect) matter of judgment. After successful engraftment Microvillus inclusion 6 0 of an isolated intestinal transplant, early liver dis- Secretory diarrhea 0 0 ease may regress with the cessation of parenteral 32,33 Autoimmune enteritis 0 0 therapy. However, liver function that is pre- Other 2 0 served at the time of intestinal resection often de- teriorates rapidly in small children,34 accounting Motility disorder for the relatively larger proportion of children who Pseudo-obstruction 9 9 receive combined organ transplants.13,35 Aganglionosis Some patients require replacement of the en- Hirschsprung’s disease 8 0 tire because of coexisting Other 1 0 intestinal disorders or disease of other organs. For example, some have had their colon removed Tumors 1 15 (Crohn’s colitis), some have had surgery Retransplantation 8 7 (gastric bypass), some have chronic pancreatitis Other 2 5 (related to parenteral nutrition), some have renal failure (because of oxalic acid stones or hyperten- * Data are from the Intestinal Transplant Registry (www.intestinaltransplant.org). sion), and some have had a host of other possible complications related to intestinal failure or par- mortality among patients awaiting intestinal trans- enteral nutrition. In such cases, the transplant plants — up to one third of patients in some age team makes an individual determination regard- groups — exceeds that among candidates for oth- ing whether to include other organs. Transplants er solid-organ transplants, making early referral that include the stomach along with the small of patients with such risk factors important.30 bowel are frequently referred to as multivisceral For patients who will have lifelong dependency (composite visceral or multiorgan) transplants. on parenteral nutrition but have not had compli- Exenteration of the entire native gastrointestinal cations and are seeking to improve their quality tract makes room for the en bloc organ graft (Fig. of life, the decision about transplantation is more 1C). Transplantation of the colon along with the controversial. Such patients often thrive after intestinal allograft was previously avoided because transplantation, but centers vary considerably in of the risk of infection,36 but it is now sometimes how they define candidacy for preemptive trans- carried out.37 Although technical refinements plantation. The limited data available corroborate continue to be made, these operations still improved quality-of-life indicators among patients roughly resemble those first described by Starzl who have undergone preemptive transplantation, over 40 years ago in dogs.38-40 as compared retrospectively with those who re- After the operation, a is inserted ceive parenteral nutrition therapy before the trans- to provide early enteral nutrition, after which the plantation.28 patient is transitioned to oral feeding. Small ba-

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Table 3. Failure of Parenteral Nutrition, as Defined by the Centers for Medicare and Medicaid Services.*

Impending or overt liver failure due to TPN-induced liver injury Thrombosis of two or more central veins Two or more episodes per year of catheter-related systemic sepsis that requires hospitalization A single episode of line-related fungemia, septic shock, or acute respiratory distress syndrome Frequent episodes of severe dehydration despite intravenous fluid supplementation in addition to TPN

* TPN denotes total parenteral nutrition. bies often must acquire feeding skills if they had nals required for the activation of T lymphocytes. not been learned before the operation. An ileos- The recent addition of induction agents acting at tomy is constructed during the transplantation signal 3, including interleukin-2 monoclonal anti- procedure to allow surveillance biopsies of the in- bodies, rabbit antithymocyte globulin (Thymoglo- testinal mucosa in order to help direct medical bulin, Genzyme), and sirolimus (also known as therapy. Graft rejection and most infections can rapamycin), have all decreased acute cellular rejec- be diagnosed histologically. Several months after tion at different centers. Although some form of transplantation, when graft function has become antilymphocyte antibodies — that is, competitive stable, the is reversed in patients who inhibitors, such as the monoclonal interleukin-2 retain a functional colon or received one as part blockers, or depleting antibodies, such as antithy- of the allograft. mocyte globulin or alemtuzumab (Campath-1H, Genzyme) — has been associated with decreased Immunologic Features early rejection rates, such therapy may result in of Intestinal Transplantation a globally increased level of immune suppression and may increase the risk of infection. Tacrolimus Transplantation of the intestine presents a great- with low-dose cortico­steroids, either alone or in er immunologic challenge than does that of oth- combination with sirolimus (rapa­my­cin), remains er solid organs. Approximately 80% of immune the most effective and reliable long-term regimen. cells normally reside in the gut, and they are re- The main complication of tacrolimus­ is chronic populated after transplantation with recipient cells, renal damage, which in rare cases may even re- whereas the genotype of the epithelium remains quire renal-replacement therapy. largely that of the donor, making the organ highly A new fusion protein that is specific for CD80 chimeric and immunogenic.41-43 Although most and CD86 is now being used in trials of renal transplanted organs are sterile, the gut relies on transplantation and would be the first ap- barrier and other immunologic mechanisms, such proved agent for use in inhibiting signal-2 acti- as the production of antimicrobial peptides, to vation.44 A single regimen has yet to be proved provide protection against invasion by extensive superior, so transplantation centers currently in- commensal flora. Breach of this ileal barrier by dividualize immunosuppression. Ideally, future ischemia or reperfusion injury, by recipient im- strategies will target mechanisms of mucosal in- mune cells, or by defects such as impaired micro- jury that are specific to the ileum. bial control mechanisms results in inf lammation and tissue damage and increases the likelihood Complications of infection. This loss of immunologic protection makes the augmented immunosuppression re- Surgical Complications quired to treat rejection particularly dangerous. Early outcomes of intestinal transplantation have Figure 2 summarizes our current understand- improved, reflecting the increase in surgical ex- ing of the immunologic characteristics of intes- perience over the past decade. The rates of graft tinal transplantation. Maintenance treatment with thrombosis, ischemia, and technical failure have tacrolimus, which inhibits signal-1 activation of all decreased, and graft losses are now more com- T lymphocytes through the inhibition of calcineu- monly attributable to medical and immunologic rin, is the basis of current intestinal transplant causes. This change probably reflects the greater immunosuppression. Signal 1 is one of three sig- experience of the teams at several centers that per-

