Nutrition support considerations in pediatric small bowel transplantation.

Enteral autonomy is the primary goal of intestinal failure therapy. Intestinal transplantation (ITx) is an option when enteral autonomy cannot be achieved and management complications become life-threatening. The purpose of this review is to summarize existing medical literature related to nutrition requirements, nutrition status, and nutrition support after pediatric ITx. Achieving or maintaining adequate growth after intestinal transplant in children can be challenging because of episodes of rejection that require the use of corticosteroids, occurrences of infection that require a reduction or discontinuation of enteral or parenteral support, and fat malabsorption caused by impaired lymphatic circulation. Nutrient requirements should be assessed and modified regularly based on nutrition status, growth, ventilatory status, wound healing, and the presence of complications. Parenteral nutrition (PN) should be initiated as a continuous infusion early postoperatively. Enteral support should be initiated after evidence of graft bowel function and in the absence of clinical complications. Foods high in simple carbohydrates should be limited, as consumption may result in osmotic diarrhea. Short-term use of a fat-free diet followed by a low-fat diet may reduce the risk of the development of chylous ascites. Micronutrient deficiencies and food allergies are common occurrences after pediatric ITx. Enteral/oral vitamin and mineral supplementation may be required after PN is weaned. Nutrition management of children after ITx can be challenging for all members of the healthcare team. Anthropometric parameters and micronutrient status should be monitored regularly so that interventions to promote growth and prevent or reverse nutrient deficiencies can be implemented promptly.

The parallel paradigm between intestinal transplant inflammation and inflammatory bowel disease.

PURPOSE OF REVIEW: A significant shift in our understanding of the molecular and cellular basis for inflammatory bowel disease (IBD) mirrors research that has been ongoing in intestinal transplantation. The blurring of lines between these two disease states creates an avenue into potential therapeutic interventions which take advantage of these molecular similarities. RECENT FINDINGS: Traditional knowledge of T-cell involvement in IBD has expanded to highlight the role of T helper 17 (Th17) cells as key effector cells. A similar role has been demonstrated in cellular rejection of intestinal allografts. Genetic polymorphism related to the propagation and function of Th17 cells has been found to confer significant risk of developing autoimmune conditions. Interleukin-23, a cytokine identified as crucial to the expansion of Th17 cells, has become a validated molecular target in psoriatic arthritis and IBD, and could become a target for intestinal transplant therapies. SUMMARY: Intestinal transplant rejection and IBD share a similar phenotype, especially as it relates to key effector cells and gene polymorphisms. Improvements in our understanding of the immune-pathogenesis of IBD, as well as molecular targeting exploiting that knowledge, provide a potential route to improve outcomes for intestinal transplant patients.

Long-term results of intestinal transplantation in children: survival after 10 years, intestinal function, quality of life.

PURPOSE OF REVIEW: The review aims to describe in detail contemporary medical, nutritional, and psychosocial results in pediatric intestinal transplant (ITx) recipients greater than 10 years removed from their transplant, and to highlight significant long-term post-ITx challenges and complications. The review will draw from recent publications in the field, the ITx registry as well as detailed unpublished data from a large, well established single center. RECENT FINDINGS: The majority of long-term ITx survivors are off parenteral nutrition altogether, but a significant number require supplemental tube feeds to gain weight and grow properly. A number of micronutrient deficiencies are observed in long-term follow-up. Renal insufficiency and posttransplant lymphoproliferative disorder are the most concerning long-term complications. Many require special education, and in certain domains some report lower health related quality of life. SUMMARY: For children more than 10 years out from ITx, growth and weight gain are sustained; oral aversion and dependence on supplemental tube feeds remain prevalent issues. Most recipients are successfully managed with frequent outpatient visits and multiple daily medications. Post-transplant lymphoproliferative disorder and chronic kidney disease are long-term concerns. Though many children require special education, most are high functioning and report good health-related quality of life.

Index Use of Smoflipid in a Tertiary Intestinal Rehabilitation and Transplantation Program.

