Recent advances and future prospects in intestinal and multi-visceral transplantation

From an experimental procedure, intestinal transplantation (ITx) has evolved over the last 10 yr into a treatment option for patients suffering from short bowel syndrome and who develop life-threatening complications from total parenteral nutrition (TPN) (e.g. liver dysfunction, line sepsis, shortage of venous access, etc.). One-year survival rates are approximately 70% and thus similar to lung Tx. However, the intestine remains the most challenging abdominal organ to transplant. This is because of the severe immune response (mostly rejection) that is produced, and therefore the need for profound immunosuppression with its attendant complications (sepsis, lymphoma, direct drug toxicity). Unlike other organs, graft loss as a result of acute rejection can occur late after transplantation (more than 1 yr post-transplant). With regard to the actual immunosuppressive regimens, considerable experience in patient management is required to optimize outcome of those complex transplants, which are permanently at risk of rejection and infection. ITx remains an unfinished product, and the application of ITx to patients doing well on TPN warrants further research in the understanding of the rejection process, in the development of less toxic and more efficient immunosuppressive protocols, and in the development of immunomodulatory strategies, to better control rejection and thereby reduce the need for immunosuppression.     

Exfoliative rejection after intestinal transplantation in children

Background: Graft rejection is the most significant cause of allograft failure after intestinal transplantation (ITx). Severity can vary and is based on histologic criteria, the most extreme form being exfoliation of the mucosa. We present the characteristics and outcome of children who developed exfoliative rejection (ER) after ITx. Methods: Between June 1990 and March 2002, 88 patients received 92 ITx which included isolated small bowel (SB, n = 26), combined liver-small bowel (LSB, n = 54), and multivisceral MV n = 12) allografts performed under tacrolimus and steroid immunosuppresson. ER was diagnosed by endoscopy and confirmed by biopsy. Results: Thirteen (15%) of 88 patients developed 15 episodes of ER in 15 intestinal allografts, and included SB (n = 8), LSB (n = 5), and MV (n = 2). Time to ER after ITx ranged from 9 days to 45.5 months (median 22 days). Eight episodes of ER developed within 1 month after ITx. Ten episodes of ER were exacerbations of prior rejection. Five episodes occurred abruptly. All but one received OKT3. Fourteen of 15 allografts were lost; six patients underwent allograft enterectomy acutely as a salvage operation because of ER. The remainder of the allografts were either removed or lost to patient death as a consequence to infection or chronic rejection after resolution of ER. Retransplantation was performed in three patients, with subsequent recurrence of ER in two retransplanted allografts. Inclusion of a liver allograft was a protective factor toward decreasing the incidence of ER. The results of cross-matching, inclusion of a colonic segment, and simultaneous bone marrow infusion did not affect the incidence of ER. Infectious complications included post-transplant lymphoproliferative disease (n = 4), cytomegalovirus (n = 5), and adenovirus infection (n = 2). Conclusions: Exfoliative rejection is associated with a high morbidity and mortality after ITx. Strategies to improve survival may include up front anti-lymphocyte antibody therapy and, when fail to respond promptly and satisfactorily, early intestinal allograft removal.     

Indications for pediatric intestinal transplantation: a position paper of the American Society of Transplantation

Parenteral nutrition represents standard therapy for children with short bowel syndrome and other causes of intestinal failure. Most infants with short bowel syndrome eventually wean from parenteral nutrition, and most of those who do not wean tolerate parenteral nutrition for protracted periods. However, a subset of children with intestinal failure remaining dependent on parenteral nutrition will develop life-threatening complications arising from therapy. Intestinal transplantation (Tx) can now be recommended for this select group. Life-threatening complications warranting consideration of intestinal Tx include parenteral nutrition-associated liver disease, recurrent sepsis, and threatened loss of central venous access. Because a critical shortage of donor organs exists, waiting times for intestinal Tx are prolonged. Therefore, it is essential that children with life-threatening complications of intestinal failure and parenteral nutrition therapy be identified comparatively early, i.e. in time to receive suitable donor organs before they become critically ill. Children with liver dysfunction should be considered for isolated intestinal Tx before irreversible, advanced bridging fibrosis or cirrhosis supervenes, for which a combined liver and intestinal transplant is necessary. Irreversible liver disease is suggested by hyperbilirubinemia persisting beyond 3-4 months of age combined with features of portal hypertension such as splenomegaly, thrombocytopenia, or prominent superficial abdominal veins; esophageal varices, ascites, and impaired synthetic function are not always present. Death resulting from complications of liver failure is especially common during the wait for a combined liver and intestinal transplant, and survival following combined liver and intestinal Tx is probably lower than following an isolated intestinal transplant. The incidence of morbidity and mortality following intestinal Tx is greater than that following liver or kidney Tx, but long-term survival following intestinal Tx is now at least 50-60%. It is probable that outcomes shall improve in the future with continued refinements in operative technique and post-operative management, including immunosuppression.     

