An international symposium convened September 9–11, 2010, in Chicago to present the state of the art and science of the multidisciplinary care of intestinal failure in children. Medical and surgical management of the child with pediatric intestinal failure was discussed with a focus on the critical importance of multidisciplinary intestinal failure management.
MEDICAL THERAPY IN INTESTINAL REHABILITATION
Two over-riding trends in intestinal rehabilitation care were highlighted during the Symposium. The first was the recognition that the population of patients has changed with regard to complexity of care. The Children's Memorial Hospital in Chicago group discussed this changing paradigm for infants with intestinal failure, which was further elaborated on by the neonatology group at Nationwide Children's in Columbus noting that as the technology and therapeutics of caring for the extremely young continues to improve, smaller and sometimes extremely premature infants are surviving with increasing frequency (1). This will affect the overall prevalence of patients with intestinal failure and the complexity of their management from comorbid conditions. Additionally, the gastroenterology group at Nationwide Children's led the discussion of the role of intestinal motility in both patients with anatomically short gut and as a primary cause of intestinal failure, highlighting a recent study finding that greater than 40% of 210 patients undergoing intestinal transplant in Pittsburgh had a primary motility disorder (gastroschisis, pseudo-obstruction, and Hirschsprung's disease) as the underlying diagnosis (2).
Patients with motility disorders are a subset of patients who represent a high-risk population who are likely to develop complications of total parenteral nutrition (TPN) therapy. Furthermore, patients who have dysmotility had a prolonged duration of TPN dependence as compared with other intestinal failure patients. Drugs used in the therapy for motility disorders are restricted as a number have been withdrawn from the market or have black box warnings. Octreotide and clonidine have been used with limited success in addition to higher doses of antibiotics such as erythromycin and amoxicillin/clavulanate. Antibiotic usage to promote gastric emptying and small intestinal motility is currently off-label. Newer drugs including linaclotide and prucalopride are currently in drug trials and may represent future therapeutic options for these patients, including the indications for manometric studies to (1) document the presence and anatomical location of dysmotility, (2) guide medical and sometimes surgical management, and (3) prognosticate and plan transplant options when medical and surgical management fail.
The second significant trend identified is the evolution of medical therapy in intestinal rehabilitation that continues to focus on both the enhancement of intestinal adaptation and improvements in supporting TPN-dependent patients. Enteral autonomy, through intestinal adaptation, continues to be a challenging goal of intestinal rehabilitation. Again, the neonatology group in Columbus discussed the concept of early enteral feeds, preferably with breast milk, as an optimal choice as soon as the patient can tolerate enteral nutrition. Milk banking is a growing area for those who desire to feed their child breast milk, given the well-documented health benefits including weaning from TPN and a decrease in the incidence of NEC (3). However, the cost is still somewhat prohibitive for the average family. Dr. Tappenden at the University of Illinois at Urbana-Champaign elaborated on the role of enteral nutrients to stimulate intestinal mucosa, most notably in the form of short chain fatty acids (SCFA), as a form of carbohydrate salvage or as a prebiotic. Acetate, proprionate, and butyrate comprise 83% of the SCFA. Animal studies suggest that their usage enhance structure and function of the mouse intestine. SCFA may also increase endogenous glucagon-like peptide-2, a hormone believed to play a role in the adaptive process (4). Although teduglutide, a GLP-2 analog, is currently in Phase III clinical trials in adults, more traditional sources of SCFA are increasingly being incorporated into newer formulas to attain the prebiotic benefits.
The ability to support patients on long-term parenteral nutrition and prevent known complications of parenteral associated liver disease and central line infections was discussed. Lipid management, as it pertains to the development of parenteral nutrition-associated cholestasis, was a theme developed in the keynote address by Dr. Lacaille of Necker-Enfants Malades in Paris (5).
The current standard of care for the provision of lipids to patients receiving parenteral nutrition continues to be the Food and Drug Administration-approved soy-based lipid emulsions. These emulsions largely consist of linoleic acid, an omega-6 fatty acid and precursor to proinflammatory derivatives through desaturation and elongation. In addition, soy-based emulsions contain phytosterols, which share significant homology to native bile acids with proposed antagonistic effects on bile acid metabolism and clearance from the hepatocyte. Accordingly, two major strategies have evolved; minimization/reduction of the potentially harmful omega-6 fatty acids and using an alternative investigational omega-3 based fish-oil product.
