Operational tolerance after intestine re-transplantation in childhood and immunological correlates. Case report and review.

BACKGROUND: Operational tolerance after retransplantation of the intestine has never been reported. PURPOSE: To two recently described intestine transplant recipients with operational tolerance, we now add a third. METHODS: Review of case record and immunological testing to confirm donor-specific hyporesponsiveness in multiple immune cell compartments. RESULTS: Re-transplanted with a multivisceral liver- and kidney-inclusive intestine allograft at age 12 years, this recipient self-discontinued immunosuppression 14 years after the retransplant and has been rejection free for 2 years thereafter. As in the two previous reports, immunological testing demonstrated decreased donor-specific inflammatory response of T-cytotoxic memory cells and B-cells, decreased presentation of donor antigen by B-cells and monocytes, absence of donor-specific anti-HLA antibodies, circulating FOXP3 + T-helper cells, and intact cellular and humoral immunity to cytomegalovirus and Epstein-Barr virus. Additionally, our recipient demonstrated enhanced donor-activation-induced apoptosis of alloreactive T-cytotoxic memory cells. CONCLUSIONS: Despite variable paths to tolerance which include graft versus host disease in two previous cases, and rejection-related loss of the primary isolated intestinal allograft in our recipient, the three cases with operational tolerance are bound by common themes: a relatively large donor antigenic load transmitted during intestine transplantation, and donor-specific hyporesponsiveness. Cell-based assays suggest enhanced donor-induced apoptosis of recipient T-cells and circulating T-regulatory cells as mechanistic links between antigenic load and donor-specific hyporesponsiveness.

Multidrug-resistant organisms: A significant cause of severe sepsis in pediatric intestinal and multi-visceral transplantation.

Severe sepsis in immunocompromised children is associated with increased mortality. This paper describes the epidemiology landscape, clinical acuity, and outcomes for severe sepsis in pediatric intestinal (ITx) and multi-visceral (MVTx) transplant recipients requiring admission to the pediatric intensive care unit (PICU). Severe sepsis episodes were retrospectively reviewed in 51 ITx and MVTx patients receiving organs between 2009 and 2015. Twenty-nine (56.8%) patients had at least one sepsis episode (total of 63 episodes) through December 2016. Bacterial etiologies accounted for 66.7% of all episodes (n = 42), occurring a median of 122.5 days following transplant (IQR 59-211.8 days). Multidrug-resistant organisms (MDROs) accounted for 73.8% of bacterial infections; extended spectrum beta-lactamase producers, vancomycin-resistant enterococcus, and highly-resistant Pseudomonas aeruginosa were the most commonly identified. Increased mechanical ventilation and vasoactive requirements were noted in MDRO episodes (OR 3.03, 95% CI 1.09-8.46 and OR 3.07, 95% CI 1.09-8.61, respectively; p < .05) compared to non-MDRO episodes. PICU length of stay was significantly increased for MDRO episodes (7 vs. 3 days, p = .02). Graft loss was 24.1% (n = 7) and mortality was 24.1% (n = 7) in patients who experienced severe sepsis. Further attention is needed for MDRO risk mitigation and modification of sepsis treatment guidelines to ensure MDRO coverage for this population.

Long-term outcomes of intestinal transplantation from donors aged under 1 year.

BACKGROUND: The aim of the study was to analyze the long-term outcomes of transplants utilizing ITx donors <1 year and to compare these results with older donors. METHODS: Between January 2007 and December 2019, the primary ITx donors in the Children's Hospital of Pittsburgh of UPMC were retrospectively reviewed. Short- and long-term outcomes of recipients receiving a deceased donor organ from donors <1 year were compared with those found in all other recipients. RESULTS: During the study period, there were 89 primary ITx donors, using 30 donors (33.7%) aged <1 year. The mean age of their recipients was 1.6 ± 0.7 (0.7-3.2) years. The 30 graft types were isolated intestine (n = 3, 10.0%), liver bowel (n = 20, 66.7%), and multivisceral (n = 7, 23.3%). Technical complications occurred in 12 (40.0%) recipients. Candidates transplanted with intestine allografts from donors <1 year of age had shorter wait times (p < .001), more liver-inclusive grafts (p < .001), and less donor-specific antibodies (DSA) (p = .014). During follow-up, the recipients had less graft loss (p = .018), and more remained alive with graft in place (p = .011). Among children transplanted with such donors, 3-year and graft survival rates were 86.7% and 82.9% compared to 62.8% and 49.9% in the cohort of donors >1 year (p = .032 and .011). CONCLUSIONS: Donor age <1 year was associated with improved graft survival. Optimal utilization of this population for toddler candidates would increase intestine availability, reduce time to transplantation, and potentially improve long-term outcome.