Current issues in the management of intestinal failure

Successful long term parenteral nutrition has transformed the prognosis for children with irreversible intestinal failure in the last three decades, but has also highlighted the long term complications: intestinal failure associated liver disease; recurrent catheter sepsis; and impaired venous access. Recent advances in small bowel transplantation and non-transplant surgical techniques now offer hope of sustained survival in the future without parenteral nutrition.     

Pediatric intestinal transplantation: historical notes,principles and controversies

The development in technique and immunosuppressive management of the last 12 yr have made intestinal transplantation an effective treatment for children with intestinal failure. The information provided in this review support such a conclusion, but was more clearly validated by the March 2001 Medicare Report which provided a national coverage decision of the Social Security Act for intestinal transplantation. As of May 2001, there were 55 centers world-wide which have performed 696 intestinal transplants in 656 patients. (Intestinal Transplant Registry, http://www.lhsc.on.ca/itr) the majority of recipients have been children, and there has been a greater need for liver replacement in conjunction with the allograft intestine because of a higher incidence of TPN-induced cholestatic liver disease in children. Though overall long-term survival is approximately 50%, similar advances in surgical, clinical and immunosuppressive management since 1995 have improved patient survival to more than 70% in most experienced programs. Over 80% of survivors are enjoying nutrition-supporting intestinal function. The major causes of graft loss and patient demise continues to be rejection and infection. Tacrolimus remains the mainstay of immunosuppressive therapy. Further experience other induction protocols utilizing rapamycin and daclizumab, as well graft pretreatment protocols may further enhance results in the future.     

Pediatric kidney transplantation and mortality: Distance to transplant center matters

Distance from pediatric kidney transplant centers may be a significant barrier in accessing care for patients and families, particularly due to the lower number of pediatric kidney transplant centers compared with the number of adult centers. We performed a retrospective cohort study using data from the Scientific Registry of Transplant Recipients to determine the effect of distance on pediatric kidney transplant waitlist outcomes. We found that distance did not play a role in the likelihood of transplantations for patients who were placed on the waitlist. However, living a greater distance from the transplant center was associated with a greater risk of death while on the waitlist. Larger volume centers attracted patients from greater distances, many of whom had other centers closer to their home. Further investigation on the role of distance to transplant center and the likelihood of being evaluated and listed for a kidney transplant would elucidate whether there are additional barriers these patients face.     

Isolated intestinal transplantation for megacystis microcolon intestinal hypoperistalsis syndrome: Case report

MMIHS is a rare congenital disease. It is characterized by distended urinary bladder, small colon and intestinal hypoperistalsis, or aperistalsis with normal morphology. There is no specific treatment for MMIHS, and most patients have to be maintained by TPN, which frequently causes TPN‐related liver failure, loss of venous access, or catheter‐related sepsis. The prognosis of patients with MMIHS is poor, and most patients die early. Multivisceral transplantation including stomach, duodenum, intestine, and liver has been used for the treatment of patients with MMIHS because these patients often have liver failure. We report an eight‐yr‐old patient with MMIHS who was treated with isolated intestinal transplantation. She had completely oral intake during the four yr of follow‐up. The experience in this case suggests isolated intestinal transplantation may be indicated in selected cases with MMIHS.     

Pediatric en bloc kidney transplantation into pediatric recipients: the French experience

Chronic shortage of available donor organs has led to re-evaluation of the use of en bloc kidney transplants. Although excellent results have been reported in adult patients, experience in pediatric patients remains limited because of potential early complications and poor long-term graft outcome. We report 14 pediatric en bloc renal transplantations into 14 pediatric recipients, performed between 1990 and 2007 in France. We retrospectively analyzed demographic data, postoperative complications, and graft function with a median follow-up of five yr. Donor age ranged from four to 54 months. Complications were vascular graft thrombosis in four patients, leading to graft loss in two cases, and to excellent long-term graft function in the two others. Two hemorrhagic complications resulted in death in one case and in graft loss in the other. Six acute rejection episodes occurred in four patients. Median glomerular filtration rate at three months, one, five, and 10 yr was 90.8, 106, 87.8, and 66.1 mL/1.73 m(2) /min. We believe that en bloc transplantation may be an option for children with end-stage kidney disease.     