Lipid minimization strategies are dependent on the concept that the amount of lipid necessary to prevent essential fatty acid deficiency (EFAD) is much less that that given to provide the calories needed for growth. Preliminary trials (6) have suggested a decline in bilirubin without a detrimental effect on growth or EFAD. Key factors which seem to allow the reduction of soy-based lipid to as little as 1 g/kg/day two to three days per week include the ability to increase dextrose calories safely and the monitoring of triene:tetraene ratios more than 0.2, a marker for EFAD. In patients with increased triene:tetraene ratios or poor growth, lipid administration is generally adjusted.
Fish-based oil, such as the investigational emulsion Omegaven, is rich in the omega-3 fatty acids docosahexaenoic acid and eicosapentaenic acid, largely believed to be protective and is devoid of phytosterols. Although there are now several fairly substantial reports suggesting its benefits in the reduction of cholestasis, there are no prospective studies based on prevention (7). Similar to lipid minimization, there is a risk of EFAD, though there seems to be enough omega-6 fatty acids to prevent fatty acid deficiency in the majority of patients (8). Although the dose of fish-oil based strategies have largely been limited to 1 g/kg/day, the growth advantage compared with severely lipid restricted individuals may prove beneficial.
A third regimen, SMOF (Soy, MCT oil, Olive oil, and Fish oil) is in early stages of development (9). The potential for SMOF lipid emulsions to provide the adequate balance of omega-3 and omega-6 fatty acids to promote growth, prevent EFAD, and reduce the prevalence of parenteral nutrition induced cholestasis is yet to be determined.
Perhaps one of the most significant recent advances in the care of children requiring long-term central access and discussed by the group at Children's Hospital of Pittsburgh of UPMC is the conceptualization of the prevention and treatment of infections through the use of antimicrobial lock therapy. The use of line locks, ethanol, or antibiotic, will likely prolong the life of central venous catheters and decrease treatment failures (10).
Children's Memorial Hospital in Chicago presented data on small bowel bacterial overgrowth (SBBO) as a frequent complication of intestinal failure (11). The gold standard for diagnosis remains a duodenal aspirate culture, though hydrogen breath tests, with its inherent limitations, have also been used. Often, patients are diagnosed based on symptomatology alone given the inherent risks of obtaining duodenal aspirates and limited value of the breath test. Studies have shown the prevalence of SBBO to be between 50% and 70%. Cole et al. (12) found that children with a history of NEC and SBBO are seven times as more likely to develop a blood stream infection than those who do not have SBBO. Newer drugs such as rifaximin and nitazoxanide have been included in the armamentarium to reduce the bacterial load in high-risk patients.
Finally, several issues pertaining to long-term developmental outcomes in children with intestinal failure were discussed. The feeding team at the Medical College of Wisconsin described key components of oral aversion, an often formidable obstacle in obtaining enteral autonomy, and the benefits of a multidisciplinary approach which use the combined expertise of physicians, occupational therapists, nutritionists, and psychologists to achieve an optimal outcome. The premature brain is at risk for periventricular white matter injury, especially in the setting of sepsis and surgical NEC. Data were presented by the Children's Memorial group in Chicago regarding the developmental outcome of patients with necrotizing enterocolitis, describing a poorer outcome than in age-matched controls (13, 14).
It was postulated that developmental delays are more common in all forms of intestinal failure calling for future studies to encompass all children on long-term parenteral nutrition.
SURGICAL APPROACHES TO INTESTINAL REHABILITATION
There has been much progress in the management of children with intestinal failure. Every aspect of care is being addressed, including improvements in parenteral nutrition management with liver protective strategies, maintenance of normal growth, improved control over intestinal adaptation, vascular access techniques, and improved results with intestinal transplantation. However, surgical strategies still remain one of the most important aspects of the care of these children and offering a hope of eventually achieving intestinal autonomy.
Prevention/Retention of Intestinal Length
Surgeons faced with children requiring intestinal resection should make every effort to preserve all potentially viable intestine. Although one is obliged to adhere to the general principles of surgical decision-making (removing all clearly nonviable bowel), it is important to preserve intestinal length that may provide future absorptive capacity. This may obligate the surgeon to a second-look laparotomy in some cases, or may require creation of additional stomas that will be closed at a later date. The overriding guiding principle should be to preserve all viable intestine, even at the expense of further procedures to deal with the consequences.