Twenty Years of Gut Transplantation for Chronic Intestinal Pseudo-obstruction: Technical Innovation, Long-term Outcome, Quality of Life, and Disease Recurrence.

OBJECTIVE: To define long-term outcome, predictors of survival, and risk of disease recurrence after gut transplantation (GT) in patients with chronic intestinal pseudo-obstruction (CIPO). BACKGROUND: GT has been increasingly used to rescue patients with CIPO with end-stage disease and home parenteral nutrition (HPN)-associated complications. However, long-term outcome including quality of life and risk of disease recurrence has yet to be fully defined. METHODS: Fifty-five patients with CIPO, 23 (42%) children and 32 (58%) adults, underwent GT and were prospectively studied. All patients suffered gut failure, received HPN, and experienced life-threatening complications. The 55 patients received 62 allografts; 43 (67%) liver-free and 19 (33%) liver-contained with 7 (13%) retransplants. Hindgut reconstruction was adopted in 1993 and preservation of native spleen was introduced in 1999. Immunosuppression was tacrolimus-based with antilymphocyte recipient pretreatment in 41 (75%). RESULTS: Patient survival was 89% at 1 year and 69% at 5 years with respective graft survival of 87% and 56%. Retransplantation was successful in 86%. Adults experienced better patient (P = 0.23) and graft (P = 0.08) survival with lower incidence of post-transplant lymphoproliferative disorder (P = 0.09) and graft versus host disease (P = 0.002). Antilymphocyte pretreatment improved overall patient (P = 0.005) and graft (P = 0.069) survival. The initially restored nutritional autonomy was sustainable in 23 (70%) of 33 long-term survivors with improved quality of life. The remaining 10 recipients required reinstitution of HPN due to allograft enterectomy (n = 3) or gut dysfunction (n = 7). Disease recurrence was highly suspected in 4 (7%) recipients. CONCLUSIONS: GT is life-saving for patients with end-stage CIPO and HPN-associated complications. Long-term survival is achievable with better quality of life and low risk of disease recurrence.

Metabolic Control and "Ideal" Outcomes in Liver Transplantation for Maple Syrup Urine Disease.

OBJECTIVES: To assess outcomes following liver transplantation for maple syrup urine disease by determining attainment and sustainability of metabolic control and apply an "ideal" outcome composite in long-term survivors. STUDY DESIGN: A single center, retrospective review collected clinical data including branched-chain amino acid (leucine, isoleucine, and valine) levels following liver transplant and determined achievement of an ideal long-term outcome profile of a first allograft stable on immunosuppression monotherapy, normal growth, and absence of common transplant-related sequelae. RESULTS: Of 77 patients meeting inclusion criteria identified, 23 were long-term (≥10-year) survivors and were additionally assessed for ideal outcome attainment. Patient and graft survival were 100% and 99%, respectively, and all patients were on an unrestricted protein intake diet. Although significant variation was noted in mean isoleucine (P < .01) and leucine (P < .05) levels postliver transplantation, no difference was seen in valine (P = .29) and overall clinical impact was likely negligible as metabolic stability was achieved and sustained beyond 3 years postliver transplantation and no metabolic crises were identified. Of 23 long-term survivors with available data, 9 (39%) achieved all composite metrics determined to define "ideal" outcomes in pediatric postliver transplantation populations. CONCLUSIONS: Liver transplant enables long-term metabolic stability for patients with maple syrup urine disease. A combination of experience and improvement in both pre- and postliver transplantation care has enabled excellent survival and minimal comorbidities following transplant.

Megacystis Microcolon Intestinal Hypoperistalsis Syndrome: A Case Series With Long-term Follow-up and Prolonged Survival.

