C. Matsumoto

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.

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.

Predicting Liver Failure in Parenteral Nutrition-Dependent Short Bowel Syndrome of Infancy

OBJECTIVES To test the hypothesis that early trends in common blood tests may delineate risks of liver failure (LF) in infants with parenteral nutrition-associated liver disease (PNALD) from short bowel syndrome and suggest criteria for transplant referral. STUDY DESIGN Total levels of bilirubin, gamma-glutamyl transferase, albumin, alanine aminotransferase, platelet count, and absolute neutrophil count were recorded every 3 months for 61 infants with PNALD who were being considered for intestinal transplant starting at age 3 months until death without transplant (n = 12), LF with transplant (n = 35), or liver recovery without transplant (n = 14). Probabilities of LF were determined with logistic regression. RESULTS Independent predictors of LF were, in descending order, total bilirubin level (odds ratio [OR] = 1.195), platelet count (OR = 0.992), and albumin level (OR = 0.248). Predicted probabilities of eventual LF varied from 36% to 38% at ages 3 to 6 months when the total bilirubin level was 6.0 mg/dL, platelet count was 220 x 10(3)/microL, and albumin level was 3.5 g/dL to 83% to 84% when the total bilirubin level was 11.7 mg/dL, platelet count was 168 x 10(3)/microL, and albumin level was 3.0 g/dL. CONCLUSIONS Transplant referral for a total bilirubin level of 6 mg/dL between 3 to 6 months of age is appropriate, because the probability of LF is at least 36%.

Successful isolated intestinal transplantation in sensitized recipients with the use of virtual crossmatching.

We evaluated virtual crossmatching (VXM) for organ allocation and immunologic risk reduction in sensitized isolated intestinal transplantation recipients. All isolated intestine transplants performed at our institution from 2008 to 2011 were included in this study. Allograft allocation in sensitized recipients was based on the results of a VXM, in which the donor‐specific antibody (DSA) was prospectively evaluated with the use of single‐antigen assays. A total of 42 isolated intestine transplants (13 pediatric and 29 adult) were performed during this time period, with a median follow‐up of 20 months (6–40 months). A sensitized (PRA ≥ 20%) group (n = 15) was compared to a control (PRA < 20%) group (n = 27) to evaluate the efficacy of VXM. With the use of VXM, 80% (12/15) of the sensitized patients were transplanted with a negative or weakly positive flow‐cytometry crossmatch and 86.7% (13/15) with zero or only low‐titer (≤1:16) DSA. Outcomes were comparable between sensitized and control recipients, including 1‐year freedom from rejection (53.3% and 66.7% respectively, p = 0.367), 1‐year patient survival (73.3% and 88.9% respectively, p = 0.197) and 1‐year graft survival (66.7% and 85.2% respectively, p = 0.167). In conclusion, a VXM strategy to optimize organ allocation enables sensitized patients to successfully undergo isolated intestinal transplantation with acceptable short‐term outcomes.

Liver allograft outcomes after laparoscopic-assisted and minimal access live donor hepatectomy for transplantation

BACKGROUND The critical shortage of deceased organ donors has led to live-donor hepatectomy as an alternative donor option for transplantation. Although laparoscopic hepatectomy has been well described for management of liver tumors and can be performed safely, few studies have examined early recipient allograft outcomes after laparoscopic live-donor hepatectomy. We describe our initial experience with laparoscopic-assisted and minimal-access donor hepatectomy and its potential as a safe alternative with graft function comparable with open resection in live-donor liver transplantation. METHODS We performed a retrospective analysis of our past 30 successive live-donor transplants between 2005 and 2009. Fifteen allografts were procured by standard open live-donor (OLD) hepatectomy, and 15 by laparoscopic-assisted (LALD) or minimal-access (MA) live-donor hepatectomy. Left lateral segment grafts were subcategorized and analyzed further. RESULTS Mean donor age, sex, and liver anatomy were comparable between donor groups. Early graft function as measured by peak total bilirubin level, aspartate aminotransferase level, alanine aminotransferase level, and international normalized ratio on postoperative days 2, 7, 30, and 90 were similar between groups, although the international normalized ratio was slightly more increased on postoperative day 7 in LALD grafts (1.75 ± .45 vs 1.28 ± .16; P = .02). Perioperative allograft biliary (2 of 15 vs 0 of 15; P = .48) and vascular (3 of 15 vs 1 of 15; P = .6) complication rates also were comparable between OLD and LALD/MA grafts. One-year graft and patient survival for LALD/MA was 100% compared with 93% for OLD. CONCLUSIONS Our experience shows that LALD or MA live-donor hepatectomy is a safe procedure and produces early graft function comparable with standard OLD hepatectomy. Multicenter, larger-volume experience will determine the widespread application of this technique.