Restoration of Intestinal Continuity
Many children with massive intestinal resection will have had stomas created at original or subsequent operations. Once these children are recovered from the initial insult, decisions arise about stoma closure. The guidelines for stoma closure have changed in the past several years. Although surgeons at one time adhered to a fairly rigid (and random) principle that children should be a certain weight or size before considering stoma closure, the current protocol should be dictated more by the physiologic status of the child. Recent trends have supported earlier and earlier stoma closure and authors support closure in the first 2 weeks after resection, to no sooner than 6 to 8 weeks (allowing for the inflammatory response and adhesions to subside) and after that time, stoma closure when the child seems fit for the operation. The most prevalent approach is to wait until the child is recovered from the initial operation, begin oral or other enteral feeding, and observe the success as measured by stool output and weight gain. Children demonstrating sufficient absorptive capacity may be allowed to make progress before stoma closure reducing the urgency to close stomas at a specific time. However, many of the children will not have sufficient absorptive capacity and will have high stoma output and inability to wean from any aspect of parenteral nutrition. In these children, it is desirable to put all available intestinal length back into continuity in an effort to capitalize on all absorptive surface area and to provide the maximal potential adaptation response.
Intestinal Lengthening Approaches
During the course of management of children with intestinal failure, children will frequently undergo a recurring course of bowel lengthening and bowel dilation. Bowel lengthening adds obvious advantages to intestinal adaptation. The additional surface area and increased intestinal transit time, with increased absorptive capacity adds to the potential for intestinal autonomy. Autonomous bowel lengthening requires no surgical intervention, but will lend confidence to the advancing feeding program. Bowel dilation also adds to the overall surface area, but may confound intestinal motility. The small bowel contents have a liquid consistency, and therefore its walls must have the ability to coapt with one another to generate forward propulsion. When bowel dilation outgrows the ability for the bowel walls to coapt, the motility is no longer forward, but has a to and fro quality that does not promote efficient forward propulsion and results in intestinal stasis. Intestinal stasis is associated with ineffective absorption and with SBBO.
Fortunately, intestinal dilation brings with it various surgical options that take advantage of the increased surface area while improving the efficiency of the intestinal motility that is compromised by the dilated segment. Two approaches have been commonly used and have been reported in the literature. Longitudinal intestinal lengthening and tailoring was first described in Europe by Bianchi (15) and is widely used throughout Europe. Serial transverse enteroplasty (STEP) was described by Kim et al. (16) is used widely in the United States and is gaining popularity in other parts of the world.
Longitudinal Intestinal Lengthening and Tailoring was originally described as an alternative to intestinal tapering when bowel dilation was found to be confounding intestinal motility. Bianchi (15) first described the technique, taking advantage of the normal bifurcations in the mesenteric vasculature, which divide into left and right near the intestinal wall. The vessels can be separated and the bowel divided longitudinally with each half retaining its own half of the blood supply. The ends are then anastomosed end to end, effectively doubling the length and preserving all available surface area. This original description has been used widely and is frequently combined with tapering techniques to create an optimal intestinal lumen with maximized intestinal length and proven to have reproducible results with acceptable morbidity (17). In his 16 year review of 20 patients, Bianchi (18) reported no operative mortality, a 10% leak rate, and a long-term survival of 45% with most deaths related to liver disease.
STEP was originally described by Kim et al. (16) and creates transverse divisions from alternating directions resulting in an accordion type lengthening of the dilated segment. This approach has been shown to be safe and has acceptable morbidity that has been confirmed by many authors. In 2007, Modi et al. (19) reported the results for STEP from the international registry. The results demonstrate the feasibility of STEP as a standard method of approaching intestinal dilation in short bowel syndrome. Thirty-eight patients achieved significant increase in intestinal length, and more importantly, enteral tolerance improved from 31% of calories to 67% of calories. The perioperative complications including staple line leak, abscess, and others occurred in approximately one fourth of the patients and 16% progressed to transplant or died. Recent interest has developed in the effect of STEP on intestinal motility. Modi et al. (20) have shown migrating motor complex (MMC) characteristics to be similar to normal intestine in a porcine model and MMC to be improved over dilated bowel in the same model. These results indicate a potential benefit of STEP in improving motility when bowel dilation is recognized. All authors have emphasized the need for these children to be cared for by a dedicated team of specialists focused on the care of the child with intestinal failure (17, 21, 22).
