Thomas M. Fishbein

2003 Report of the Intestine Transplant Registry: A New Era Has Dawned

Summary Background Data:The intestine has been more difficult to transplant than other solid organs. We analyzed registry data to determine the scope and success of intestine transplantation in the current era. Methods:All known intestinal-transplant programs participated. Patient- and graft-survival estimates were obtained using the Kaplan-Meier product limit method and were analyzed with the Wilcoxon statistic. Results:Sixty-one programs provided data on 989 grafts in 923 patients. Four patients were lost to follow-up. The short-gut syndrome was the most common primary indication for transplantation. Sixty-one percent of the recipients were ≤18 years. Proportionally more combined intestinal and liver transplants were performed in this group. More than 80% of all current survivors had stopped parenteral nutrition and resumed normal daily activities. A multivariate analysis of cases within the last 5 years revealed that transplantation of patients waiting at home, recipient age, antibody induction immune suppression, and center experience with at least 10 cases were associated with improved patient survival. One-year graft survival rates of 81% were achieved in patients who were induced with antithymocyte globulin and maintained on tacrolimus. Conclusions:Transplantation is an effective therapy for the treatment of patients with end-stage intestine failure who cannot tolerate parenteral nutrition. With newer immune suppressive protocols, 1-year graft and patient survival rates approach the results of liver transplantation. Further improvement in survival are expected with early referral since suitable donor organs are scarce and survival rates are better when patients are well enough to wait at home for their transplant.

Human gut microbiome adopts an alternative state following small bowel transplantation

Small bowel transplants provide an exceptional opportunity for long-term study of the microbial ecology of the human small bowel. The ileostomy created at time of transplant for ongoing monitoring of the allograft provides access to samples of ileal effluent and mucosal biopsies. In this study, we used qPCR to assay the bacterial population of the small bowel lumen of 17 small bowel transplant patients over time. Surprisingly, the posttransplant microbial community was found to be dominated by Lactobacilli and Enterobacteria, both typically facultative anaerobes. This represents an inversion of the normal community that is dominated instead by the strictly anaerobic Bacteroides and Clostridia. We found this inverted community also in patients with ileostomies who did not receive a transplant, suggesting that the ileostomy itself is the primary ecological determinant shaping the microbiota. After surgical closure of the ileostomy, the community reverted to the normal structure. Therefore, we hypothesized that the ileostomy allows oxygen into the otherwise anaerobic distal ileum, thus driving the transition from one microbial community structure to another. Supporting this hypothesis, metabolomic profiling of both communities demonstrated an enrichment for metabolites associated with aerobic respiration in samples from patients with open ileostomies. Viewed from an ecological perspective, the two communities constitute alternative stable states of the human ileum. That the small bowel appears to function normally despite these dramatic shifts suggests that its ecological resilience is greater than previously realized.

Intestinal transplant registry report: global activity and trends.

The Registry has gathered information on intestine transplantation (IT) since 1985. During this time, individual centers have reported progress but small case volumes potentially limit the generalizability of this information. The present study was undertaken to examine recent global IT activity. Activity was assessed with descriptive statistics, Kaplan–Meier survival curves and a multiple variable analysis. Eighty‐two programs reported 2887 transplants in 2699 patients. Regional practices and outcomes are now similar worldwide. Current actuarial patient survival rates are 76%, 56% and 43% at 1, 5 and 10 years, respectively. Rates of graft loss beyond 1 year have not improved. Grafts that included a colon segment had better function. Waiting at home for IT, the use of induction immune‐suppression therapy, inclusion of a liver component and maintenance therapy with rapamycin were associated with better graft survival. Outcomes of IT have modestly improved over the past decade. Case volumes have recently declined. Identifying the root reasons for late graft loss is difficult due to the low case volumes at most centers. The high participation rate in the Registry provides unique opportunities to study these issues.

NOD2-expressing bone marrow-derived cells appear to regulate epithelial innate immunity of the transplanted human small intestine

Background: Intestinal allograft rejection resembles Crohn’s disease clinically and pathologically. An understanding of its mechanism could impact this life-saving procedure, as well as provide insight into the pathophysiology of inflammatory bowel disease. The NOD2 protein has been implicated as a key player in intestinal immune health, as a consequence of the discovery of three polymorphisms linked with Crohn’s disease. An investigation was carried out to determine whether epithelial immune function and graft survival were influenced by NOD2 mutations in an intestinal transplant population. Methods: The NOD2 genotypes of 34 transplants performed consecutively over the past 3 years were determined. The NOD2 genotypes were related to clinical outcomes and the expression of certain intestinal antimicrobial peptides (AMPs) believed to protect the epithelium. Results: An unexpectedly high percentage of recipients, 35%, possessed NOD2 polymorphisms, while 8.6% of donors had comparable mutations. The likelihood of allograft failure was about 100-fold higher in recipients with mutant NOD2 alleles compared with recipients with wild-type NOD2 loci. Rejection in NOD2 mutant recipients was characterised by decreased expression of certain Paneth cell and enterocyte AMPs, prior to the onset of epithelial injury and inflammation. Conclusions: Crohn’s disease-associated polymorphisms in the NOD2 gene in the recipient represent a critical immunological risk factor for intestinal allograft rejection. Compromised epithelial defences precede visible epithelial injury and inflammatory infiltration. The association of impaired epithelial immunity with the recipient’s genotype suggests that certain NOD2-expressing cells of haematopoietic origin play a role in the process, perhaps by regulating expression of certain epithelial AMPs within the allograft.