Long-term parenteral nutrition (PN) may be complicated by PN-associated liver disease (PNALD), and some studies suggest an association between the use of soy-based fat emulsions and PNALD development. Patients' liver function typically improves and PNALD resolves after reducing or stopping a soy-based fat emulsion, and thus lipid minimization has been the primary strategy for managing PNALD in many intestinal rehabilitation programs. However, fat emulsions often cannot be stopped entirely, leading some patients to develop PNALD even after lipid reduction strategies have been implemented. Smoflipid emulsion (Kabi-Fresenius, Bad Homburg, Germany), a balanced mixture of soybean oil, medium-chain triglycerides (MCTs), olive oil, and fish oil, was recently approved by the Food and Drug Administration for use in the United States as an equivalent alternative to Intralipid (Baxter Healthcare Corporation, Deerfield, IL). In several pediatric studies, patients who received Smoflipid had significantly lower serum bilirubin levels than those who received Intralipid. In this case report, we present a patient who developed severe PNALD with subsequent resolution after 20 weeks on Smoflipid.

Redefining short bowel syndrome in the 21st century.

In 1968, Wilmore and Dudrick reported an infant sustained by parenteral nutrition (PN) providing a potential for survival for children with significant intestinal resections. Increasing usage of TPN over time led to some patients developing Intestinal Failure Associated Liver Disease (IFALD), a leading cause of death and indication for liver/intestinal transplant. Over time, multidisciplinary teams called Intestinal Rehabilitation Programs (IRPs) began providing meticulous and innovative management. Usage of alternative lipid emulsions and lipid minimization strategies have resulted in the decline of IFALD and an increase in long-term and transplant-free survival, even in the setting of ultrashort bowel (< 20 cm). Autologous bowel reconstructive surgeries, such as the serial tapering enteroplasty procedure, have increased the likelihood of achieving enteral autonomy. Since 2007, the number of pediatric intestinal transplants performed has sharply declined and likely attributed to the newer innovations healthcare. Recent data support the need for changes in the listing criteria for intestinal transplantation given the overall improvement in outcomes. Over the last 50 y, the diagnosis of short bowel syndrome has changed from a death sentence to one of hope with a vast improvement of quality of life and survival.

Luminal solutions protect mucosal barrier during extended preservation.

BACKGROUND: Mucosal barrier injury during intestinal preservation (IP) and transplantation favors life-threatening infections. Luminal delivery of solutions containing amino acids or polyethylene glycols (PEGs) may improve preservation results and reduce this injury. We tested if solutions containing glutamine and PEG influence the mucosal injury. MATERIALS AND METHODS: Rat intestines were perfused and stored in Viaspan-University of Wisconsin solution. Before IP, a PEG 3350 solution was introduced intraluminally alone (group 1) or supplemented with 40 mmol/L L-glutamine (group 2). Controls underwent vascular flush alone (group 3). Preservation injury was evaluated after 8, 14, and 24 h by histology and goblet cell count. Tight-junction proteins zonula occludens-1, claudin-3, claudin-4, and caveolin-1 were studied by immunofluorescence. Maltase and caspase-3 activity were also analyzed. RESULTS: Group 1 showed mild edema at 8 h and mucosal disruption by 24 h; these features were greatly improved in group 2 where continuous mucosa was found after 24 h of IP. Intestines in group 3 did worse at all time points with subepithelial edema (Park/Chiu grade 3) and marked goblet cell depletion; caspase-3 activity was lowest in group 2. Tight-junction proteins varied continuously during IP; zonula occludens-1 expression and colocalization with claudins decreased significantly in group 3 but not in other groups. Claudin-3 was distinctly localized in the membrane, but stained diffuse, cytoplasmic at later time-points. Claudin-4 changed to a cytoplasmic granular pattern. No caveolin-1 colocalization was observed. CONCLUSIONS: Luminal PEG and glutamine delay epithelial breakdown and preserve several important mucosal features during extended IP.