Intestine Donor Assessment and Waiting List Trends
Previously, death on the waiting list had been highest for intestinal transplant recipients compared with any other organ. Various weighting systems had been used including the pediatric end-stage liver disease scoring system to try to overcome some of these inequities over recent years. Data were presented from the United Network for Organ Sharing (UNOS) database that the death on the waiting list rate for intestinal recipients is now similar to that of other organs (23). Over the past 10 years, the survival of intestine transplant candidates on the waitlist showed the greatest improvement among solid organ waiting lists (2009 OPTN/Scientific Registry for Transplant Results [SRTR] Annual Report, Table 1.6), although there still is a higher mortality rate for infants and for those requiring a combined (liver containing) allograft. Waitlist mortality is also more pronounced in adult patients where no compensatory weighting in model for end-stage liver disease score is allowed for those requiring the liver. Local Organ Procurement Organizations' (OPOs) management strategies and United Network for Organ Sharing registry allocation policies continue to be at the cornerstone of maximizing organ availability and utilization.
The limited data on live donor intestine donation were presented. Although not currently being routinely used, data from Dr. Benedetti and also the Intestinal Transplant Registry (ITR) do not demonstrate a clear advantage of live donor intestine donation over deceased donor intestine transplant. The challenge is to consider using this method under the right circumstances, such as combined intestine and liver failure patients in whom the wait list mortality remains high (24).
Although intestinal allografts have been recovered for over 20 years, there still persists uncertainty and even at times mistrust about this form of organ procurement. Many (OPOs) are not aware or willing to look at recovery of the intestine, so there is significant underutilization of the organ. Currently, only between 1.2% and 2.4% of deceased donors of at least one organ also yield intestine allografts annually. Reasons for lack of utilization of intestine donors include not obtaining consent, consent refused, and lack of standardized criteria for suitable deceased donor intestinal grafts (23). Much work in education has been done in promoting the recovery of this organ, and fostering better relationships with the local OPOs and surgeons. Local interest in an intestinal program also helps foster a higher intestinal recovery rate, and investigating other possible intestinal allografts from OPOs outside their region that may not be as attuned to the need.
Additionally, the intestine is one of the organs most sensitive to ischemia damage, and many factors may influence the organs suitability from any particular donor. Such factors include cause of death and any cardiovascular down time, use of vasopressors (in particular vasopressin), hypoxia, and electrolyte abnormalities such as severe hypernatremia. Communication between the donor OPO and the recipient intestinal program as to donor management strategies to optimize the intestinal allograft is vital, although there may arise conflicting strategies with other organ team (in particular lung teams who like the patient to be relatively “dry” and use pressors that may be disadvantageous to the intestinal allograft). Also, it is important that other transplant teams be aware of the ability to use the intestine and still make the isolated pancreas a viable option, and occasional technical issues with the modified multivisceral allograft (where sharing of vasculature is necessary). Close working communication between the donor surgeons and their recipient teams is essential to a smooth and successful donor procurement. Interposition vessel sharing can also be an important issue when multiple organs are being recovered; hence, availability and use of the carotid artery and jugular veins may be needed.
Previously the cytomegalovirus (CMV) status of donor and recipient had been considered to be an important negative factor in a CMV +ve donor to CMV −ve recipient, and many programs refrain from this combination. With better CMV monitoring (using CMV polymerase chain reaction) and preemptive therapy and use of cytogam, this has become less of an issue, making more donors available to the intestinal recipients.
Relative size matching of donor and recipient still is an important issue, as previous experiences with reduced bowels have not always been favorable. Blood group matching (identical, not just compatible) is also preferred. Both of these factors further restrict donor options, making it even more vital that all potential donors from around the country at least be considered where possible. Intraoperative recovery factors that need to be considered include need for antibiotic bowel prep, donor pretreatment with lymphocyte depleting agents (which other recovery teams may not favor) and type of infusion solutions (UW vs. HTK).
The effect of a positive crossmatch is also a potential issue, especially with more emphasis being placed on humoral rejection, hence the importance of a positive B-cell crossmatch. Some programs consider running a crossmatch ahead of time and avoiding those which are positive. Time restrictions do not always allow this to be feasible or practical. More recently, “virtual” crossmatches have been run, especially in cases of retransplant or sensitized patients, to help decide on the likelihood of suitability even before recovery.