OBJECTIVES: Describe clinical characteristics, management, and outcome in a cohort of megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) patients. METHODS: We conducted a retrospective chart review of MMIHS patients followed at a large transplant and intestinal rehabilitation center over a period of 17 years. RESULTS: We identified 25 patients with MMIHS (68% girls, 13 transplanted). One transplanted and 1 nontransplanted patient were lost to follow-up. We estimated 100, 100, and 86% for 5-, 10-, and 20-year survival, respectively, with only 1 death. Of the 22 patients alive at the time of study (11 transplanted, 11 nontransplanted), median age was 9.2 years (range 2.7-22.9 years). Longest posttransplant follow-up was 16 years. Seventeen patients had available prenatal imaging reports; all showed distended bladder. Eight had genetic testing (5, ACTG2; 2, MYH11; 1, MYL9). Almost all patients had normal growth with median weight z-score -0.77 (interquartile range -1.39 to 0.26), height z score -1.2 (-2.04 to -0.48) and body mass index z-score 0.23 (-0.37 to 0.93) with no statistical difference between transplanted and nontransplanted patients. All nontransplanted patients were on parenteral nutrition with minimal/no feeds, and all except 1 of the transplanted patients were on full enteral feeds. Recent average bilirubin, INR, albumin, and creatinine fell within the reference ranges. CONCLUSIONS: This is the largest single-center case series with the longest duration of follow-up for MMIHS patients. In the current era of improved intestinal rehabilitation and transplantation, MMIHS patients have excellent outcomes in survival, growth, and liver function. This observation contradicts previous reports and should alter counselling and management decisions in these patients at diagnosis.

Induction regimens and post-transplantation lymphoproliferative disorder after pediatric intestinal transplantation: Single-center experience.

Pediatric recipients of intestinal transplants have a high incidence of PTLD, but the impact of specific induction immunosuppression agents is unclear. In this single-center retrospective review from 2000 to 2017, we describe the incidence, characteristics, and outcomes of PTLD after primary intestinal transplantation in 173 children with or without liver, after induction with rATG, alemtuzumab, or anti-IL-2R agents. Thirty cases of PTLD occurred among 28 children, 28 EBV+ and 2 EBV-. Although not statistically significant, the PTLD incidence was higher after isolated intestinal transplant compared with liver-inclusive allograft (19.3% vs 13.3%, P = .393) and after induction with anti-IL-2R antibody and alemtuzumab compared with rATG (28.6% and 27.3% vs 13.3%, P = .076). The 30 PTLD cases included 13 monomorphic PTLD, 13 polymorphic PTLD, one spindle cell, one Burkitt lymphoma, and two cases too necrotic to classify. After reduction of immunosuppression, management was based on disease histology and extent. Resection with or without rituximab was used for polymorphic tumors and limited disease extent, whereas chemotherapy was used for diffuse disease. Of the 28 patients, 11 recovered with functioning allografts (39.3%), 10 recovered after enterectomy (35.7%), and seven patients died (25%), three due to PTLD and four due to other causes. All who died of progressive PTLD had received chemotherapy, highlighting the mortality of PTLD, toxicity of treatment and need for novel agents. Alemtuzumab is no longer used for induction at our center.

CD154-expressing CMV-specific T cells associate with freedom from DNAemia and may be protective in seronegative recipients after liver or intestine transplantation.

Cell-mediated immunity to CMV, if known, could improve antiviral drug therapy in at-risk children and young adults with LT and IT. Host immunity has been measured with CMV-specific T cells, which express IFNγ, but not those which express CD154, a possible substitute for IFNγ. CMV-specific CD154+ T cells and their subsets were measured with flow cytometry after stimulating PBL from recipient blood samples with an overlapping peptide mix of CMV-pp65 antigen for up to 6 hours. CMV-specific CD154+ T cells co-expressed IFNγ in PBL from three healthy adults and averaged 3.8% (95% CI 3.2%-4.4%) in 40 healthy adults. CMV-specific T cells were significantly lower in 19 CMV DNAemic LT or IT recipients, compared with 126 non-DNAemic recipients, 1.3% (95% CI 0.8-1.7) vs 4.1 (95% CI 3.6-4.6, P < .001). All T-cell subsets demonstrated similar between-group differences. In logistic regression analysis of 46 training set samples, 12 with DNAemia, all obtained between days 0 and 60 from transplant, CMV-specific T-cell frequencies ≥1.7% predicted freedom from DNAemia with NPV of 93%. Sensitivity, specificity, and PPV were 83%, 74%, and 53%, respectively. Test performance was replicated in 99 validation samples. In 32 of 46 training set samples, all from seronegative recipients, one of 19 recipients with CMV-specific T-cell frequencies ≥1.7% experienced DNAemia, compared with 8 of 13 recipients with frequencies <1.7% (P = .001). CMV-specific CD154+ T cells are associated with freedom from DNAemia after LT and IT. Among seronegative recipients, CMV-specific T cells may protect against the development of CMV DNAemia.