Hepatic Explant Pathology of Pediatric Intestinal Transplant Recipients Previously Treated with Omega-3 Fatty Acid Lipid Emulsion

OBJECTIVE To evaluate and compare the biochemical and histologic effect of parenteral fish oil lipid emulsion that is rich in omega-3 polyunsaturated fatty acids (O3FAs), Omegaven (Fresenius Kabi AG, Bad Homburg, Germany) with standard omega-6 polyunsaturated fatty acid (O6FA) parenteral nutrition. STUDY DESIGN Comparison of hepatic explant pathology and biochemical outcome on pediatric patients with intestinal failure treated with either parental O3FA or O6FA who had received a liver-inclusive intestine transplant. RESULTS Seven liver-inclusive intestinal transplants were performed in 7 patients who received O3FA for a mean of 62% ± 13% of total patient life-span (16.1 ± 7.0 months) before transplant. Median total bilirubin fell from 6.9 mg/dL at the start of treatment to 0.7 mg/dL at the time transplant (P < .02), which was a significant decrease compared with the similarly matched O6FA cohort (P = .012). All 7 of the 03FA-treated patients received a liver-inclusive intestinal transplant had advanced fibrosis (stage 3 or 4) noted on explant pathologic examination, despite a resolution of cholestasis at the time of transplant. Histologic inflammatory scores were lower (P = .056) in the 03FA group with similar degrees of advanced fibrosis as in the O6FA group. CONCLUSIONS In a matched comparison of patients undergoing intestinal transplantation with a history of extended O3FA lipid emulsion therapy that successfully reversed hyperbilirubinemia, significant hepatic fibrosis was present in the explanted livers despite a reduction in inflammation. This result confirms concern that the use of O3FA may have a limited role in altering the development of hepatic fibrosis from parenteral nutrition.

Metabolomics of human intestinal transplant rejection.

Surveillance endoscopy with biopsy is the standard method to monitor intestinal transplant recipients but it is invasive, costly and prone to sampling error. Early noninvasive biomarkers of intestinal rejection are needed. In this pilot study we applied metabolomics to characterize the metabolomic profile of intestinal allograft rejection. Fifty‐six samples of ileostomy fluid or stool from 11 rejection and 45 nonrejection episodes were analyzed by ultraperformance liquid chromatography in conjunction with Quadrupole time‐of‐flight mass spectrometry (UPLC‐QTOFMS). The data were acquired in duplicate for each sample in positive ionization mode and preprocessed using XCMS (Scripps) followed by multivariate data analysis. We detected a total of 2541 metabolites in the positive ionization mode (mass 50–850 Daltons). A significant interclass separation was found between rejection and nonrejection. The proinflammatory mediator leukotriene E4 was the metabolite with the highest fold change in the rejection group compared to nonrejection. Water‐soluble vitamins B2, B5, B6, and taurocholate were also detected with high fold change in rejection. The metabolomic profile of rejection was more heterogeneous than nonrejection. Although larger studies are needed, metabolomics appears to be a promising tool to characterize the pathophysiologic mechanisms involved in intestinal allograft rejection and potentially to identify noninvasive biomarkers.

Pediatric intestinal and multivisceral transplantation : a new challenge for the pediatric intensivist

IntroductionWith increasing survival rates, intestinal transplantation (ITx) and multivisceral transplantation have reached the mainstream of medical care. Pediatric candidates for ITx often suffer from severe multisystem impairments that pose challenges to the medical team. These patients frequently require intensive care preoperatively and have unique intensive care needs postoperatively.MethodsWe reviewed the literature on intensive care of pediatric intestinal transplantation as well as our own experience. This review is not aimed only at pediatric intensivists from ITx centers; these patients frequently require ICU care at other institutions.ResultsPreoperative management focuses on optimization of organ function, minimizing ventilator-induced lung injury, preventing excessive edema yet maintaining adequate organ perfusion, preventing and controlling sepsis and bleeding from varices at enterocutaneous interfaces, and optimizing nutritional support. The goal is to extend life in stable condition to the point of transplantation. Postoperative care focuses on optimizing perfusion of the mesenteric circulation by maintaining intravascular volume, minimizing hypercoagulability, and providing adequate oxygen delivery. Careful monitoring of the stoma and its output and correction of electrolyte imbalances that may require renal replacement therapy is critical, as are monitoring for and aggressively treating infections, which often present with only subtle clinical clues. Signs of intestinal rejection may be non-specific, and early differentiation from other causes of intestinal dysfunction is important. Understanding of the expanding armamentarium of immunosuppressive agents and their side-effects is required.Conclusions As outcomes of ITx improve, transplant teams accept patients with higher pre-operative morbidity and at higher risk for complications. Many ITx patients would benefit from earlier referral for transplant evaluation before severe liver disease, recurrent central venous catheter-related sepsis and venous thromboses develop.

Liver Transplantation in the Management of Hepatic Epithelioid Hemangioendothelioma: A Single-Center Experience and Review of the Literature

Hepatic epitheliod hemangioendothelioma (HEHE) is a rare tumor of vascular origin with unpredictable malignant potential. We describe our experience with four biopsy-proven HEHE cases that were considered for orthotopic liver transplant (OLT). Three patients had preserved hepatic function and despite extensive disease burden did not develop disease progression while awaiting OLT. We were able to utilize the review process allowed by United Network of Organ Sharing to obtain additional priority for OLT for these patients. This led to expedited organ allocation and excellent post-OLT outcomes.

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.