Micronutrient deficiencies in pediatric and young adult intestinal transplant patients.

Intestinal transplant recipients are at risk of micronutrient deficiency due to the slow process of post-transplant adaptation. Another contributing factor is calcineurin inhibitor-induced renal tubular dysfunction. Patients are typically supplemented with micronutrients during PN; however, the risk of deficiency may persist even after a successful transition to FEN. The goal was to determine the prevalence of, and associated risk factors for, iron, zinc, magnesium, phosphorus, selenium, copper, folate, and vitamins A, D, E, and B12 deficiency in pediatric intestinal transplant recipients after successful transition to FEN. A retrospective review of prospectively collected data from children who underwent intestinal transplantation at Cincinnati Children's Hospital Medical Center was done. Deficiencies of various micronutrients were defined using the hospital reference values. Twenty-one intestinal transplant recipients, aged one to 23 yr, who were successfully transitioned to FEN were included in the study. The prevalence of micronutrient deficiency was 95.2%. The common deficient micronutrients were iron (94.7%) and magnesium (90.5%). Age ≤ 10 yr (p = 0.002) and tube feeding (p = 0.02) were significant risk factors for micronutrient deficiencies. Pediatric intestinal transplant recipients have a high risk of micronutrient and mineral deficiencies. These deficiencies were more common among younger patients and those who received jejunal feeding.

Autologous gastrointestinal reconstructive surgery: complement or alternative to intestinal transplantation.

PURPOSE OF REVIEW: Autologous intestinal reconstructive surgery has evolved over the past 3 decades from rescue to main surgical procedure in the multidisciplinary approach to short bowel syndrome (SBS) patients with intestinal failure. The purpose of this review is to clarify the actual place of intestinal reconstructive surgical techniques in the management of intestinal failure related to SBS and their relationship with intestinal transplantation. RECENT FINDINGS: Recent reports from centers of excellence in intestinal rehabilitation underline the efficacy and safety of autologous intestinal reconstructive surgery in patients with SBS. Outcome parameters as survival, parenteral nutrition weaning, and clinical conditions were improved in SBS patients treated by gastrointestinal reconstructive surgery. SUMMARY: Autologous intestinal reconstructive procedures are pivotal to achieve enteral autonomy in patients with intestinal failure related to SBS. They should be considered mutually supportive and not antagonistic to intestinal transplantation.

Computed tomography (CT) colonography with CT arteriography and venography for the workup of intestinal transplant candidates.

Prior to intestinal transplantation, prospective candidates must undergo a series of radiologic examinations to address a variety of clinical issues. To date, little literature exists to guide physicians in this preoperative assessment. Multiple imaging studies can provide overlapping information. We have developed a simple two- or three-test protocol to streamline the workup. Sixteen adult patients presented as potential intestinal transplant candidates to Georgetown University Hospital. All but two patients underwent the full protocol of a biphasic IV contrast-enhanced computed tomography (CT) scan of the chest, abdomen, and pelvis with rectal carbon dioxide, an upper gastrointestinal study with small bowel follow through, and fistulogram when appropriate. Three-dimensional (3-D) reconstructions of the vascular anatomy as well as the colon were also generated. A telephone survey to other transplant centers was additionally conducted to compare radiographic evaluations. Overall, 15 of the 16 scans were diagnostic. One patient required a barium enema. Mean examinations per patient was 2.4. Only one of seven other centers was performing CT colonography in prospective intestinal transplant candidates. Our protocol provided all the necessary anatomic information needed to evaluate prospective transplant candidates. CT colonography with angiography is a suitable alternative to more time-consuming radiological studies.

Assessment of quality of life on home parenteral nutrition and after intestinal transplantation using treatment-specific questionnaires.