Technique and outcome of domino liver transplantation from patients with maple syrup urine disease: Expanding the donor pool for live donor liver transplantation.

AIM/BACKGROUND: Domino liver transplantation (DLT) using liver allografts from patients with metabolic disorders enhances organ utilization. Short- and long-term course and outcome of these patients can impact the decision to offer this procedure to patients, especially those with diseases that can potentially be cured with liver transplant. We reviewed the outcomes of DLT from maple syrup urine disease (MSUD) patients in our large academic pediatric and adult transplant program. METHODS: All patients receiving DLT were analyzed retrospectively with a minimum of one-year follow-up period for patient and donor characteristics, early and late postoperative complications and patient and graft survival with their MSUD donors in terms of age, weight, MELD/PELD scores, cold ischemia time, postoperative leucine levels, and peak ALT (alanine aminotransferase) levels during the first 48 postoperative hours. RESULTS: Between 2006 and May 2019, 21 patients underwent domino liver transplantation with live donor allografts from MSUD patients. Four patients transplanted for different metabolic diseases are focus of a separate report. Seventeen patients with minimum one-year follow-up period are reported herein. The indications were primary sclerosing cholangitis (PSC, n = 4), congenital hepatic fibrosis (CHF, n = 2), alpha-1 antitrypsin deficiency (A-1 ATD, n = 2), progressive familial intrahepatic cholestasis (PFIC, n = 2), cystic fibrosis (n = 1), primary biliary cirrhosis (PBC, n = 1), neonatal hepatitis (n = 1), embryonal sarcoma (n = 1), Caroli disease (n = 1), hepatocellular carcinoma (HCC, n = 1), and chronic rejection after liver transplantations for PSC (n = 1). All patients and grafts survived at median follow-up of 6.4 years (range 1.2-12.9 years). Median domino recipient age was 16.2 years (range 0.6-64.6 years) and median MSUD recipient age was 17.6 years (range 4.8-32.1 years). There were no vascular complications during the early postoperative period, one patient had portal vein thrombosis 3 years after DLT and a meso-Rex bypass was successfully performed. Small for size syndrome (SFSS) occurred in reduced left lobe DLT recipient and was managed successfully with conservative management. Biliary stricture developed in 2 patients and was resolved by stenting. Comparison between DLT and MSUD recipients' peak postoperative ALT results and PELD/MELD scores showed lower levels in DLT group (P-value <.05). CONCLUSIONS: Patient and graft survival in DLT from MSUD donors was excellent at short- and long-term follow-up. Metabolic functions have been normal in all recipients on a normal unrestricted protein diet. Ischemia preservation injury based on peak ALT was significantly decreased in DLT recipients. Domino transplantation from pediatric and adult recipients with selected metabolic diseases should be increasingly considered as an excellent option and alternative to deceased donor transplantation, thereby expanding the living donor pool. This, to date, is the largest world experience in DLT utilizing livers from patients with MSUD.

Donor mucosal immunocytes perpetuate refractory GVHD after intestinal transplantation without engrafting in recipient bone marrow: Case report and review of the literature.