Parenteral nutrition associated liver disease

Liver disease is relatively common during parenteral nutrition (PN). Cholestasis predominates in infants, and ranges in severity from mild increases in plasma conjugated bilirubin to progressive liver failure that results in death of the patient. Severity of liver disease depends primarily on the magnitude of the underlying intestinal problem that indicated PN. Transient ileus resulting from a non-intestinal disorder usually results in trivial, self-limited liver injury. Removal of a large segment of the intestinal tract because of necrotizing enterocolitis or a congenital malformation predicts a more prolonged course with a guarded prognosis, particularly when initially complicated by sepsis. Pathogenesis of PN-associated liver disease is not completely understood. There is no proven treatment short of ending PN through adaptation of remnant intestine or intestinal transplantation, with or without a concurrent liver graft. Effective interventions that are less radical than transplantation are needed. Research that includes prospective trials of novel therapies in PN-associated liver disease is the key to improving outcome.

Transforming growth factor-β suppresses nonmetastatic colon cancer through smad4 and adaptor protein ELF at an early stage of tumorigenesis

Although transforming growth factor-beta (TGF-beta) is both a suppressor and promoter of tumorigenesis, its contribution to early tumor suppression and staging remains largely unknown. In search of the mechanism of early tumor suppression, we identified the adaptor protein ELF, a beta-spectrin from stem/progenitor cells committed to foregut lineage. ELF activates and modulates Smad4 activation of TGF-beta to confer cell polarity, to maintain cell architecture, and to inhibit epithelial-to-mesenchymal transition. Analysis of development of colon cancer in (adult) elf+/-/Smad4+/-, elf+/-, Smad4+/-, and gut epithelial cells from elf-/- mutant mouse embryos pinpoints the defect to hyperplasia/adenoma transition. Further analysis of the role of ELF in human colorectal cancer confirms reduced expression of ELF in Dukes B1 stage tissues (P < 0.05) and of Smad4 in advanced colon cancers (P < 0.05). This study indicates that by modulating Smad 4, ELF has a key role in TGF-beta signaling in the suppression of early colon cancer.

Liver and intestine transplantation: summary analysis, 1994–2003

With nearly two years of data available since the inception of the MELD and PELD allocation system, this article examines national OPTN/SRTR data to describe trends in waiting list composition, waiting list mortality, transplant rates, and patient and graft outcomes for liver transplantation.

The Value of Plasma Citrulline to Predict Mucosal Injury in Intestinal Allografts

Diagnosis of intestinal transplant rejection depends on clinical assessment, endoscopy and most importantly, histology of intestinal biopsies. Plasma citrulline levels (P‐Cit) reflect functional enterocyte mass in nontransplant patients and have been evaluated in two small series after transplant. This study was designed to determine the sensitivity and specificity of P‐Cit as diagnostic tool for allograft injury, especially to distinguish between viral enteritis and rejection. We prospectively collected 403 P‐Cit samples within 24 h of intestinal biopsy in 49 patients. P‐Cit levels were correlated with the mucosal damage and histopathological diagnoses. P‐Cit levels in bowels with significant mucosal damage (i.e. moderate or severe rejection, viral enteritis, PTLD, ischemia reperfusion injury, allergic enteritis) were significantly lower than in intestines with no or mild injury (i.e. indeterminate or mild rejection, nonspecific enteritis): 22.9 ± 15.4 versus 38 ± 23.2 nmol/mL (p < 0.0001). Sensitivity and specificity of the test were 80% and 58.1% for rejection, and 56.5% and 66% for viral enteritis, thereby unable to distinguish between both entities. In conclusion, P‐Cit reflects the extent of mucosal injury regardless of the etiology, but does not seem to be a predictive marker for rejection or viral enteritis, as its values may decline only when diffuse mucosal damage has occurred.

Utilization of Donors Who have Suffered Cardiopulmonary Arrest and Resuscitation in Intestinal Transplantation

Background. Cardiopulmonary resuscitation (CPR) of a person destined to become an organ donor has been associated with overall poor donor quality, especially for the intestinal donor, as splanchnic vasoconstriction that is intended to preserve coronary and cerebral blood flow may result in clinically relevant intestinal ischemia. Outcomes of recipients who receive intestine grafts that have suffered CPR are unknown. We sought to analyze our clinical experience in using intestinal grafts from donors who suffered cardiopulmonary arrest and resuscitation and to evaluate the outcome of recipients of organs coming from resuscitated donors when compared with recipients of nonresuscitated donors. Methods. We retrospectively analyzed the donor and recipient charts of all of our intestinal transplants with regard to the performance of donor CPR. Results. Sixty-seven intestinal transplants were performed in 65 patients from November 2003 to December 2007. Twelve donors (18%) were identified as having suffered cardiac arrest and subsequent CPR. Mean duration of CPR was 19.3±12.7 min. Terminal laboratory profiles of CPR donors and non-CPR donors were similar. Of the 12 resuscitated grafts, two were used for multivisceral, one for a modified multivisceral, seven for liver–intestine, and two for isolated intestinal transplant. There were no significant differences in outcome parameters such as operative time, blood use, ventilation days, length of stay, time to enteral independence, rejection, enteric bacteremia, and survival between the 12 resuscitated grafts and the 55 nonresuscitated grafts. Conclusion. A donor history of cardiac arrest should not automatically exclude the use of the intestine graft for transplantation.

Sirolimus for solid organ transplantation in children

Abstract:u2002 Sirolimus represents a major advancement in the field of solid organ transplantation and is being used as a rescue agent for acute and chronic rejection as well as for primary immunosuppression with good graft outcome. Although initial studies with sirolimus were in adults, now significant data have accumulated on the role of sirolimus in pediatric solid organ transplantation. This article reviews the current status of sirolimus in pediatric transplantation.