In order to investigate the quality of life on home parenteral nutrition and after intestinal transplantation using comparable questionnaires, the treatment-specific quality of life questionnaire for adult patients on home parenteral nutrition was adapted for intestinal transplant recipients. Both instruments were composed of 8 functional scales, 9 symptom scales, 3 global health status/quality of life scales and 2 single items. A preliminary cross-sectional study enrolling all the patients currently cared at the same hospital was carried out. Exclusion criteria were age ≥ 60 years and hospitalization at time of assessment. Thirty-three home parenteral nutrition patients (100% answered) and 22 intestinal transplant recipients (82% answered) were enrolled. Intestinal transplant recipients showed a better score in following scales: ability to holiday/travel (p < 0.001), fatigue (p = 0.022), gastrointestinal symptoms (p < 0.001), stoma management/bowel movements (p = 0.001) and global health status/quality of life (p = 0.012). A better score for ability to eat/drink (p = 0.070) and a worse score for sleep pattern (p = 0.100) after intestinal transplantation were also observed. The results of this preliminary study with specific instruments were consistent with the main expected improvement of the quality of life related to intestinal transplantation. Further studies in larger patient cohorts are required to confirm these data.

The reduction of allograft arteriosclerosis in intestinal transplant is associated with sphingosine kinase 1/sphingosine-1-phosphate signaling after fish oil treatment.

BACKGROUND: Transplant arteriosclerosis is a major cause of late intestinal allograft dysfunction. However, little is known about the immunologic and molecular mechanisms underlying it, and no effective treatment is available. This study aimed to investigate the role of sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) in transplant arteriosclerosis and find out whether fish oil (FO) attenuates allograft arteriosclerosis through S1P signaling. METHODS: A rat model with orthotopic intestinal transplantation was conducted in this study. Animals received daily FO supplementation after intestinal transplant. The allogeneic recipients by phosphate-buffered saline or corn oil treatment served as controls. The allograft arteriosclerosis was characterized, and the expression of SPHK1 and S1P receptors (S1P1, S1P2, and S1P3) was determined on day 190 posttransplant. RESULTS: The allogeneic controls presented transplant vasculopathy in mesenteric vessels, including intimal thickening, fibrosis, and leukocyte infiltration. The transplant arteriosclerosis was markedly reduced in FO-fed animals. The pression of SPHK1 and its activity were significantly augmented, and the expression of S1P1 and S1P3 messenger RNA was up-regulated in the allogeneic controls. FO supplementation suppressed the activation of SPHK1 and led to a decrease in the expression of S1P1 and S1P3 in these tissues in transplant arteriosclerosis. CONCLUSIONS: These results demonstrate that the activation of SPHK1/S1P signaling plays a possible role in the pathogenesis of transplant arteriosclerosis. The reduction of allograft arteriosclerosis by FO may be associated with down-regulation of SPHK1/S1P signaling. Understanding the role of FO for SPHK1/S1P may help us to identify considerable therapeutic targets for transplant arteriosclerosis.

Use of an omega-3 fatty acid-based emulsion in the treatment of parenteral nutrition-induced cholestasis in patients with microvillous inclusion disease.

Microvillous inclusion disease is a congenital intestinal epithelial cell disorder leading to lifelong intestinal failure. In this report, we discuss the use of a fish oil-based lipid emulsion in the treatment of 3 patients with microvillous inclusion disease who developed parenteral nutrition-associated liver disease.

Fish oil enhances recovery of intestinal microbiota and epithelial integrity in chronic rejection of intestinal transplant.