GVHD as a complication of SOT presents both a diagnostic and therapeutic challenge. Typically affecting the skin, gastrointestinal tract, and liver, GVHD occurs when donor lymphocytes engrafted in recipient tissues are activated by host antigen-presenting cells resulting in cytokine release and donor cell-mediated cytotoxicity to host tissue. Here, we describe a 5-year-old girl who developed fatal, refractory GVHD after isolated intestinal transplantation when recipient immune cells failed to repopulate the allograft in the setting of CMV viremia. Persistence of the donor immune cells in the allograft mucosa, rather than engraftment in the recipient bone marrow, likely perpetuated this refractory GVHD. Early diagnosis and intervention are critical to reduce morbidity and mortality. Thus, periodic monitoring of peripheral blood and allograft mucosal chimerism with sensitive detection methods may allow early detection and potentially curative enterectomy in similar cases of refractory GVHD.

Severe Sepsis in Pediatric Liver Transplant Patients: The Emergence of Multidrug-Resistant Organisms.

OBJECTIVES: To describe characteristics of liver transplant patients with severe sepsis in the PICU. DESIGN: Retrospective descriptive analysis. SETTING: Tertiary children's hospital PICU. PATIENTS: Liver transplant recipients admitted January 2010 to July 2016 for pediatric severe sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between January 2010 and July 2016, 173 liver transplants were performed, and 36 of these patients (21%) were admitted with severe sepsis (54 episodes total). Median age at admission was 2 years (1-6.5 yr), 47.2% were male. Bacterial infections were the most common (77.8%), followed by culture negative (12.9%) and viral infections (7.4%). Fungal infections accounted for only 1.9%. Median time from transplant for viral and culture negative infections was 18 days (8.25-39.75 d) and 25 days (9-41 d), whereas 54.5 days (17-131.25 d) for bacterial infections. Bloodstream and intra-abdominal were the most common bacterial sites (45% and 22.5%, respectively). Multidrug-resistant organisms accounted for 47.6% of bacterial sepsis. Vancomycin-resistant Enterococcus and extended-spectrum beta-lactamase producers were the most frequently identified multidrug-resistant organisms. Patients with multidrug-resistant organism sepsis demonstrated higher admission Pediatric Logistic Organ Dysfunction scores (p = 0.043) and were noted to have an odds ratio of 3.8 and 3.6 for mechanical ventilation and multiple organ dysfunction syndrome, respectively (p = 0.047 and p = 0.044). Overall mortality was 5.5% (n = 2 patients), with both deaths occurring in multidrug-resistant organism episodes. CONCLUSIONS: We report that multidrug-resistant organisms are increasingly being identified as causative pathogens for sepsis in pediatric liver transplant recipients and are associated with significantly higher odds for mechanical ventilation and higher organ failure. The emergence of multidrug-resistant organism infections in pediatric liver transplant patients has implications for patient outcomes, antibiotic stewardship, and infection prevention strategies.

Long-term outcomes and predictors in pediatric liver retransplantation.

Historically, 9-29% of pediatric liver transplant recipients have required retransplantation. Although outcomes have improved over the last decade, currently published patient and graft survival remain lower after retransplant than after primary transplant. Data from liver retransplantation recipients at our institution between 1991 and 2013 were retrospectively reviewed. Kaplan-Meier estimates were used to depict patient and graft survival. Predictors of survival were analyzed using a series of Cox proportional hazards models. Predictors were analyzed separately for patients who had "early" (≤ 30 days after primary transplant) and "late" retransplants. Eighty-four patients underwent retransplant at a median time of 241 days. Sixty percent had late retransplants. At one, five, and 10 yr, actuarial patient and graft survival were 73%/71%, 66%/63%, and 58%/53%, respectively. Since 2002, patient and graft survival improved to 86%/86% at one yr and 93%/87% at five yr. While operative complications were a common cause of death after earlier retransplants, since 2002, infection has been the only cause of death. Significant morbidities at five-yr follow-up include renal dysfunction (15%), diabetes (13%), hypertension (26%), chronic rejection (7%), and PTLD (2%). Current survival after pediatric liver retransplantation has improved significantly, but long-term immunosuppressant morbidity remains an opportunity for improvement.

Visual diagnosis: 12-year-old girl with constipation and rectal bleeding.