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ABC

Figure 1. Three Types of Transplants in Intestinal Failure. When the small intestine (jejunoileum) is transplanted alone, it is referred to as an isolated intestinal transplant (Panel A), with systemic drainage to the vena cava. A composite liver and intestinal transplant usually includes the duodenum and an intact biliary system and portal circulation,COLOR FIGUREwith the native foregut preserved (Panel B). In a multivisceral transplant, which involves the liver, stomach, duodenum, pancreas,Draft 2and small intestine,08/17/09 the foregut is removed and a new stomach is transplanted (Panel C). This type of transplant sometimes Authorincludes Fishbeinthe colon, kidney, or both. The transplanted organs are shown in pink, and the native organs or structures are shown in light Figbrown. # 1 Title ME DE form most of the transplantations. Transplanta- tion. Among 922 recipients of intestinal trans- Artist SBL tion of the isolated intestine before the onset of plants between 2002 and 2007, rejection was AUTHOR PLEASE NOTE: Figure has been redrawn andliver type has failure been reset improves early outcomes, decreases the strongly associated with both graft loss and pa- Please check carefully length of hospitalization, and allows more rapid tient death (Grant D, Intestinal Transplant Regis- Issue date conversion to a full enteral diet, as compared with try). Multiple factors have led to a decrease in the multiorgan transplantation.45 The advantage of rates of rejection. Early diagnosis is critical for suc- single-organ over multiorgan transplantation with cessful reversal of the rejection process. Despite respect to long-term sur vival has yet to be proved. considerable effort to find one, no minimally in- However, in the case of life-threatening complica- vasive marker reliably predicts rejection. Endoscop- tions, an isolated intestinal graft may be removed ic surveillance biopsy remains the standard for and parenteral nutrition temporarily reinstituted diagnosing this problem (Fig. 3). The standard- while the patient awaits repeat transplantation.27 ized histologic grading of rejection has allowed Earlier referral and prioritized allocation of pedi- more consistent early diagnosis and has helped to atric transplants to children in need of multior- discriminate graft rejection from viral infection.47 gan grafts have also decreased the number of Several centers have reported decreases in the rate deaths among children on the waiting list.46 and severity of early acute rejection with the use of newer medications, including monoclonal in- Graft Rejection terleukin-2 antagonists, polyclonal antithymocyte Graft failure and death after transplantation are antibodies, and sirolimus.48-50 Acute cellular re- most closely related to the development of rejec- jection in the first 90 days, which previously oc-

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Figure 2. Immunologic Response to the Donor Allograft in Intestinal Transplantation. The immunologic response involves six steps, some of which may occur simultaneously. Naive T cells infiltrate the allograft and undergo priming and activation in the donor mesenteric lymph nodes and Peyer’s patches. In other solid organs, such priming occurs primarily COLOR FIGURE in recipient lymphoid tissues. Donor antigen-presenting cells, such as dendritic cells, then ingest and display the “foreign” graft anti- gens in associationDraft 4 with 08/05/09class I and II molecules of the major histocompatibility complex (MHC) (see inset). Antigen-presenting cells are stimulatedAuthor toFishbei expressn costimulatory effectors required to “arm” naive CD8+ cytotoxic T cells and predominantly CD4+ type 1 helper T cells (Th1Fig #cells). The2 CD8+ cytotoxic T cells attack certain donor-cell targets and produce substances, including perforin, granzyme, and Fas ligand,Title that lead to crypt-cell apoptosis. Armed Th1 cells provoke an inflammatory state driven by the production of cytokines, including interferon-γ.ME The dendritic cell also maintains immune defenses of the epithelium by regulating secretion of the antimicrobial peptide humanDE defensin 5 from Paneth cells by means of NOD2-dependent circuits. Recipients with mutations in the NOD2 gene are at signifi- cantlyArtist increasedSBL risk for immunologic graft loss, possibly owing to inadequate antimicrobial defense, which results in epithelial damage, AUTHOR PLEASE NOTE: bacterialFigure invasion, has been redrawn and and typea secondary has been reset inflammatory response. The inset shows the signals involved in the immune response involving the recipient naivePlease T cell check andcarefully antigen-presenting cells. Tacrolimus interferes with signal 1. To date, no inhibitors to block signal 2 have been approvedIssue date for use in humans. Interleukin-2 monoclonal antibodies and sirolimus (rapamycin) inhibit signal 3. TCR denotes T-cell receptor, and TNF tumor necrosis factor.