BACKGROUND: The intestinal chronic rejection (CR) is the major limitation to long-term survival of transplanted organs. This study aimed to investigate the interaction between intestinal microbiota and epithelial integrity in chronic rejection of intestinal transplantation, and to find out whether fish oil enhances recovery of intestinal microbiota and epithelial integrity. METHODS/PRINCIPAL FINDINGS: The luminal and mucosal microbiota composition of CR rats were characterized by DGGE analysis at 190 days after intestinal transplant. The specific bacterial species were determined by sequence analysis. Furthermore, changes in the localization of intestinal TJ proteins were examined by immunofluorescent staining. PCR-DGGE analysis revealed that gut microbiota in CR rats had a shift towards Escherichia coli, Bacteroides spp and Clostridium spp and a decrease in the abundance of Lactobacillales bacteria in the intestines. Fish oil supplementation could enhance the recovery of gut microbiota, showing a significant decrease of gut bacterial proportions of E. coli and Bacteroides spp and an increase of Lactobacillales spp. In addition, CR rats showed pronounced alteration of tight junction, depicted by marked changes in epithelial cell ultrastructure and redistribution of occuldin and claudins as well as disruption in TJ barrier function. Fish oil administration ameliorated disruption of epithelial integrity in CR, which was associated with an improvement of the mucosal structure leading to improved tight junctions. CONCLUSIONS/SIGNIFICANCE: Our study have presented novel evidence that fish oil is involved in the maintenance of epithelial TJ integrity and recovery of gut microbiota, which may have therapeutic potential against CR in intestinal transplantation.

The prevention and treatment of intestinal failure-associated liver disease in neonates and children.

Intestinal Failure Associated Liver Disease (IFALD) is a common and potentially life-threatening problem for pediatric patients receiving long-term parenteral nutrition (PN). Risk factors for IFALD include premature birth, low birth weight, long-term PN, intestinal stasis and sepsis. Preventative strategies are the cornerstone of improving outcomes in IFALD and include enteral feeding, weaning of PN, reduced dose lipid emulsions and the early recognition and treatment of sepsis. Recent work also demonstrates the efficacy of fish-oil based lipid emulsions in the prevention and treatment of IFALD. Transplantation is an option for end-stage liver disease but is associated with significant morbidity and mortality.

¿Hay novedades en el tratamiento del síndrome de intestino corto en el paciente pediátrico? Situación actual / Is there anything new in treating pediatric patients with short bowel syndrome? State of the art

El síndrome de intestino corto es una afección clínica poco frecuente, que origina un fallo intestinal prolongado o permanente en lactantes y niños. Hasta la disponibilidad del trasplante intestinal, muchos de estos niños requerían nutrición parenteral de forma prolongada o permanente. Sin embargo, en los últimos años se han desarrollado nuevas estrategias en el manejo de pacientes con síndrome de intestino corto. La creación de equipos multidisciplinarios compuestos por gastroenterólogos, cirujanos, nutricionistas, dietistas y enfermeras ha contribuido a mejorar los resultados en el tratamiento del fallo intestinal. Se han establecido criterios que permitan anticipar qué pacientes pueden llegar a alcanzar la adaptación intestinal. Junto con las medidas anteriores, se ha optimizado la forma en que se proporcionan tanto la nutrición parenteral (menor carga lipídica, uso de soluciones lipídicas con omega-3) como la nutrición enteral (empleo precoz, glutamina). También se dispone de fármacos, sobre todo factores de crecimiento, con resultados esperanzadores. Destacan fundamentalmente dos: la hormona del crecimiento y un análogo del péptido similar alglucagón tipo 2. Asimismo, el recurso a nuevos procedimientos de alargamiento intestinal (enteroplastia transversa seriada) o más clásicos (tipo Bianchi) ha contribuido a evitar, en casos seleccionados, el trasplante intestinal. Esta opción continúa siendo válida en los casos en que ninguna de las medidas anteriores funcione y se presenten complicaciones graves de la nutrición parenteral (AU)

Short bowel syndrome is an uncommon condition leading to prolonged or permanent intestinal failure in unweaned babies and children. Until intestinal transplantation is available, most of these children required a long-term parenteral nutrition. In the last few years’ new strategies have been developed for the management of short bowel syndrome patients. The implementation of multidisciplinary teams’ composed of(gastroenterologist, surgeon, nutritionist, dietician, nurse) has significantly improved the outcomes of the intestinal failure. Criteria to foresee which patients will achieve nutritional adaptation have been implemented. Beside these actions, there have been changes in the way parenteral nutrition (low fat, omega 3 fatty acids) as enteral nutrition (early use, glutamine) is provided. New medical treatments have been applied, mainly growth factors. Two of them stand out: growth hormone and an analogue of glucagonlikepeptide-2 have shown promising results. At the same time surgical small bowel lengthening procedures (Bianchi, STEPS) in well-selected cases help to avoid intestinal transplantation. If finally a severe complication of home parenteral nutrition appears and no further possibility exists, intestinal transplantation is a valuable option (AU)

Chronic kidney disease--a common and serious complication after intestinal transplantation.