Although there is a growing trend in other organ types to use an expanded pool such as declaration after cardiac death donors, these have not been deemed suitable to intestinal recipients due to concern of organ quality, hence, the importance of optimizing use of “standard” donors.
A recent analysis investigating rates of potential underutilization of donor intestine allografts was recently reported. OPTN data from donors of at least one organ using the following criteria: age younger than 50 years, terminal aspartate aminotransferase and alanine aminotransferase less than 500, terminal sodium less than 170 meq/L, age specific serum creatinine, hepatitis and human immunodeficiency virus serology negative, two inotropes or less at time of recovery, cardiac arrest (if occurred) less than 15 min, and donation after brain death. In 2008, more than one third of the donors met the selection criteria yet more than 86% of these donors did not include recovery of the intestine (23). As described in this section, multiple factors are involved in optimizing intestine utilization; however, data suggest that improvements in intestine recovery and allocation can be made.
In the end, after reviewing all the available donor data, the intestine is an organ that requires intraoperative assessment by a surgeon experienced in its recovery, as implantation of a suboptimal allograft may well set up the recipient for significant reperfusion injury and a posttransplant course fraught with increased complications in what is already a challenging form of transplantation. The recovery operation may be lengthier than other transplant procedures and cooperation between the various transplant teams is essential.
Patient Selection, Long-Term Outcomes and Reporting, Immunosuppressive Strategies
Appropriate patient selection for intestinal transplantation involves a keen understanding of the benefits and risks of prolonged TPN, intestinal transplantation and individualizing operative choices to patient need. Long-term results with TPN have recently been published (25) and coupled with consensus expert opinion on optimal guidelines for intestine transplantation (26, 27) can inform clinical decision making. Surgical options include isolated intestine, liver and intestine replacement, and stomach containing allografts in cases of dysmotility syndromes such as chronic intestinal pseudo-obstruction. In selected infants with a history of enteral tolerance whose liver decompensation has overwhelmed the patient's capacity for enteral adaptation, isolated liver transplantation may be an appropriate therapeutic option (28).
Review of the current outcomes reported by the ITR (29) and updated by Grant highlighted progress with early to intermediate outcomes after intestine transplantation (Fig. 1a). Between 1985 and May 2009, more than 1236 pediatric intestine transplants have been performed with more than 500 survivors. The conditions leading to transplant are comprised primarily of surgical loss of the intestine (volvulus 15%, gastroschisis 24%, necrotizing enterocolitis 16%, and intestinal atresia 9%) with motility disorders, primary mucosal diseases, and retransplantation comprising 14%, 10%, and 5% of the remaining indications, respectively. Despite improvement in 5 year outcomes over the past 25 years, conditional 5-year survival has not improved (Fig. 1b) with intestine recipients overall being as likely to do well for 5 years in 2003 as in 1998 if they survived the initial transplant year. Data demonstrating the protective effect of the liver on graft survival also corroborates single center data demonstrating reduced incidence of chronic rejection (CR) in liver containing allografts (30). These findings, and data from the SRTR underscore the need for further improvement in minimizing long-term patient morbidities such as infection, posttransplant lymphoproliferative disorder (31), renal failure, and impacting on sources of graft loss such as CR by improvement of immune monitoring techniques. An initial step will be to improve or optimize current registry efforts (ITR and SRTR) by improving the data elements that are pediatric specific (infectious disease, growth, development, nutritional, and quality-of-life measures) and gather data to gauge immune risk (impact of sensitization) and improve data capture of significant posttransplant morbidity.
Immunosuppression strategies used in intestine transplantation were also reviewed. In the pretransplant phase, donor pretreatment with rATG, ATGAM, or OKT3 has not been well studied. OPTN data demonstrate induction protocols with antilymphocyte therapies such as rabbit antilymphocyte globulin (rATG, thymoglobulin, Genzyme Corp., Cambridge, MA) or interleukin-2 receptor antagonists such as basiliximab (Simulect, Novartis, Basel, Switzerland) being associated with improvements in survival and reduction in acute rejection episodes as compared with noninduction therapy regimens. Tacrolimus therapy remains the standard baseline immunosuppressant used in intestine transplantation; at discharge 98.8% of intestine recipients were on tacrolimus, 24% on mycophenolate mofetil, and 78.4% on steroids. Maintenance at 1 year posttransplant consisted of steroids in 68.3%, antimetabolite use in 10.1%, sirolimus use in 6.5% while 68.3% of patients remained on prednisone (Table 1.9a, Immunosuppression Use by Organ in 2007 and 2008, OPTN/SRTR data as of May 4, 2009).