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Figure 3. Endoscopic Views and Biopsy Specimen A with Evolving Rejection of an Ileal Allograft. Edema and erythema are evident in this endoscopic view of graft rejection after ileal transplantation (Panel A). A histologic specimen from the endoscopic biopsy re- veals increased destruction of crypt cells, apoptosis, and a lamina propria infiltrate of mixed cellularity, find- ings that are characteristic of evolving rejection (Panel B, hematoxylin and eosin). If untreated, the rejection pro- cess progresses to erosions and eventually mucosal dissolution (Panel C).

in specimens from surveillance biopsies correlates with late graft loss suggests that early intervention in such cases could further improve survival.51 B The effect of other conditions, such as mutations of NOD2 (the gene encoding nucleotide-binding oligomerization domain–containing 2) that are associated with Crohn’s disease, is just now be- ing recognized as a cause of increased immuno- logic risk.52-54

Infection Infections remain common after transplantation.46 In the medical management of intestinal-transplant recipients, it is essential to distinguish viral or bac- terial enteritis from rejection. Both conditions may be characterized by diarrhea, and endoscopic eval- C uation of the graft mucosa is warranted if they are suspected at any interval after transplantation. Adenovirus, calicivirus, Clostridium difficile, and cy- tomegalovirus infections may all masquerade as rejection, and biopsy evaluation by a pathologist experienced with intestinal transplants is neces- sary.55,56 Only recently has the number of misdi- agnoses been decreased by sufficient experience and detailed descriptions of the differences in biopsy specimens between infection with these pathogens and graft rejection. Whereas augmented immunosuppression is the treatment for rejection, it may have disastrous consequences in the pres- ence of viral infection. Post-transplantation lym- phoproliferative disorder, driven by Epstein–Barr virus, was initially common after pediatric intes- tinal transplantation, occurring in 20% of pat ients curred in 70 to 90% of transplant recipients, is now in 1992 but decreasing to only 7% by 2007. With seen in only one third to one half of patients. Bet- early detection of viremia by a quantitative poly- ter controlICM AUTHOR of rejection Fishbein has improvedRET earlyAKE graft1st merase-chain-reaction assay and treatment with REG F FIGURE 3a-c 2nd survivalCASE and can be expected to have an effect3rd on rituximab, a monoclonal antibody against the TITLE Revised long-termEMail survival as experienceLine 4-C increases. Some B-lymphocyte CD20 receptor, this problem is now SIZE evidenceEnon thatARTIST asymptomatic: mst H/T rejectionH/T as detected managed much more effectively. FILL Combo 16p6 AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset. Please check carefully. 1004 n engl j med 361;10 nejm.org september 3, 2009 JOB: 36110 ISSUE: 9-3-09 current concepts