BACKGROUND: Chronic kidney disease after organ transplantation is a serious complication that negatively impacts on long-term patient survival. We describe long-term renal function after intestinal transplantation by serial measurements of glomerular filtration rates (GFR) with Chromium EDTA clearance. MATERIALS AND METHODS: Ten patients with at least 6 months survival form the basis of this report. Glomerular filtration rate measurements were performed at baseline, 3 months posttransplantation, and yearly thereafter. Median follow-up time for the cohort was 1.5 years (0.5-7.8 years). Tacrolimus (Prograf) was discontinued in four patients because of impaired renal function. These four patients were switched to sirolimus (Rapamune) at 11, 18, 24, and 40 months posttransplantation. RESULTS: Median baseline GFR was 67 (22-114) mL/min/1.73 m. In the adult patients, GFR 3 months posttransplantation had decreased to 50% of the baseline. At 1 year, median GFR in the adult patients was reduced by 72% (n=5). Two patients developed renal failure within the first year and required hemodialysis. One of the pediatric patients fully recovered her renal function, the second pediatric patient lost 20% of her baseline GFR at 6 months posttransplantation. Glomerular filtration rate calculated with the modified diet in renal disease formula consistently overestimated GFR by approximately 30% compared with measured GFR. CONCLUSION: Chronic kidney disease and renal failure are common after intestinal transplantation. These two factors significantly contribute to poor long-term survival rates. Measurements of GFR may help to identify those individuals at risk for developing chronic kidney disease to implement renal sparing strategies.

Therapeutic efficacy of intestinal and multivisceral transplantation: survival and nutrition outcome.

The clinical introduction of intestinal transplantation has added a new dimension and offered a valid therapeutic option for patients with irreversible intestinal failure. In the year 2000, the Center for Medicare & Medicaid Services (CMS) recognized intestinal, combined liver-intestinal, and multivisceral transplantation as the standard of care for patients with irreversible intestinal and parenteral nutrition (PN) failure. Accordingly, the indications for the procedure are currently limited to those who develop life-threatening PN complications. However, a recent improvement in survival similar to other solid organ transplant recipients should justify lifting the current restricted criteria, and the procedure should be considered before the development of PN failure. Equally important is the awareness of the recent evolution in nutrition management and outcome after transplantation. Early and progressive enteral feeding using a complex polymeric formula is safe and effective after successful transplantation. Full nutrition autonomy is universally achievable among most intestinal and multivisceral recipients, with enjoyment of unrestricted oral diet. Such a therapeutic benefit is commonly maintained among long-term survivors, with full rehabilitation and restoration of quality of life.

Determinants of quality of life in home parenteral nutrition.

PURPOSE OF REVIEW: To highlight the most important and salient articles regarding home parenteral nutrition and quality of life published within the last 3 years. RECENT FINDINGS: In recent years, quality of life research in home parenteral nutrition has highlighted the need for a therapy-specific validated questionnaire. Several papers suggest a greater psychological input is required to better understand and evaluate this patient population. Issues surrounding the use of home parenteral nutrition in malignancy have arisen, prompting discussion on ideal timing and candidacy for home parenteral nutrition. Intestinal transplantation is evolving and improving, making it a possible alternative to home parenteral nutrition. Earlier referral is suggested as late referral can result in poorer outcome. SUMMARY: Home parenteral nutrition is a life-sustaining therapy for individuals with intestinal failure. There is now a relatively large amount of research into the quality of life in this population, but more focused measurements (in the form of validated therapy-specific questionnaires) are required to answer questions relating to cancer and intestinal transplantation.