Rectal duplication cysts are rare, thought to be due to defects in embryologic development, and often associated with other structural abnormalities. Clues to the existence of a rectal cyst are mainly due to bowel compression and presence of ectopic gastric mucosa within the cyst, leading to rectal bleeding. The diagnosis of a rectal duplication cyst requires a high index of suspicion. Confirming the diagnosis can be difficult based on the location of the cyst. Efforts to confirm the diagnosis include digital rectal examination, computed tomography, magnetic resonance imaging, ultrasonography, and Meckel scan. Surgical resection is the treatment of choice, especially because of the cyst's potential for malignant transformation. Because of the cyst's proximal location to the nerves innervating the anal canal and sphincters, surgical resection can lead to fecal incontinence.

Intestinal Transplant for Hirschsprung's Disease: Stoma for Life or Not?

Hirschsprung's disease is a dysmotility disease caused by lack of ganglion cells in the bowel wall that can affect varying lengths of the intestine. In extreme circumstances, there can be little remaining ganglionated bowel, and the patient becomes dependent on parental nutrition (PN) for survival. Intestinal transplant has been utilized to salvage these patients suffering terminal complications of PN. The question as to whether to reestablish intestinal continuity, and thus not require a stoma is vexed. However, data and experience would suggest this can be safely done with good functional results.

Right diaphragmatic hernia after liver transplant in pediatrics: a case report and review of the literature.

Diaphragmatic hernias (DH) are an unusual complication after pediatric liver transplantation; however, they have been reported with increased frequency in the past few years. DHs are responsible for nearly half of the small bowel obstructions requiring surgical intervention in this patient population. It has been suggested that the use of a left lobe liver graft, surgical trauma, malnourishment, elevated intra-abdominal pressures, and mTor inhibitors may predispose to development of DH. The use of a segmental graft may increase the recognition of diaphragmatic hernia because the surgically damaged right hemi-diaphragm often remains exposed to underlying viscera, instead of being covered by the right hepatic lobe. Treatment is surgical reduction, with up to 20% of the patients requiring resection of the herniated intestine. Herein we describe a case of DH after left segmental liver transplant in a two- yr-old boy that presented one month post left lobe split liver transplant with abdominal pain, anorexia, and respiratory distress. Just like in the majority of the reported cases, an urgent laparotomy with primary repair was performed. No resection of the herniated segment of intestine was required. For pediatric patients with otherwise unexplained respiratory or gastrointestinal symptoms after a left lateral segment liver transplant, right-sided diaphragmatic hernias should always be high in the differential diagnosis.

Impaired Cellular and Antibody immunity after COVID-19 in Chronically Immunosuppressed Transplant Recipients.

Assessment of cellular immunity to the SARS-CoV-2 coronavirus is of great interest in chronically immunosuppressed transplant recipients (Tr), who are predisposed to infections and vaccination failures. We evaluated CD154-expressing T-cells induced by spike (S) antigenic peptides in 204 subjects-103 COVID-19 patients and 101 healthy unexposed subjects. S-reactive CD154+T-cell frequencies were a) higher in 42 healthy unexposed Tr who were sampled pre-pandemic, compared with healthy NT (p=0.02), b) lower in Tr COVID-19 patients compared with healthy Tr (p<0.0001) and were accompanied by lower S-reactive B-cell frequencies (p<0.05), c) lower in Tr with severe COVID-19 (p<0.0001), or COVID-19 requiring hospitalization (p<0.05), compared with healthy Tr. Among Tr with COVID-19, cytomegalovirus co-infection occurred in 34%; further, incidence of anti-receptor-binding-domain IgG (p=0.011) was lower compared with NT COVID-19 patients. Healthy unexposed Tr exhibit pre-existing T-cell immunity to SARS-CoV-2. COVID-19 impairs anti-S T-cell and antibody and predisposes to CMV co-infection in transplant recipients.

Long-term survival, nutritional autonomy, and quality of life after intestinal and multivisceral transplantation.