The use of bi‐planar tissue expanders to augment abdominal domain in a pediatric intestinal transplant recipient

Intestinal transplantation is a well‐accepted treatment for SBS. However, patients with SBS often have decreased abdominal capacity, which makes size‐matching of donor organs more difficult, thus decreasing organ availability. Reported approaches for addressing this problem include surgically reducing the graft size, leaving an open abdomen for a prolonged period, and cotransplanting rectus fascia as a non‐vascularized allograft. Each approach has significant disadvantages. There has been one previous report of tissue expanders used intra‐abdominally and two reports of subcutaneous use to increase intra‐abdominal capacity prior to transplantation. We report the first use of bi‐planar expander placement for this purpose. In our case, a two‐yr‐old male child with SBS due to malrotation was treated with tissue expanders 10 months prior to intestinal transplantation, thus allowing transplantation of a larger graft with the ability to close the abdomen safely. There were no complications, and the patient is now doing well and tolerating diet off PN. The use of tissue expanders prior to intestinal transplantation is a promising approach for such patients and avoids the morbidity associated with other approaches. This approach requires a multidisciplinary effort by gastroenterology, transplant surgery, and plastic surgery teams.     

Enteric Adenovirus Infection in Pediatric Small Bowel Transplant Recipients

Three of 70 small bowel transplant recipients were diagnosed with adenovirus enteritis. The biopsies were performed for surveillance in one patient at 2.7 years after transplantation and in two symptomatic children 1.5 years and 4.5 months after transplantation. In all three patients the characteristic epithelial changes were not noted by the primary observers. Two biopsies had been called “suggestive of acute rejection” and both patients had been so treated. One biopsy had been diagnosed as “regenerative”. Once the epithelial changes were recognized as being viral, confirmation was possible by stool culture in one patient, immunohistochemistry in two patients, or by lift technique of the H&E sections for electron microscopy. The immune suppression was reduced and none of the patients developed disseminated infection. As in other transplanted organs, such as lung and liver, adenovirus infection may be limited largely to the allograft but can be destructive. Early recognition of the characteristic changes that are illustrated can lead to confirmation of the virus and appropriate reduction of immune suppression. A mistaken diagnosis of rejection and augmentation of immune suppression can lead to viral dissemination and potential fatality. Received January 19, 2000; accepted April 17, 2000.     

Addressing extreme size mismatch in pediatric intestinal transplantation: Outcomes of intestinal length reduction

Background

Bench liver reduction, with or without intestinal length reduction (LR) (coupled with delayed closure and abdominal wall prostheses), has been a strategy adopted by our program for small children due to the limited availability of size-matched donors. This report describes the short, medium, and long-term outcomes of this graft reduction strategy.

Methods

A single-center, retrospective analysis of children that underwent intestinal transplantation (April 1993 to December 2020) was performed. Patients were grouped according to whether they received an intestinal graft of full length (FL) or following LR.

Results

Overall, 105 intestinal transplants were performed. The LR group (n = 10) was younger (14.5 months vs. 40.0 months, p = .012) and smaller (8.7 kg vs. 13.0 kg, p = .032) compared to the FL group (n = 95). Similar abdominal closure rates were achieved after LR, without any increase in abdominal compartment syndrome (1/10 vs. 7/95, p = .806). The 90-day graft and patient survival were similar (9/10, 90% vs. 83/95, 86%; p = .810). Medium and long-term graft survival at 1 year (8/10, 80% vs. 65/90, 71%; p = .599), and 5 years (5/10, 50% vs. 42/84, 50%; p = 1.00) was similar.

Conclusion

LR of intestinal grafts appears to be a safe strategy for infants and small children requiring intestinal transplantation. This technique should be considered in the situation of significant size mismatch of intestine containing grafts.     

Studies of Pediatric Liver Transplantation 2002: patient and graft survival and rejection in pediatric recipients of a first liver transplant in the United States and Canada