Graft Dysfunction results at centers where larger numbers of trans- The common symptom in virtually all cases of plantations are performed include survival rates allograft dysfunction is diarrhea, which may be exceeding 90% at 1 year and should translate into caused by an infection, rejection, antibiotic use, or improved long-term survival.33,57,58 Patients who poor food choice. In the absence of known food have been admitted directly from home to under- allergy or rapid gastric emptying (the dumping syn- go transplantation, younger patients, those who drome), histologic examination is essential for have received a first transplant, and those who an accurate diagnosis. Assessment for infectious receive ant ibody induct ion therapy or maintenance agents is performed with the use of stool cultures, sirolimus are most likely to survive.15,19,54,59-79 plasma assays (for adenovirus, Epstein–Barr virus, These findings emphasize the importance of early and norovirus), and immunohistochemical stud- referral of patients who are well enough to await ies of graft-biopsy specimens (for cytomegalovi- transplantation at home and to tolerate aggressive rus, Epstein–Barr virus, norovirus, and adenovirus). induction immunosuppression. Viral infections are more common in children and during the first 3 months after transplantation, Quality of Life and Cost when levels of immunosuppression are still high. Several studies confirm that the state of intesti- Judicious withdrawal of immunosuppressive ther- nal failure is associated with significant psycho- apy is coupled with the administration of antivi- social disability, decreased quality of life, and in- ral medication. Owing to the poorly understood, creased narcotic dependence, all of which improve multifactorial nature of the diarrhea, the standard after successful transplantation.68,80,81 More t han evaluations — that is, testing for fecal reducing 80% of transplant recipients who survive attain substances and obtaining stool cultures to detect freedom from parenteral nutritional support and overgrowth — are rarely helpful. Bloody diarrhea can resume regular activities (with high Karnof- is frequently a sign of severe rejection with mu- sky performance scores).15 One study assessed the cosal erosion or sloughing. However, ileal ulcers quality of life among adults who were receiving near an anastomotic site may also cause chronic parenteral nutrition at home after intestinal trans- anemia; these ulcers sometimes respond to treat- plantation. They were weaned from nutritional ment with antibodies against tumor necrosis fac- support at a median of 18 days after transplanta- tor, but they often recur in the absence of any dis- tion and reported improvements in quality-of-life cernible cause, suggesting mechanisms similar indicators such as anxiety, depression, cognitive to those causing other inflammatory bowel dis- emotion, stress, parenting, digestive and urinary eases.54 The causes of such lesions remain poorly function, control of impulsiveness, medical com- understood even today. pliance, quality of social relations, and leisure and recreation.28 Dependence on narcotics decreased Outcomes after transplantation. Responses on the Child Health Questionnaire were similar among chil- Graft and Patient Survival dren who had undergone transplantation 5 years Marked improvements in survival have occurred earlier and healthy children, although the parents over the past decade.15,33,57 The 1-year rate of graft of the treated children perceived mild decreases survival for recipients of intestinal and multiorgan in physical and psychosocial functioning. transplants in North America increased from 52% Extensive data on costs are also lacking, but in 1997 to 75% in 2005.1 Similarly, the 1-year rate published information to date indicates that, of patient survival improved from 57% in 1997 to like renal transplantation, intestinal transplan- 80% in 2005.1 Rates of patient survival at 3 and tation becomes cost-effective after approximate- 5 years for transplantations performed between ly 2 years.82 1997 and 2000 have remained modest at 61% and 47%, respectively, according to pooled data (http:// Nutrition optn.transplant.hrsa.gov). Such large database out- Intestinal function after transplantation is usually comes are limited by variations in survival rates mildly abnormal, necessitating some dietary re- among centers and the changes in practice that strictions. Foods containing insoluble cellulose or have occurred over the past decade. More recent high in simple carbohydrates (salad, citrus fruits,

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refined sugars) may cause type 1 (early) dumping livery of home parenteral nutrition and transplan- symptoms. Thus, the diet may be modified by an tation, with the promise of an eventual return to individual clinician and patient according to tol- normal life. Although the number of intestinal erance. In patients with a longer colonic remnant transplants remains relatively small nationally, the or a transplanted colon, function may improve, but rapid improvement in outcomes seen over the past the use of antidiarrheal medications (e.g., diphe- decade presages a substantial increase in volume noxylate and atropine [Lomotil, Pfizer] or lop- as well as broader indications to include preemp- eramide [Imodium, McNeil]) is common. Vita- tive transplantation for patients at low risk for min, mineral, and micronutrient absorption is complications and lifesaving treatment in cases generally good, and routine assessments are not once considered to be terminal. Isolated intesti- necessary. Several studies in children have shown nal transplantation before liver failure occurs and linear growth and development after a transition the use of multiorgan transplants are likely to in- to enteral feeding 83-86 but failed to show “catch up” crease as long-term outcomes improve. Internists, from the depressed growth curves seen before pediatricians, and surgeons on the front lines con- transplantation in virtually all these patients. tinue to incorporate these procedures into their practices. Further insights into the immunologic Future Applications characteristics of intestinal transplantation, with its associated inflammation, should also contin- Each year thousands of patients who have total ue to improve our understanding of intestinal in- intestinal infarction due to mesenteric ischemia, flammatory conditions in general. necrotizing enterocolitis, volvulus, or other disor- ders that lead to irreversible intestinal failure die No potential conflict of interest relevant to this article was reported. from sepsis because a planned resection is can- I thank my clinical mentors, Dr. Charles Miller and Dr. Jorge celed. This practice of aborting resection is chang- Reyes, my scientific collaborators, Dr. Michael Zasloff and Dr. Kenneth Newell, and the patients whose contributions have ing as such patients are given the opportunity to helped further our knowledge and improve treatment for future have an acceptable quality of life through the de- patients.

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