Despite the improved short-term outcome in intestinal transplant graft survival, a number of speakers highlighted that 5 to 10 year graft survival remains at 40% to 60%. Dependence on robust immune suppression in children with intestinal allografts with the concomitant predictable side effects has highlighted the need for more specific immunosuppressive strategies with diminished long-term dependence on calcineurin inhibitors and corticosteroids.
Suzanne Ilstad reviewed the progress in tolerance induction in organ transplants. The emerging role of a bone marrow cell termed the “facilitating cell” in improving the engraftment rates of stem cells after stem-cell transplants and diminishing the severity of graft versus host disease was highlighted. Future therapies aimed at induction of tolerance in intestinal transplant recipients and reducing or eliminating dependence on potentially toxic drugs may hinge on exploiting the role of the facilitating cell after tolerogenic induction strategies in children who receive intestinal grafts.
Immunologic and Histologic Monitoring of the Intestine Transplant Recipient
Monitoring of intestine transplant recipients is based on parameters that are associated with, or can predict acute cellular rejection (ACR) and CR, successful engraftment, or response to immunosuppression. Guerra et al. from Georgetown emphasized the importance of the Crohn's disease (CD)-associated single nucleotide polymorphisms in identifying rejection-prone ITx recipients as reported previously from their group (32). In 99 pediatric intestine transplant (ITx) recipients at Pittsburgh, the CD-associated single nucleotide polymorphisms were primarily associated with intestinal failure, which evolved to liver failure and combined liver-ITx, and with rejection and septic death only in this population. No association was found in isolated ITx (33). Traditional immune monitoring methods based on detection of anti-donor antibodies such as, crossmatch and PRA, seemed relatively insensitive and were associated with less than 20% of ACR episodes in 103 pediatric ITx from Pittsburgh (34). However, data from Miami and the Pittsburgh group found donor-specific anti-human leukocyte antigen antibodies (DSA) measured with single antigen bead arrays in two thirds of ACR episodes after ITx among pediatric recipients. Measured on a relative scale with mean fluorescence intensity as the unit, DSA declined as rejection episodes resolved. Interestingly, pre- and post-ITx measurements of cellular donor- specific alloreactivity with allospecific CD154+T-cytotoxic memory cells and allospecific CD154+B cells predicted ACR with sensitivities and specificities of 70% to 90% in pediatric ITx recipients from Pittsburgh (35, 36). The reporting unit for these tests is the immunoreactivity index, or the ratio of donor-specific to third-party alloresponse. An immunoreactivity index more than 1 predicts ACR. The dynamic nature and sensitivity of DSA and allospecific CD154+T-cytotoxic memory cells and CD154+B cells suggests their potential utility in clinical immune monitoring after ITx.
A multivariate analysis of 106 ITx in 88 recipients by Farmer et al. (37) from UCLA identified a strong association between DSA and graft loss. Similar findings were reported from 163 adult ITx recipients from Pittsburgh, in whom graft loss was also associated with nonspecific anti-human leukocyte antigen antibodies.
The diagnostic and prognostic issues related to the tissue-based biopsy visualization of the antibody mediated rejection (AMR) process remain to be defined in the transplanted intestine. The NIH Conference in 2003 (38) defined four stages of AMR, of which the highest, stage IV, is defined by a combination of tissue pathology and graft dysfunction. Experience is greater with allograft kidney and heart biopsy. Use of a panel of six antibodies on fixed and frozen tissue has led to the claim that AMR is present in a high proportion, 54%, of cardiac recipients (39). This cumbersome and technically challenging procedure on mucosal bowel biopsies is unlikely to become standard and the Pittsburgh group illustrated that the combination of immune deposition (C4d), endothelial activation or damage, intravascular response (platelet/fibrin thrombi) and intravascular cells (neutrophils, macrophages) correlates well with the presence of circulating antibodies even in the absence of “graft dysfunction.” The implication for prognosis of lower grades of AMR in the biopsy remains to be determined.