OBJECTIVE: To assess long-term survival, graft function, and health-related quality of life (QOL) after visceral transplantation. BACKGROUND: Despite continual improvement in early survival, the long-term therapeutic efficacy of visceral transplantation has yet to be defined. METHODS: A prospective cross-sectional study was performed on 227 visceral allograft recipients who survived beyond the 5-year milestone. Clinical data were used to assess outcome including graft function and long-term survival predictors. The socioeconomic milestones and QOL measures were assessed by clinical evaluation, professional consultation, and validated QOL inventory. RESULTS: Of 376 recipients, 227 survived beyond 5 years, with conditional survival of 75% at 10 years and 61% at 15 years. With a mean follow-up of 10 ± 4 years, 177 (92 adults, 85 children) are alive, with 118 (67%) recipients 18 years or older. Nonfunctional social support and noninclusion of the liver in the visceral allograft are the most significant survival risk factors. Nutritional autonomy was achievable in 160 (90%) survivors, with current serum albumin level of 3.7 ± 0.5 gm/dL and body mass index of 25 ± 6 kg/m(2). Despite coexistence or development of neuropsychiatric disorders, most survivors were reintegrated to society with self-sustained socioeconomic status. In parallel, most of the psychological, emotional, and social QOL measures significantly (P < 0.05) improved after transplantation. Current morbidities with potential impact on global health included dysmotility (59%), hypertension (37%), osteoporosis (22%), and diabetes (11%), with significantly (P < 0.05) higher incidence among adult recipients. CONCLUSIONS: With new tactics to further improve long-term survival including social support measures, visceral transplantation has achieved excellent nutritional autonomy and good QOL.

Increased expression of peripheral blood leukocyte genes implicate CD14+ tissue macrophages in cellular intestine allograft rejection.

Recurrent rejection shortens graft survival after intestinal transplantation (ITx) in children, most of whom also experience early acute cellular rejection (rejectors). To elucidate mechanisms common to early and recurrent rejection, we used a test cohort of 20 recipients to test the hypothesis that candidate peripheral blood leukocyte genes that trigger rejection episodes would be evident late after ITx during quiescent periods in genome-wide gene expression analysis and would achieve quantitative real-time PCR replication pre-ITx (another quiescent period) and in the early post-ITx period during first rejection episodes. Eight genes were significantly up-regulated among rejectors in the late post-ITx and pre-ITx periods, compared with nonrejectors: TBX21, CCL5, GNLY, SLAMF7, TGFBR3, NKG7, SYNE1, and GK5. Only CCL5 was also up-regulated in the early post-ITx period. Among resting peripheral blood leukocyte subsets in randomly sampled nonrejectors, CD14(+) monocytes expressed the CCL5 protein maximally. Compared with nonrejectors, rejectors demonstrated higher counts of both circulating CCL5(+)CD14(+) monocytes and intragraft CD14(+) monocyte-derived macrophages in immunohistochemistry of postperfusion and early post-ITx biopsies from the test and an independent replication cohort. Donor-specific alloreactivity measured with CD154(+) T-cytotoxic memory cells correlated with the CCL5 gene and intragraft CD14(+) monocyte-derived macrophages at graft reperfusion and early post-ITx. CCL5 gene up-regulation and CD14(+) macrophages likely prime cellular ITx rejection. Infiltration of reperfused intestine allografts with CD14(+) macrophages may predict rejection events.

Liver transplantation for classical maple syrup urine disease: long-term follow-up in 37 patients and comparative United Network for Organ Sharing experience.

OBJECTIVE: To assess clinical and neurocognitive function in children who have undergone liver transplantation for classical maple syrup urine disease (MSUD). STUDY DESIGN: A total of 35 patients with classical MSUD (age 9.9 ± 7.9 years) underwent liver transplantation between 2004 and 2009. Six patients donated their liver to recipients without MSUD ("domino" transplant). We analyzed clinical outcomes for our cohort and 17 additional cases from the national United Network for Organ Sharing registry; 33 patients completed IQ and adaptive testing before transplantation, and 14 completed testing 1 year later. RESULTS: Patient and graft survival were 100% at 4.5 ± 2.2 years of follow-up. Liver function was normal in all patients. Branched-chain amino acid levels were corrected within hours after surgery and remained stable, with leucine tolerance increasing more than 10-fold. All domino transplant recipients were alive and well with normal branched-chain amino acid homeostasis at the time of this report. Patient and graft survival for all 54 patients with MSUD undergoing liver transplantation in the United States during this period were 98% and 96%, respectively. One-third of our patients were mentally impaired (IQ ≤ 70) before transplantation, with no statistically significant change 1 year later. CONCLUSION: Liver transplantation is an effective long-term treatment for classical MSUD and may arrest brain damage, but will not reverse it.