Studies of Pediatric Liver Transplantation (SPLIT) is a cooperative research network comprising 38 pediatric liver transplant centers in North America. Data from the 1092 patients who have received a first liver transplant since 1995 were analyzed for factors influencing patient survival, graft survival and acute rejection. The 3, 12, 24 and 36 month Kaplan-Meier estimates of patient/graft survival were 90.9/85.5, 86.3/80.2, 84.3/76.0, and 83.8/75.3% respectively. Univariate analysis identified initial diagnosis, type of graft (whole vs. living and cadaveric technical variant), growth failure and continuous hospitalization or ICU admission prior to transplantation as significantly influencing patient and graft survival. Subsequent multivariate analysis identified as risk factors for death: fulminant liver failure (RR = 3.05, p < 0.05), cadaveric technical variant grafts (RR = 1.95, p < 0.05), continuous hospitalization pre-transplant (RR = 1.79, p < 0.05), height deficit >2 s.d. from mean (RR = 3.22, p < 0.05). Risk factors for graft loss included: fulminant liver failure (RR = 2.27, p < 0.05), cadaveric technical variant grafts, (RR = 1.97, p < 0.05). Eleven percent of the 1092 patients were re-transplanted; vascular complications, particularly hepatic artery thrombosis (8.3% overall; 36.3% of graft failures), were responsible for the majority of re-transplants. Infection was the single most important cause of death (40 of 141, 28.4%) and was a contributing cause in 55 (39%), particularly with bacterial or fungal organisms. The cumulative Kaplan-Meier estimates of first rejection at 3, 12, 24 and 36 months were 44.8, 52.9, 59.1, and 60.3%. Initial immunosuppression with tacrolimus reduced the probability of rejection (RR = 0.62, p < 0.05). Eleven percent of rejections were steroid-resistant; chronic rejection led to 7 of 121 (5.8%) re-transplants. The SPLIT registry, in compiling data from a large number of centers, reflects the current outcomes for pediatric liver transplants in North America.     

Liver and intestinal transplantation in a child with cystic fibrosis: a case report

Cystic fibrosis (CF) is an inherited disorder that presents as a multisystem disease with meconium ileus being the presenting symptom in 20% of patients. Approximately half of these patients present with complicated meconium ileus mandating early surgical intervention, potentially resulting in short gut syndrome. Although liver transplantation in children with CF has been described, this is the first report of a combined liver and small bowel transplant in a recipient with CF. A 7-month-old boy with CF presented with short bowel syndrome following extensive small bowel resection for meconium ileus and progressive cholestatic liver failure from intravenous hyperalimentation. He underwent combined liver and small intestinal transplant. He was discharged home three weeks post-transplant on enteral feeds with supplemental intravenous fluid. He has had routine protocol small bowel allograft biopsies with no documented rejection episodes. He has been treated for minor respiratory infections without major sequelae. Improvements in pulmonary therapy have impacted on the survival in the CF population to the point where the need for multiorgan transplantation will be increased in the future. Extrapolating from the excellent experience of liver transplantation in children with CF, early liver and small intestinal multivisceral transplantation, if indicated, can be performed safely in children with CF.     

Post‐transplant lymphoproliferative disorder in pediatric intestinal transplant recipients: A literature review

Intestinal transplantation is a successful treatment for children with intestinal failure, but has many potential complications. PTLD, a clinically and histologically diverse malignancy, occurs frequently after intestinal transplantation and can be fatal. The management of this disease is particularly challenging. The rejection‐prone intestinal allograft requires high levels of immunosuppression, a precondition for PTLD. While EBV infection clearly plays a role in disease pathogenesis, the relatively naïve immune system of children is another likely contributor. As a result, pediatric intestine recipients have a higher risk of developing PTLD than other solid organ recipients. Other risk factors for disease development such as molecular and genomic changes that precipitate malignant transformation are not fully understood, especially among children. Studies on adults have started to describe the molecular pathogenesis of PTLD, but the genomic landscape of the malignancy remains largely undefined in pediatric intestinal transplant patients. In this review, we describe what is known about PTLD in pediatric patients after intestinal transplant and highlight current knowledge gaps to better direct future investigations in the pediatric population.     

Chronic rejection with sclerosing peritonitis following pediatric intestinal transplantation

Intestinal transplantation is considered the usual treatment for patients with permanent intestinal failure when parenteral nutrition has failed. Chronic rejection is a complication difficult to diagnose because of the scarcity and lack of specificity in the symptoms and the characteristics of typical histological findings. We report the case of a four-yr-old patient who received an isolated intestinal transplant. After developing a chronic rejection he presented an intestinal obstruction secondary to a sclerosing peritonitis that required the surgical removal of the graft.     

Pediatric post‐transplant metabolic syndrome: New clouds on the horizon

Liver transplantation (LT) is a standard treatment for children with end‐stage liver disease, standing at more than 90% survival rate after one yr, and at over a 70% survival rate after five yr. The majority of transplanted children enjoy an excellent quality of life but complications can occur in the long term, and can develop subclinically in otherwise well children; there are various underestimated nutritional and metabolic aspects, including the so‐called post‐transplant metabolic syndrome (PTMS). During the post‐transplant period, the use of immunosuppressants, corticosteroids, calcineurin inhibitors, and the presence of risk factors, including non‐alcoholic fatty liver disease (NAFLD), and kidney and bone complications have been largely implicated in PTMS development. Strategies to reduce the progression of PMTS should include careful screening of patients for diabetes, dyslipidemia, and obesity, and to support weight reduction with a carefully constructed program, particularly based on diet modification and exercise. With early identification and appropriate and aggressive management, excellent long‐term health outcomes and acceptable graft survival can be achieved.     