Collectively, these presentations suggested that DSA may contribute to a coordinated cellular and humoral anti-donor alloresponse during ACR, and to CR (Fig. 2). Because a significant proportion of ITx rejection episodes recur or are steroid resistant, and T-cell depletion is the mainstay of refractory rejection management, several attendees expressed interest in early use of novel regimens for AMR during ACR. It was concluded that clear guidelines to integrate immunologic and histologic findings must be defined to improve the management of ITx rejection. Furthermore, the implications of improved immune monitoring were also discussed in terms of impacting the major determinants of long-term outcome. Allograft loss or dysfunction from CR and nonallograft morbidities such as the aforementioned morbidities of renal failure, posttransplant lymphoproliferative disorder, diabetes, and hypertension remain fundamental long-term opportunities for improvement that will be impacted by reproducible predictors of rejection risk or allograft tolerance.
Success with management of the pediatric intestinal failure patient with both long-term parenteral nutritional management and improving early- to intermediate-term results with intestine transplantation are changing the paradigm for care of these patients. Indications, optimal timing for referral and improving long-term outcomes are coming under increasing focus and scrutiny. Management by multidisciplinary teams with pediatric gastroenterology, pediatric surgery, transplant, and immunology experience is critical to ongoing success.
The 6th International Pediatric Intestinal Failure and Rehabilitation Symposium was cosponsored by the Children's Hospital of UPMC Pittsburgh, PA, and the Children's Memorial Hospital, Chicago, IL.
Children's Hospital of Pittsburgh faculty included Kareem Abu-Elmagd, MD; Geoffrey Bond, MD, FACS; R. Cartland Burns, MD; Mike Green, MD, MPH; Roy Hill; Ron Jaffe, MBBCh; Beverly Kosmach Park, DNP; George Mazariegos, MD, FACS; Marsha Odille, RN; Jeffrey Rudolph, MD; Rakesh Sindhi, MD; Robert Squires, MD; Sharon Strohm, MBA, RD, LDN; Raman Venkataramanan, PhD, FCP; Jane Anne Yaworski, MSN, RN. Children's Memorial Faculty included Hardik Bhagat, PharmD; Valeria Cohran, MD; Jonathan Fryer, MD; Courtney Hillyard, BS, CCLS; Wendy Kazlusky; Stanley Kim, MD; Barbara McCormick, RN; Ryan Mitchell; Kathryn Pilarski, RN, BSN, CPN; Renee Shores; Lisa Sorensen, PhD; Riccardo Superina, MD; Jessica Zimont, APN; Carmyn Zoller, RD, CSP. Additional expert faculty and affiliation listed alphabetically included Jane Balint, MD (Nationwide Children's Hospital, Columbus, OH); Enrico Benedetti, MD, FACS (University of Chicago, Chicago, IL); Glendon Burress, MD (Children's Medical Center, Rockford, IL); Carlo Di Lorenzo, MD (Nationwide Children's Hospital, Columbus, OH); Andrew Ellenwood, RN, BSN, CPTC (Indiana Organ Procurement Organization, Inc., Indianapolis, IN); Doug Farmer, MD (UCLA Medical Center Los Angeles, CA); Tom Fishbein, MD (Georgetown University Transplant Surgery, Washington, DC); David Grant, MD (Toronto General Hospital, Toronto, ON); Tracy Grikscheit, MD (Children's Hospital of Los Angeles, Los Angeles, CA); Simon Horslen, MB, ChB (Seattle Children's Hospital, Seattle, WA); Suzanne Ildstad, MD (University of Louisville, Louisville, KY); Tomoaki Kato, MD (Columbia University, New York, NY); Heung Bae Kim, MD (Children's Hospital Boston, Boston, MA); Sam Kocoshis, MD (Cincinnati Children's Hospital, Cincinnati, OH); Florence Lacaille, MD (Hospital Necker-Enfants Malades, Paris, France); Alan Langnas, DO (Nebraska Medical Center, Omaha, NE); John Magee, MD (University of Michigan Health System, Ann Arbor, MI); Richard Noel, MD, PhD (Medical College of Wisconsin, Milwaukee, WI); Jorge Reyes, MD (University of Washington, Seattle, WA); Debra Sudan, MD (Duke University, Durham, NC); Kelly Tappenden, PhD, RD (University of Illinois at Urbana-Champaign, Urbana, IL); Andres Tzakis, MD, PhD (University of Miami Miller School of Medicine, Miami, FL); Christina Valentine, MD (Nationwide Children's Hospital, Columbus, OH); Brad Warner, MD (Washington University School of Medicine, St. Louis, MO).
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