Better renal function with enhanced immunosuppression and protocol biopsies after kidney transplantation in children

Subclinical rejection may be associated with decreased graft function after renal transplantation (Tx). Detection by protocol biopsies and treatment could thus be important for the long-term prognosis. We have earlier discovered that glomerular filtration rate (GFR) declined in young children during the first 18 months. Consequently, we slightly enhanced and individualized each patient's immunosuppression. This was a retrospective study of 59 pediatric renal Tx patients between 1995 and 2001. The 35 historical controls received triple-therapy of azathioprine, methylprednisolone and cyclosporine. GFR was measured by protocol at discharge, 6 and 18 months, and a core biopsy was obtained at 18 months. The 24 study patients in addition received basiliximab, had GFR measured at 3 and 12 months, and a biopsy taken at 3 months. Based on histology and function, immunosuppression was individually adjusted. The groups were compared for GFR and histology at 18 months after Tx. There were less acute rejection episodes in the study group (0.38 vs. 1.23 per patient) and serum creatinine concentrations were lower. Subclinical rejection was detected and treated in 39% at 3 months. There were more chronic changes in the control (47%) than in the study group (29%) at 18 months. GFR was significantly higher in the study group at 18 months (87 vs. 68 mL/min/1.73 m(2)), most remarkably in patients < or =2 yr of age (99 vs. 68 mL/min/1.73 m(2)). Detection of subclinical rejection and slightly enhanced and individualized immunosuppression improved GFR 18 months after renal Tx, especially in the youngest patients.     

Sclerosing peritonitis after intestinal transplantation in children

Long-term graft dysfunction and/or graft loss after intestinal transplantation (ITx) is a significant concern. Sclerosing peritonitis (SP) is a manifestation of chronic allograft failure and its presence may also include classic arterial obliterative arteriopathy (OA) as in chronic rejection. We describe the clinical presentation and management of SP occurring after ITx in children. Case records of 121 children undergoing ITx from 1990 to 2003 were reviewed. Three children (2.4%) presented with SP of the intestine allograft at a mean time of 6.6 yr following ITx as follows: age at Tx (yr) 8.2, and 3.7, with indication for ITx being gastroschisis in two and midgut volvulus in one patient. Type of ITx was isolated intestine in one and liver/intestine in two patients. Gross findings of SP included fibrosis/strictures; microscopically SP showed fibrosis/serositis, and fibrous adhesions; one patient had evidence of chronic allograft vasculopathy. All patients presented with clinical signs and symptoms of bowel obstruction and gastrointestinal contrast studies confirmed distal ileal obstruction (DIO). Operative findings confirmed SP and DIO in all patients; all patients were initially treated with distal segmental intestine allograft resection and lysis of the fibrous peel. All three patients recovered, although two required repeat laparotomy, there is only one long-term survival. SP after ITx may be a different manifestation of long-term intestine allograft degeneration. Surgical resection appears to offer palliation.     

A systematic review of immunosuppressant adherence interventions in transplant recipients: Decoding the streetlight effect

Non‐adherence to immunosuppressant medications is an important risk factor for graft dysfunction. To evaluate the effectiveness of adherence‐enhancing interventions, we reviewed adherence intervention studies in solid organ transplant recipients (all ages). Using the following databases: PsycINFO, PubMed, Scopus, and ScienceDirect, we identified 41 eligible studies. Only three non‐randomized trials showed a possible positive effect on objective indicators of transplant outcomes (such as rejection, liver enzyme levels, kidney function). None of the 21 RCTs showed an improvement in transplant outcomes. Three studies showed a higher rate of adverse events in the intervention group as compared with controls, although this may be related to ascertainment bias. Improvement in adherence as measured indirectly (eg, with electronic monitoring devices) was not aligned with effects on transplant outcomes. We conclude that adherence interventions, to date, have largely been ineffective in improving transplant outcomes. To improve this track record, intervention efforts may wish to concentrate on non‐adherent patients (rather than use convenience sampling, which excludes many of the patients who need the intervention), use direct measures of adherence to guide the interventions, and employ strategies that are intensive and yet engaging enough to ensure that non‐adherent patients are able to participate.